Professional Documents
Culture Documents
Newborn screening for “The central idea of early disease detection and treatment is
inborn errors of metabolism: essentially simple. However the path to its successful achievement
(on the one hand, bringing to treatment those with previously
principles, policies and undetected disease and, on the other, avoiding harm to those
persons not in need of treatment) is far from simple though
J V Leonard
Box 1
C Dezateux
hypothyroidism. Newborn screening programmes for these two
disorders are now almost universal in high- and middle-income
countries throughout the world. While regarded as examples of
Abstract
Newborn screening for metabolic disorders has become a contentious effective preventive medicine, almost half a century later expe-
issue. The aim of screening is to identify individuals at risk and start treat- rience with newborn screening for these conditions exemplifies
ment before they become ill. To this end newborn screening programmes some of the difficulties in establishing that all those identified
are well established in many countries and recent technological develop- and treated as a consequence of screening do in fact need treat-
ments have lead to an expansion of these programmes. These require care- ment, and the nature of the benefit conferred.
ful evaluation, both of the process and the outcome. The original Wilson More recently there has been a marked expansion of newborn
and Jungner criteria for evaluation are still valid but, in this review, three screening programmes, driven by the development of technolo-
main points are particularly considered. The burden and the natural history gies adaptable for high through-put analyses of biomarkers in
of the disease need to be defined. The test should predict accurately those newborn dried blood spots, notably tandem mass spectrometry
who would develop clinical disease but current screening programmes (MS-MS). It is likely that future expansion will be driven by the
detect many with ‘mild’ disease, the importance of which is often unclear. development of new treatments for rare disorders or by new
This is particularly relevant when assessing any improvement in outcome approaches to identify risk for or susceptibility to more complex
which should be seen in terms of the advantages and problems for both or chronic diseases, as much as by new technologies. Currently
the individual and the family. parents of newborns in many countries are now offered testing
for more than 30 disorders, many of them very rare. However,
Keywords genetic testing; healthcare evaluation mechanisms; health not all countries have implemented ‘expanded’ newborn
policy; high-throughput screening assays; infant, newborn; mass
screening on this scale, reflecting different screening policies and
screening; metabolism, inborn errors; Neonatal screening; public health
approaches to their evaluation.
practice; tandem mass spectrometry
In this contribution, we review the criteria by which proposed
screening programmes are assessed and discuss aspects that are
specific to the assessment of newborn screening for rare condi-
tions such as inborn errors of metabolism. We highlight some of
the challenges in obtaining and evaluating the evidence needed
Introduction to inform screening policies for these conditions. Detailed infor-
Newborn screening for inborn errors of metabolism is now well mation about screening for specific disorders is covered by other
established in developed countries worldwide. As noted by Wilson contributors to this mini-symposium.
and Jungner in their 1968 WHO report on the Principles and
Practice of Screening for Disease (Box 1), screening seems both Definition of screening
intuitive and attractive: it aims to detect and manage serious
Wald defined screening as the ‘systematic application of a test or
diseases in order to secure an outcome better than that which
enquiry to identify individuals at sufficient risk of a specific
might be achieved following clinical presentation or diagnosis.
disorder to warrant further investigation or direct preventive
The recognition that presymptomatic diagnosis and treatment
action, amongst persons who have not sought medical attention
could profoundly alter the outcome for phenylketonuria (PKU)
on account of symptoms of that disorder.’ [Wald N. Guidance on
drove Guthrie to develop a screening test based on dried blood
terminology. J Med Screening 1994; 1(1): 76].
spots that was cheap and feasible for mass screening of newborn
While the rationale for screening is driven primarily by
infants. Screening for PKU was first introduced in the 1960s and
concern to improve outcome for affected individuals, in this
was followed, in the 1970s, by screening for congenital
definition, Wald reminds us that all those offered screening do
not usually have any concerns or symptoms related to that
condition that has so far prompted them to seek medical care. In
J V Leonard PhD FRCP FRCPCH is Professor Emeritus at UCL Institute of Child doing so, he highlights an implicit and ethical imperative to do
Health, 30 Guilford Street, London WC1 1EH, UK. no harm to those screened. The implication is that the potential
benefits of screening should be positively balanced in relation to
C Dezateux MD FMedSci is Professor of Paediatric Epidemiology and potential harms. This requires a judgement based on a range of
Director of MRC Centre of Epidemiology for Child Health, London, UK. complex and often imperfect information.
PAEDIATRICS AND CHILD HEALTH 21:2 56 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Approaches to evaluating screening programmes diseases, drawing on the UK National Institute for Health and
Clinical Excellence (NICE) guidance on the principles to be used
In their original WHO publication, Wilson and Jungner distin-
when applying social value judgements to policy evaluations and
guished the evaluation of screening procedures from the evaluation
guidance.
of effects of screening (namely reduced morbidity and mortality).
Newborn screening as a process, not just a test: the various stages in
this process require careful assessment to ensure that the perceived Epidemiological considerations: the burden of disease
advantages are genuine and outweigh any potential harm. While
The importance of a condition for which screening is offered
most would agree that there need to be demonstrable benefits to
relates not just to its frequency but also to its consequences.
screening, views vary regarding the types of benefits to be consid-
Wilson and Jungner noted that ‘phenylketonuria is extremely
ered, the weighting given to those benefits, and the evidence of
uncommon but warrants screening on account of the very serious
benefit which is needed before screening policy can be made and
consequences if not discovered and treated very early in life.’
programmes implemented. For example, some argue that early
A rare disease has been defined as a condition which affects
diagnosis per se is a legitimate goal of screening, irrespective of
less than five people in 10,000: by this definition almost all inborn
evidence of improved health outcomes.
errors of metabolism are rare. Many are, in fact, very rare which
Wilson and Jungner were the first to outline a broad and
pose problems in acquiring reliable and unbiased information
systematic approach to evaluation and in their original report
about their frequency, natural history, clinical outcome and the
identified 10 major criteria which needed to be addressed (see
effects of treatment. In the UK all paediatricians contribute to the
Box 2). In the United Kingdom these criteria have been extended
surveillance of rare diseases through a monthly active reporting
into a framework comprising 22 criteria which are used for the
scheme run by the British Paediatric Surveillance Unit. This has
evaluation of all screening programmes by a National Screening
proved a valuable mechanism for studying the epidemiology and
Committee. In certain countries, specific policies have been pub-
early clinical course of a wide range of candidate conditions for
lished about newborn blood spot screening, for example, by the
newborn screening, including galactosaemia, medium chain acyl
Human Genetics Society of Australasia or the American College of
CoA dehydrogenase deficiency (MCADD), glutaric aciduria type 1
Medical Genetics. All these frameworks have common elements
and congenital adrenal hyperplasia. This scheme can also be used
and there is broad consensus that decisions should be informed by
to obtain useful information about the burden of clinically pre-
the evaluation of scientific evidence. In this article we have iden-
senting and diagnosed disease and importantly helps to identify
tified three main areas for evaluation, summarized as (1) the
whether there is a window of opportunity for screening to make
burden of the disease for which screening is being offered; (2) the
a difference, referred to by Wilson and Jungner as a latent or early
clinical validity of the screening test and (3) the clinical utility of
symptomatic phase which allows time for diagnosis and initiation
the screening programme. Below we discuss these in the context of
of definitive treatment and management.
newborn screening for inborn errors of metabolism and highlight
While the natural history of those with severe disease may be
some specific challenges in programmes for rare diseases. We
well documented, the course of those with ‘mild’ disease may
conclude by considering some additional issues related to rare
not: such individuals may present infrequently to a clinician or
may not be ascertained at all clinically but are nevertheless
identified by screening. The problems associated with the wide
The Wilson and Jungner criteria for evaluating range of the clinical phenotype are discussed later.
screening programmes Surveillance studies of rare diseases may also provide infor-
1 The condition sought should be an important health problem. mation about their geographical variation, but this is not usually
2 There should be an accepted treatment for patients with helpful in determining whether screening should be offered to
recognized disease. geographically defined populations. It can in practice be difficult to
3 Facilities for diagnosis and treatment should be available. determine whether an apparent geographical cluster of a rare
4 There should be a recognizable latent or early symptomatic disease ascertained by active surveillance relates to a true differ-
stage. ence in its frequency, to differential ascertainment or reporting, or
5 There should be a suitable test or examination. to availability of specialist services and referral patterns. While
6 The test should be acceptable to the population. targeting higher risk populations that may be geographically iso-
7 The natural history of the condition, including development lated or separated by custom or religion is an attractive proposi-
from latent to declared disease, should be adequately tion, this presupposes a robust strategy for selecting those at
understood. higher risk. For example, although tyrosinaemia type 1 was
8 There should be an agreed policy on whom to treat as patients. recognized to be more prevalent in one area of Quebec e Sague-
9 The total cost of case finding (including diagnosis and treat- nay-Lac St Jean e in practice screening is offered throughout the
ment of patients diagnosed) should be economically balanced province. Similarly where the risk of a rare disease is higher in
in relation to possible expenditure on medical care as a whole. certain ethnic groups it may appear attractive to consider using
10 Case finding should be a continuous process, not a “once ethnicity as a basis for offering screening. However the difficulties
and for all” project. of ascertaining ethnic origin in contemporary populations with
Wilson and Jungner, 1968, WHO high rates of migration and inter-ethnic union make such selection
unreliable, as has been demonstrated by the progressive aban-
donment of ‘selective’ newborn screening strategies for sickle cell
Box 2 disorders in the United States.
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SYMPOSIUM: INBORN ERRORS OF METABOLISM
These epidemiological considerations remain important when The precise approach to ascertaining diagnoses will depend on the
considering the scientific rationale for screening policies that natural history of the condition (determining the duration of
utilize one technology for multiplex testing such as tandem mass follow up of a screened birth cohort), the likelihood of clinical
spectrometry: the addition of any individual disorder to diagnosis in death or life (reflecting access to specialist diagnostic
a screening panel requires careful appraisal of disease burden services), as well as the availability of surveillance systems to
and the likely health gain for those affected. obtain and collate reports and data. For rare diseases, data are
needed at a national level, but for very rare diseases, international
collaboration may be needed in order to derive sufficiently precise
Evaluating the screening procedure: clinical validity
estimates.
Conventionally we think of a screening procedure as discrimi- The third challenge lies in relating the screening phenotype to
nating those with a condition from those without, however the clinical phenotype. It is well recognized that the frequency of
technological developments in presymptomatic diagnosis are a rare disease rises following the introduction of screening,
such that a broader phenotype than that which presents clinically reflecting the identification of individuals who might never have
is detected which challenges pre-existing definitions and developed symptoms or adverse outcomes from their disease
concepts of disease. Clinical validity refers to the accuracy with (milder phenotypes). It may not be possible, on the basis of tests
which a screening test can predict the presence or absence of carried out on newborns, to differentiate those with milder
latent clinical disease, principally a clinical relevant phenotype phenotypes from those likely to present clinically and hence to
that provides the rationale for screening. determine whom to treat. This often means that all or most of those
By definition, screening tests are not diagnostic tests. So detected by screening are treated. As a consequence it can be
screening implies the need for further assessment by a diagnostic difficult to be sure these are all ‘true’ cases (in the sense of having
test or tests to be offered to those above a predefined threshold the clinically relevant phenotype), to calculate screening test
on that screening test in order to separate reliably those with performance (detection and false positive rates) and to characterize
a specific condition from those without. This threshold is usually the benefits of screening (in terms of reduced morbidity and
set to optimize detection of affected individuals while avoiding mortality).
falsely labelling health individuals who may be worried unnec-
essarily or be exposed to the risks of subsequent diagnostic tests.
Evaluating the effects of screening: clinical utility
The specific threshold is informed by the biomarker distribution
in the normal population, the analytic validity (accuracy and Clinical utility refers to the likelihood that screening will lead to
reliability) of the test, the aims of screening and the drawbacks of an improved outcome for the affected individual and their family.
an inaccurate positive or negative result. Data from screening Conventionally interest has focused on health outcomes, princi-
large population samples using standardized protocols are pally mortality and morbidity. While these are crucial there is
needed to evaluate proposed newborn screening procedures for increasing recognition of the importance attached by affected
rare diseases. individuals and their families to other health outcomes, including
A diagnostic test is essential in order to provide those tested, or patient reported outcome measures: these may include measures
their parents, with confirmation of diagnosis and information of quality of life, broad aspects of cognition, intellectual and
about prognosis and future management. It is also essential in emotional development, adult health including future reproduc-
order to evaluate the screening procedure, the effects of screening tive potential, and so on. All reflect a wider view and concept of
in terms of reduced morbidity and mortality of those affected by benefit. Grosse and Khoury reviewing the concept of clinical
the target condition, or the unintended identification of other utility in relation to genetic testing note the shift to a broader
conditions and their significance. Readers will be familiar with the perception of benefits in debates around expanded newborn
conventional measures used when evaluating screening proce- screening, including reduction in the ‘diagnostic odyssey’, the
dures (detection rate, false positive rate and predictive value). right to diagnosis even in the absence of effective treatments, and
Although simple to compute, collection of such information for future reproductive choices (for the parents) in the case of
rare diseases poses specific challenges. inherited disorders. Hence it is important to consider and agree
The first challenge is the need for an agreed method to define the outcomes which screening seeks to improve and to define the
who is affected: this requires case definitions and diagnostic objectives of screening in relation to these outcomes. Whatever
criteria that work in the absence of clinical symptoms, as the the outcomes selected, Grosse and Khoury emphasize the
majority of new diagnoses will be identified through screening and importance of using objective measures for the assessment.
will, by definition, be presymptomatic. Specifying ‘gold standard’ As diagnosis alone will not achieve better health outcomes,
diagnostic tests and their interpretation can be challenging where the clinical utility of screening will also depend on the avail-
a state of the art diagnostic technology, such as tandem mass ability of effective treatments or other interventions. This in turn
spectrometry, is also used for newborn screening and where depends on evidence about two distinct aspects of effectiveness:
clinicians have historically interpreted biochemical findings in the firstly, whether treatment improves the specific outcomes of
context of the presenting clinical features. interest and secondly whether treatment following screening, i.e.
The second relates to the need to ascertain all those ever before symptoms are evident, results in a greater improvement in
diagnosed with the condition, irrespective of whether this has outcome than achieved when treatment is given following clin-
been through screening or clinical presentation. Underascertain- ical diagnosis. Unfortunately in the case of most inborn errors of
ment of those ‘missed’ by screening (false negatives) will, by metabolism, such evidence is rarely obtained from clinical trials,
definition, overestimate the detection rate or sensitivity of a test. rarely pertains to the range of outcomes of interest or to the
PAEDIATRICS AND CHILD HEALTH 21:2 58 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
duration of follow up needed to assess them fully. Observational judgements about effectiveness, cost effectiveness and allocation
studies of screening often rely on comparison with the outcome of resources. NICE highlights the importance of developing
of children diagnosed in the past before screening started or evidence-based guidance recognizing that recommendations
contemporaneously following clinical diagnosis in an area where should not be made where evidence is too weak to permit
screening is not offered. Neither is ideal since outcome may be reasonable conclusions to be drawn. Where there is a lack of
confounded with differences in access to other treatments or to evidence of effectiveness more research is needed and it is
overall management and healthcare. Wilcken has argued that the important that there is a mechanism for funding such research
lack of evidence on outcome should not delay the introduction of based, if necessary, on large-scale pilot studies.
screening e this argument has proved persuasive in the United
States but less so in the United Kingdom. She has at the same Public involvement and informed choices
time highlighted the paucity of data on longer-term outcome and
Implicit in much of our discussion about outcomes and social
the need to collect it and the challenges in doing so for very rare
values is the need for scientists and clinicians to work in part-
conditions. One implication of this is the need to collect outcome
nership with parents and the public in order to develop guidance
data following implementation.
and policies and then to implement them. The rapid expansion in
Finally, assessments of utility also need to incorporate the
screening programmes in the United States, driven in part by
disbenefits, real and perceived, of screening in order to ensure
advocacy from groups representing families affected by specific
that overall there is more harm than good. This can be very
rare conditions, now means that the parents of a new baby are
challenging since the majority of those tested will not have the
being asked to consent to testing of up to 30 conditions. This
condition of interest and may have concerns relating to the
poses challenges in obtaining informed consent. Qualitative
potential for misdiagnosis, medicalization, stigma and anxiety,
research suggests that relative ineffectiveness of some treatment
however transient, which need to be respected. As with benefits,
may moderate parental enthusiasm for some tests and more
evidence of disbenefits e objectively measured e is needed and
work is needed if we are to implement programmes that respect
is often lacking.
autonomy of child and parent in their decision making in
a meaningful way.
Generating and weighing evidence: effectiveness, cost
effectiveness, social values Summary
We have outlined the most common elements of the frameworks We have set out a broad framework which we believe should be
used in many countries to assess whether a new screening pro- employed for the evaluation of proposed newborn screening
gramme should be introduced. Such assessments should be programmes, elaborating some challenges which apply when
based on high quality, objective and scientifically rigorous considering rare inborn errors of metabolism. It is essential to
information on a range of benefits and disbenefits relevant to the establish the goals and outcomes of screening for each condition
goals of screening, which can be objectively measured. We have and then to appraise the evidence for disease burden, clinical
identified some of the challenges in acquiring such information, validity and clinical utility. In weighing this evidence a set of
especially for rare disorders such as many inborn errors of procedural and ethical principles can be applied in order to make
metabolism. Policy makers typically need to consider not only difficult decisions in the best way possible.
the benefits and disbenefits but also the value for money and
opportunity costs of deploying limited healthcare resources into Role of the funding source
a new screening programme. Health economists help to make
James Leonard is retired and has no sources of funding.
these decisions more rationally based by using formal methods of
Carol Dezateux is employed by University College London. Her
combining evidence and its uncertainty in cost effectiveness
post is funded by the Higher Education Funding Council of
analyses that incorporate multiparameter evidence synthesis.
England (HEFCE) and the Department of Health. Work carried
This allows the costs and effects of different policy options to be
out at the MRC Centre of Epidemiology for Child Health benefits
compared and may provide conclusive support for one particular
from funding from the Medical Research Council (G0400546).
option.
None of these sponsors had any role in the writing of this
Such decisions need also to take account of wider social values
manuscript.
and the ethical principles which underlie decisions on healthcare.
These have been clearly summarized in a very useful document
Conflict of interest
produced by the UK National Institute of Health and Clinical
Excellence which sets out some of the procedural and bioethical James Leonard is chairman of the Diagnostic Review Panel of the
principles to be considered in developing guidance and policies UK Collaborative Study of Newborn Screening for MCADD. He
formulated and developed following wide public consultation. The has chaired and received payment for a workshop funded by
processes which lead to guidance or policy should be scientifically Swedish Orphan on newborn screening for Tyrosinaemia type 1
rigorous, including all parties with a legitimate interest in the (fumarylacetoacetase deficiency).
guidance under consideration, be transparent, independent, open Carol Dezateux is Strategic Director of the UK Newborn
to challenge and timely. The ethical and moral principles which Screening Programme Centre which is funded by the UK Depart-
underpin clinical and public health practice include respect for ment of Health but has contributed to this article in a personal
autonomy, non-maleficence, beneficence and distributive justice capacity. She is principal investigator of the UK Collaborative Study
or fairness and these need to be considered when making of Newborn Screening for MCADD which is funded by the UK
PAEDIATRICS AND CHILD HEALTH 21:2 59 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Department of Health. The opinions expressed here are her own Wilcken B. Expanded newborn screening: reducing harm, assessing
and she has no conflicts of interest to declare. A benefit. J Inherit Metab Dis 2010. doi:10.1007/s10545-010-9106-6.
Wilson JMG, Jungner G. Principles and practice of screening for disease.
Geneva: World Health Organization, 1968.
FURTHER READING
ACMG Newborn Screening Expert Group. Newborn screening panel and Practice points
system. Genet Med 2006; 8: 1Se252.
Grosse SD, Khoury MJ. What is the clinical utility of genetic testing? Genet C Newborn screening programmes for inborn errors of meta-
Med 2006 Jul; 8: 448e50. bolism should be evaluated using recognized frameworks.
Human Genetics Society of Australasia. HGSAeRACP Newborn Screening C It is essential to establish the goals and outcomes of
Joint Subcommittee. Newborn blood spot screening; 2008. screening for each disorder.
National Institute For Health And Clinical Excellence. Social value judge- C Screening policy requires evidence on the burden of the
ments: principles for the development of NICE guidance. 2nd Edn; disorder for which screening is being offered, the clinical
2008. validity of the test and the outcome.
National Screening Committee. Criteria for appraising the viability, effec- C For rare diseases, systematic strategies to evaluate longer-
tiveness and appropriateness of a screening programme. London: term outcomes are needed in order to evaluate benefits of
Department of Health, 2003. www.library.nhs.uk/screening (accessed screening.
Sep 2010).
PAEDIATRICS AND CHILD HEALTH 21:2 60 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
PAEDIATRICS AND CHILD HEALTH 21:2 61 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Figure 1 The phenylalanine hydroxylation system. It is vital to monitor phenylalanine levels, usually through
frequent blood spot analysis. Guidelines vary between countries
relatively common in some parts of China but is rare in African regarding frequency and acceptable phe levels. In the UK, infants
nations. The highest incidence is observed in Turkey where the and young children should have weekly samples aiming at levels
incidence is 1 in 2600. 120e360 mmol/l; school-age children fortnightly samples with
a range of 120e480 mmol/l; and in adolescents and adults
Biochemistry and genetics of PKU monthly samples with an upper limit of 700 mmol/l. These
guidelines are currently under review and changes can be viewed
Phenylalanine is an essential amino acid which is metabolized in through the UK newborn blood spot screening programme
the liver by the enzyme phenylalanine hydroxylase (PAH). The website (see below). In addition to monitoring phe levels, other
first step of catabolism of phenylalanine is irreversible conver- nutritional indices such as vitamin B12, folate, iron, calcium,
sion to tyrosine. The PAH enzyme requires tetrahydrobiopterin phosphate and essential fatty acids should be measured in those
as its co-factor. PKU develops due to deficiency in, or absent with poor dietary adherence. Growth parameters are also moni-
activity, of the PAH enzyme and results in elevated phenyalanine tored. Some clinics advocate regular neuropsychological testing
and reduced levels of tyrosine. When the pathway to tyrosine is whereas others only refer for such assessment where difficulties
blocked, excess phe is transaminated to phenylpyruvic acid and are suspected.
excreted in urine. The enzyme is coded by the PAH gene located
on the long arm of chromosome 12. More than 400 pathological Nutritional issues in PKU
mutations are recognized and most affected subjects are
compound heterozygotes in that they carry two different muta- The nutritional sufficiency of the PKU diet must be regularly
tions. There is a good correlation between pre-treatment phe monitored by a specialist dietician. Vitamin B12 deficiency is
levels, phe tolerance and genotype. However, outcome is affected a particular risk in adolescents and adults who have stopped
by many factors and genotype knowledge is of limited value in taking their supplements but are still restricting their protein
predicting clinical management. But mutation analysis has some intake by habit. Other vitamin or mineral deficiencies have
value in predicting BH4 responsiveness (see below). occasionally been noted in PKU such as iron, selenium and
PKU is inherited as an autosomal recessive condition. Prenatal calcium. Bone mineral density may be lower than normal in this
diagnosis, although rarely requested, is possible by mutation group of patients although the reasons for this are unclear.
analysis if the mutations are already identified in the index case. Polyunsaturated fatty acids levels are frequently low in the
plasma and red cells of PKU children on diet. This is probably
Treatment due to its low animal protein content. Although it seems prudent
to supplement PUFAs, there is not yet clear evidence on
The aim of PKU treatment is the reduction of blood phe to a level requirements in this group nor on the long-term impact on
allowing normal brain development. An individual’s blood neurodevelopment.
phe depends upon dietary intake of phe and the residual activity
of phe hydroxylase. Although in some cases it is possible to
Dietary adherence
augment phe hydroxylase activity (see new treatments), in most
cases treatment relies upon reducing phe intake by a restriction of Adherence to treatment in PKU is particularly challenging for
natural protein. In most cases meat, cheese, bread, fish and milk several reasons: the strict diet creates awkward social occasions;
must be avoided. A semi-synthetic diet is used which comprises: the diet itself is unpalatable; frequent blood tests lead to needle
foods of low phe content in unlimited amounts such as many phobia in some children; and the diet is time consuming and may
fruits and vegetables; be costly in some countries. It is important to provide education
weighed amounts of foods containing medium amounts of programmes to help compliance; such as toddler groups and
phe (e.g. broccoli, potato). The amount of phe ingested is teenage camps.
PAEDIATRICS AND CHILD HEALTH 21:2 62 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
PAEDIATRICS AND CHILD HEALTH 21:2 63 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Maternal PKU Blau N, Erlandsen H. The metabolic and molecular bases of tetrahy-
drobiopterin-responsive phenylalanine hydroxylase deficiency.
Infants born to mothers with blood phe above 1200 mmol/l show
Mol Genet Metab 2004 Jun; 82: 101e11.
fetal damage including low birth weight, microcephaly, dys-
DeRoche K, Welsh M. Twenty-five years of research on neurocognitive
morphic facies, slow postnatal growth and development and
outcomes in early-treated phenylketonuria: intelligence and executive
intellectual impairment. The facial features are similar to fetal
function. Dev Neuropsychol 2008; 33: 474e504.
alcohol syndrome: small palpebral fissures, epicanthic folds, long
Feillet F, Agostoni C. Nutritional issues in treating phenylketonuria.
philtrum and thin upper lip. Although congenital heart disease is
J Inherit Metab Dis; 2010 Feb 12 [Epub ahead of print].
the most common, other organ malformation can occur. The risk
Koch R. Maternal phenylketonuria: the importance of early control during
to mothers with milder PKU is smaller and appears to correlate
pregnancy. Arch Dis Child 2005; 90: 114e5.
with phe level. In view of these risks all females with PKU must
MRC. Recommendations on the dietary management of phenylketonuria.
be monitored for the duration of their lives, being counselled
Arch Dis Child 1993; 68: 426e7.
early in their childhood and having a longstanding trusting
Van Spronsen FJ. Future treatment strategies in phenylketonuria.
relationship with their PKU team. The aim for managing
Mol Genet Med 2010; 99(Suppl 1): S90e5.
maternal PKU is for women to be on a strictly controlled diet
www.nspku.org.
preconception with regular phe monitoring showing levels
www.newbornbloodspot.screening.nhs.uk.
between 100 and 250 mmol/l. There is also evidence that if diet is
www.bh4.org.
started by 10e12 weeks of pregnancy a satisfactory outcome can
be achieved.
PAEDIATRICS AND CHILD HEALTH 21:2 64 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Galactosaemia an update in the UK. This is in keeping with most of Western Europe,
however the incidence in different subpopulations varies greatly.
This is especially true in Ireland, where the incidence in the
AA Broomfield
travelling population is one in 450 live births whilst the overall
C Brain incidence is nearer to 1: 20,000. Worldwide the incidence does
S Grunewald appear to be lower than in Western Europe, being quoted as one
in 50,000 in the USA and as little as one in 100,000 in Japan.
The mild asymptomatic phenotype of GALE is relatively
common, with a frequency of 1: 6,200 in the African American
Abstract population, but the severe “generalized” presentation of GALE,
While galactosaemia was originally documented over 100 hundred years whose presentation is similar to that of classical galactosaemia is
ago, it still remains poorly understood and recognized. Classical galacto- limited to a few case studies worldwide. The GALK deficiency is
saemia is an inherited disorder of galactose metabolism, whose main die- rare <1/100,000.
tary source is lactose. In the UK which does not currently screen for
Galactosaemia lack of recognition of key symptoms can lead to delays in Genetics
diagnosis. However it has become clearer that Galactosaemia is not only
The GALT gene is located on chromosome 9p13 and consists of
an acute disease of the neonatal period but affected children potential
11 exons. Over 230 mutations have been described. The most
are prone to a number of chronic problems later in life. This review looks
frequent mutation in the Caucasian population, with an overall
at the current thinking concerning the pathogenesis and complications of
frequency of 65% (96% in the Irish population), is the Q188R
galactosaemia and summaries our current management of patients.
mutation, which results in a complete loss of enzymic activity.
The second commonest European mutation is the K285N,
Keywords galactitol; galactosaemia; galactose-1-phosphate; genetic;
a missense mutation, which predominates in central European
inherited metabolic disease; leloir pathway
counties. This also results in a complete lack of GALT activity.
In contrast, S135L, which accounts for 50% of mutate alleles in
African Americans, shows near normal activity in mouse models.
Definition Whilst there is a relatively good correlation between genotype
and residual enzymic function, the correlation between genotype
The pathogenic potential of ingested galactose was originally
and clinical phenotype is more enigmatic, though Q188R is
described over 100 years ago. It results from a defect in the galactose
predicative of a poorer clinical outcome, whereas S135L is
metabolic pathway, the Leloir pathway, which consists of three
associated with the milder phenotype seen in Afro-Caribbean
enzymes, the galactose specific kinase (Galactokinase/GALK),
patients.
galactose-1-Phosphate uridyltransferase (GALT) and uridine
The N314D mutation (c. 940A>G), so called Duarte variant,
diphosphate galactose 40 epimerase (GALE). While a deficiency in
can exist in two different forms: Duarte-1 and Duarte-2 has
any of these enzymes will lead to the biochemical finding of gal-
a good clinical outcome. The Duarte-2 mutation is interesting, as
actosaemia i.e. an elevated plasma galactose, only deficiencies in
compound heterozygotes for the Duarte-2 variant and classical
GALT or GALE have the potential to cause the ‘classical Gal-
galactosaemia, typically manifest 14e25% of normal GALT
actosaemia’ phenotype: an acute toxicity syndrome which resolves
activity resulting in some protection against severe toxicity.
on removal of exogenous galactose intake with more recently
recognized long-term complications of chronic neurological, endo-
Pathology
crine, and orthopaedic problems. The outcome of these chronic
problems seems to be far less tightly linked to galactose intake. The exact mechanisms underlying the pathophysiology of clas-
sical galactosaemia is still not fully understood with the lack of
Incidence/epidemiology a good animal model hampering research; the GALT mouse
The overall incidence of classical galactosaemia, secondary to knockouts, having few of the clinical features found in humans.
GALT deficiency, is estimated at between 1: 23,500 and 1: 44,000 However, the potential mechanisms can be grouped into,
primary effects which include the buildup of toxic metabolites
Abbreviations: GALE, Galactose 40 epimerase; GALK, Galactokinase; and the reduction in end products of the Leloir pathway and
GALT, Galactose-1-Phophate uridyltransferase (Gal-1-Put); GALK Gal- secondary effects due to disruption of other interlinked
actokinase, GALE Galactose 40 epimerase; GAL-1-P, Galactose-1-Phopshate. pathways.
AA Broomfield MSC is a Specialist Registrar in the Metabolic Medicine With any disruption of the Leloir pathway, there is the
Unit, Great Ormond Street Hospital for Children, London WC1N 3JH, UK. potential for excess galactose accumulation, which if uncon-
trolled will also result in accumulation of Galactitol and Gal-
C Brain MD is a Consultant Paediatric Endocrinologist in the Endocrine, actonate. These are formed due to the actions of the alternative
Department of Great Ormond Street Hospital for Children, London pathways of galactose metabolism i.e. aldase reductase and the
WC1N 3JH, UK. pentose phosphate pathway respectively (Figure 1).
Given that the GALK deficient patients do not manifest either
S Grunewald PhD is a Consultant in Paediatric Metabolism in the the acute toxicity, or any of the chronic manifestations seen in
Metabolic Medicine Unit, Great Ormond Street Hospital for Children, GALT patients, it seems likely that Galactose-1-P which is absent
London WC1N 3JH, UK. in GALK but present in GALT, plays a major role in their
PAEDIATRICS AND CHILD HEALTH 21:2 65 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
PAEDIATRICS AND CHILD HEALTH 21:2 66 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
The routine biochemical investigations for suspected neonates with severe hepatic dysfunction
Table 1
metabolism (IEM). Thus any child with acute liver Galactosaemia is considered with suitable milk formulations
dysfunction in the neonatal period should be thoroughly being either soya based preparations, or in patients with a degree
investigated both biochemically and radiologically. Of the of acute hepatic dysfunction and possibly limited absorption,
IEMs, urea cycle, fatty acid oxidation disorders and organic Pregestimil (which still contains traces of galactose). The support
acidemias can present with impairment in liver function. of severe liver dysfunction includes the administration of vitamin
However the inborn error that most closely mirrors gal- K, antacids, the maintenance of at least 6 mg/kg/min of glucose
actosaemia’s presentation is tyrosinaemia type 1 which also (often requiring high concentration dextrose, as fluid restriction
presents in the neonatal period with acute liver and renal is normally recommended).
tubular dysfunction. The investigations listed above while
not an exhaustive list are designed to exclude most of the Chronic manifestations of galactosaemia
more common causes (see Table 1).
Despite early dietary intervention Glactosaemic patients may still
Management develop a number of long-term complications:
Table 2
PAEDIATRICS AND CHILD HEALTH 21:2 67 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
thought to be secondary to the osmotic action of increasing recognized to cause particular problems for galactosaemics is
amount of intracerebral galacticol and has only been noted in language with 56% of patients having language difficulties with
neonates. problems in articulation being particularly common i.e. verbal
Some galactosaemic patients may develop a progressive dyspraxia. This appears to be related to, but is not only the result,
extrapyramidal disorder, which tends to manifest as tremor and of the lower cognition found in patients. The overall impact of
ataxia, though infantile onset of choreiform movements is also speech therapy on outcome in galactosaemic patients is still to be
known. The cause is unknown but functional scanning with PET determined.
scans has shown both a decrease in activity in the cerebellum
and an increase in activity in the basal ganglia; the latter being is Endocrine/fertility: impairment in ovarian function was initially
also observed in Parkinsonian patients. noted by Kaufman et al in 1979, with over 80% of female patients
Significant involvement of the cerebral white matter has also being observed to have hypergonadotorphic hypogonadism with
been noted, with widespread decreases in metabolism across increased FSH levels, often from an early age. This presents
most of the cerebral cortex. This mirrors what has been seen on with pubertal delay or with primary or secondary amenorrhoea,
both autopsies and neuroimaging of GALT patients. Indeed up to with subsequent progression to premature ovarian failure. The
1/3 of patients show some signs of cerebral atrophy on MRI proposed mechanisms for the ovarian failure include, the direct
scanning, with a corresponding amount having abnormal EEGs. effect of galactose and its metabolites leading to early oocyte
However the day-to-day correlation of these changes with the toxicity effects or effects secondary to hypoglycosylation of FSH,
overall clinical outcome is still unclear and the precise under- resulting in an aberrant isoform, which is unable to induce cyclic
lying pathological mechanisms which result in these white AMP activation. Recent work highlighting a reduction in anti-
matter changes are still unknown. mullerian hormone from early in life, coupled with normal
bioactivity of FSH from Galactosaemics would suggest that the
Neuropsychological/language reduction in ovarian function, is through primary toxicity (at least
The structural and functional changes of the cerebral white matter partially in utero), rather than due to secondary insensitivity. The
underlie the verbal dyspraxia and intellectual impairment which risk of premature ovarian failure does not seem to be reduced by
has been witnessed in many galactoseamic patients. Overall the good dietary control, also suggesting early gonadal toxicity Some
mean IQ of patients with classical galactosaemia has typically been Galactosaemia women can spontaneously become pregnant
found to be in the range of 70e90 though normal intelligence however, with 55 reported cases in the medical literature.
has been noted. There is no evidence from the longitudinal studies There has been no convincing evidence of male gonadal
published that there is any decline in IQ with age though this impairment and normal testosterone levels have been seen in
conflicts with large cross sectional studies from the early 1990s. a number of studies.
There appears to be a generalized impairment in both Apart from the rise in FSH, relatively low levels of IGFBP-3
performance related IQ and verbal IQ. One area that long been and IGF-1 have also been shown in patients of both sexes, there
Table 3
PAEDIATRICS AND CHILD HEALTH 21:2 68 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
has however been no incidence of defects in the thyroid function, see Further reading) for monitoring are listed below are listed in
cortisol or prolactin profiles of 37 patients on a lactose free diet. the table above (Table 3).
Bone metabolism/growth
The work of Panis et al has shown a predisposition of gal- Prevention
actosaemic patients towards generalized osteopenia in treated Unlike much of Europe and most of the United States there is no
children. This was despite normal levels of all trace elements, newborn screening program for galactosaemia in the UK. The
calcium, 1,25-dihydroxy-vitamin D and PTH in 40 patients rational behind this is that potentially clinical symptoms start
studied. Lower IGF-1, a stimulator of osteoblast division and prior to when screening is performed which is usually on days
matrix production, and decreased levels of carboxylated osteo- 5e7, the relative infrequency of the disease and the current lack
calcin was found. Subsequently supplementation with a combi- of demonstrable impact on long-term outcome in early screened
nation of vitamin K and vitamin D3 showed significant increases population. Against this only 79% present by 2 months, the
in prepubertal Bone mineral content on Dexa scanning, leading diagnosis can still be missed in the presence of typical signs and
to their proposal of regular 2-yearly assessment with Dexa dietary treatment is started sooner where screening is performed.
scanning and supplementation if required. It is to be remembered While the early commencement of dietary treatment is yet to
however that pubertal delay & ovarian failure will also contribute convincingly be shown to impact on neurological outcome, this
to reduced bone mineral acquisition. must be balanced with the greater need of intensive care and
Growth in galactosaemics has been controversial with longer inpatient medical care, as well as the impact on the family
prenatal growth/birth weight, found to be reduced or normal. of having a sick infant, when with screening this is often
Panis et al found decreased height velocity in female patients, preventable. A
with the mean corrected height when compared to mid-parental
target height Z-score was less than the target height in most
patients. The low IGF-1 and IGFBP-3 levels found were thought FURTHER READING
to be significant, without any apparent nutritional deficiencies Bandyopadhyay S, Chakrabarti J, Banerjee S, et al. Prenatal exposure to
being apparent in these patients. However as in the Waggoner high galactose adversely affects initial gonadal pool of germ cells in
review, there is often apparent physiological delay with eventual rats. Hum Reprod 2003 Feb; 18: 276e82.
normal achievement in height. Careful monitoring of growth and Berry GT. Galactosemia and amenorrhea in the adolescent. Ann N Y Acad
pubertal development is recommended. Sci 2008; 1135: 112e7.
Bosch AM. Classic galactosemia: dietary dilemmas. J Inherit Metab Dis;
Eyes/cataracts
2010;. doi:10.1007/s10545-010-9157-8.
The overall frequency of cataracts was reported initially at about
Bosch AM. Classical galactosaemia revisited. J Inherit Metab Dis 2006; 29:
30%. Nearly half of the cataracts in this study were described as
516e25.
“mild”, “transient” or “neonatal” and tended to resolve with
Bosch M, Bakker HD, Van Gennip AH, van Kempen JV, Wanders RJ,
dietary treatment; though one neonatal onset cataract did require
Wijburg FA. A clinical features of galactokinase deficiency: a review of
surgery. However more recent reviews indicate that the rate of
the literature. J Inherit Metab Dis 2002; 25: 629e34.
cataracts is lower (14%) and none had a significant impact on
Chhay JS, Vargas CA, McCorvie TJ, Fridovich-Keil Jl, Timson DJ. Analysis of
vision. There have been no recorded cases of development of
UDP-galactose 40 -epimerase mutations associated with the interme-
cataracts in patients who are compliant with diet.
diate form of type III galactosaemia. J Inherit Metab Dis 2008; 31:
Treatment 108e16.
Honeyman MM, Green A, Holton JB, Leonard JV. Galactosaemia: results of
Long-term management is dietary, with the current recommen- the British Paediatric Surveillance Unit study. 1988e90 Archives of
dations being to avoid lactose containing foods with no restric- Disease in Childhood 1993; 69: 339e41.
tions beyond this. The rational being that although fruit, Holton JB, Walter JH, Tyfield LA. Galactosemia. In: Scriver CR, Beaudet AL,
vegetables and offal are known to contain small amounts of Sly WS, Valle D, eds. The metabolic and molecular bases of inherited
lactose, the concentration is minimal, <30 mg/day in a typical disease. 8th Edn. New York: McGraw-Hill, 2001: 1553e88.
unrestricted diet to 54 mg/day in a fruit enriched diet, when Kaufman FR, McBride-Chang C, Manis FR, Wolff JA, Nelson MD. Cognitive
compared to the endogenous production of galactose which has functioning, neurologic status and brain imaging in classical galacto-
been calculated at >1000 mg/day in a typical adult. There are semia. Eur J Pediatr 1995; 154: S2e5.
reported cases of adults homozygous for the Q188R mutation Lai K, Tang M, Yin X, Wierenga K, Elsas L. ARHI: a new target of
who had discontinued their diet in early childhood without galactose toxicity in classic galactosemia. Biosci Hypotheses 2008;
apparent ill effects. Generally however the current recommen- 1: 263e71.
dations are to continue the use of galactose restricted diet life- Lia K, Elsa LJ, Wierenga KJ. Galactose toxicity in animals. Life 2009; 61:
long. Those patients on this diet should insure an adequate 1063e74.
calcium intake. Menezo YJ, Lescaille M, Nicollet B, Servy EJ. Pregnancy and delivery after
stimulation with rFSH of a galatosemia patient suffering hyper-
Follow up
gonadotropic hypogonadism: case report. J Assist Reprod Genet 2004;
Ideally follow up should be based on the shared care model 21: 89e90.
between a specialized regional centre and the local paediatric Panis B, Gerver WJ, Rubio-Gozalbo ME. Growth in treated classical
teams. The Current UK recommendations (Walter JH et al 1999 galactosemia patients. Eur J Pediatr 2007 May; 166: 443e6.
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Panis B, van Kroonenburgh MJ, Rubio-Gozalbo ME. Proposal for the Walter JH, Collins JE, Leonard JV. Recommendations for the management
prevention of osteoporosis in paediatric patients with classical of galactosaemia. Arch Dis Child 1999; 80: 93e6.
galactosaemia. J Inherit Metab Dis 2007; 30: 982. Webb AL, Singh RH, Kennedy MJ, Elsas LJ. Verbal dyspraxia and galac-
Potter NL, Lazarus JA, Johnson JM, Steiner RD, Shriberg LD. Correlates of tosemia. Pediatr Res 2003; 53: 396e402.
language impairment in children with galactosaemia. J Inherit Metab Dis Widger J, O’Toole J, Geoghegan O, O’Kefffe M, Manning R. Diet and
2008; 31: 524e32. visually significant cataracts in galactosaemia: is regular follow up
Prestoz LL, Couto AS, Shin YS, Petry KG. Altered follicle stimulating necessary? J Inherit Metab Dis 2010; 33: 129e32.
hormone isoforms in female galactosaemia patients. Eur J Pediatr
1997; 156: 116e20.
Ridel KR, Leslie ND, Gilbert DL. An updated review of the long-term
neurological effects of galactosemia. Pediatr Neurol 2005; 33: 153e61.
Sanders RD, Spencer JB, Epstein MP, et al. Biomarkers of ovarian function Practice points
in girls and women with classic galactosemia. Fertil Steril 2009; 92:
344e51.
C Any neonate or infant with either progressive or severe liver
Schadewaldt P, Hoffmann B, Hammen HW, Kamp G, Schweitzer-Krantz S, dysfunction should be considered to be galactosaemic and
Wendel U. Longitudinal assessment of intellectual achievement in started on either a soya based formulation or progestamil
patients with classical galactosemia. Pediatrics 2010; 125: 374e81. until the results of the initial investigations are available.
Schweitzer-Krantz S. Early diagnosis of inherited metabolic disorders
C Initial investigation for Galactosaemia should include both
towards improving outcome: the controversial issue of galactosaemia. gal-1-P and GAL1PUT (taken prior to any blood transfusions).
Eur J Pediatr 2003; 162: S50e3.
C The current recommended treatment is a lifelong minimal
Tyfield L, Reichardt J, Fridovich-Keil J, et al. Classical galactosemia and galactose diet, which is insured by having a lactose free diet.
mutations at the galactose-1-phosphate uridyltransferase (GALT)
C There are a number of increasingly well defined long-terms
gene. Hum Mutat 1999; 13: 417e30. problems, that affect SOME galactosaemic children, thus
Waggoner DD, Buist NRM, Donnell GN. Long-term prognosis in gal- children should continued to have regular reviews to identify
actosaemia: results of a survey of 350 cases. J Inher Metab Dis 1990; potential problems early and institute supportative measures.
13: 802e18.
PAEDIATRICS AND CHILD HEALTH 21:2 70 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Peroxisomal disorders proteins termed peroxins which are encoded by PEX genes. As
a consequence peroxisomal biogenesis involves the correct
expression of multiple PEX genes of which 16 have been identi-
Camilla Scott
fied in humans. There are also a large number of single enzyme
Simon Olpin functions within the peroxisome encoded by non-PEX genes &
defects in these results in a range of disorders with single enzyme
deficiency.
Peroxisomal disorders are broadly categorized into defects of
Abstract peroxisomal biogenesis with deficiencies of multiple pathways
Peroxisomes are complex single-membrane cell organelles found in all
e.g. Zellweger spectrum or defects affecting single enzymes such
cell types except erythrocytes. Peroxisomes have both catabolic and
as D-bifunctional protein deficiency. Most disorders are auto-
anabolic functions & these functions include the synthesis of plasmalo-
somal recessive, however the commonest peroxisomal disorder
gens, the formation of bile acids, polyunsaturated fatty acids, cholesterol
X-linked adrenoleukodystrophy has an X-linked mode of
& isoprenoids, & the degradation of very long-chain fatty acids (VLCFA’s).
inheritance.
Peroxisomes multiply by division of existing peroxisomes & this complex
Peroxisomal disorders present with a wide spectrum of clin-
process is regulated by both PEX & non-PEX genes. Peroxisomal disor-
ical disease ranging from the severe neonatal Zellweger
ders are broadly categorized into defects of peroxisomal biogenesis
syndrome with dysmorphic features, neurological abnormalities,
with deficiencies of multiple pathways e.g. Zellweger spectrum or defects
hepatorenal and gastrointestinal dysfunction with death typically
affecting single enzymes such as D-bifunctional protein deficiency.
occurring within the first 6 months of life to adult onset X-linked
Peroxisomal disorders present with a wide spectrum of clinical
adrenoleukodystrophy which can be confined only to adrenal
disease ranging from the severe neonatal Zellweger syndrome with dys-
insufficiency.
morphic features, neurological abnormalities, hepatorenal and gastroin-
testinal dysfunction with death typically occurring within the first 6
months of life to adult onset X-linked adrenoleukodystrophy which can Peroxisomal assembly
be confined only to adrenal insufficiency.
Peroxisomal biogenesis is complex and peroxisomes multiply
by division of pre-existing peroxisomes. Peroxisomes do not
Keywords bile acids; peroxisomes; PEX genes; plasmalogens; VLCFA; contain any DNA and subsequently all of the proteins required
X-linked ALD; Zellweger for assembly and function are encoded by nuclear genes and
synthesized on free polyribosomes in the cytosol before post-
translational import into the peroxisome. Transportation is
highly selective and requires the presence of specific import
Introduction sequences known as peroxisomal targeting sequences (PTSs).
PTS1 is the C-terminal peroxisome targeting sequence and
Peroxisomes are complex single-membrane cell organelles found
PTS2 is the N-terminal peroxisomal targeting sequence. PTSs
in all cell types except erythrocytes. Peroxisomes have both
are recognized by receptors (PTS1 receptor and PTS2 receptor)
catabolic and anabolic functions & these functions predomi-
which direct the peroxisomal proteins to the peroxisomal
nantly involve lipid metabolism. Peroxisomal functions include
membrane. The target protein then enters the peroxisome by
the synthesis of plasmalogens which are important constituents
a sequential multi-step process involving recognition, dock-
of cell membranes & myelin. They are also involved in the
ing, translocation across the peroxisomal membrane and
formation of bile acids, polyunsaturated fatty acids, cholesterol &
recycling.
isoprenoids. Peroxisomes b-oxidise very long-chain fatty acids
All proteins (peroxins) involved in peroxisomal biogenesis
(VLCFA’s), a-oxidise phytanic acid and catabolize lysine via
are encoded by PEX genes. To date 16 PEX genes have been
pipecolic acid and glyoxylate to glycine. Importantly they also
identified as essential for human peroxisomal formation. PEX5
contain catalase which converts highly reactive hydrogen
encodes for the PTS1 receptor and PEX7 encodes for the PTS2
peroxide into oxygen & water.
receptor. PEX1, PEX6 and PEX26 are required for matrix protein
Peroxisomes multiply by division of existing peroxisomes.
import and encode proteins involved in the recycling of the
Peroxisomal membranes are assembled & peroxisomal matrix
PTS1 and PTS2 receptors. PEX2, PEX10 and PEX12 encode
proteins are targeted from the cytosol & then imported into the
proteins involved in matrix protein import. PEX13 encodes
organelle by a highly complex process dependent on specialized
a docking factor for PTS1 and is also required for matrix
protein import. PEX3, PEX16 and PEX19 encode proteins
involved in the production of peroxisomal biogenesis proteins.
Camilla Scott MSc FRCPath is a Principal Clinical Scientist in the In addition to the assembly proteins, the peroxisome also
Department of Clinical Chemistry at Sheffield Children’s Hospital, contains over 50 matrix proteins and numerous membrane
Western Bank, Sheffield S10 2TH, UK. Conflict of interest: none. proteins.
PAEDIATRICS AND CHILD HEALTH 21:2 71 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
a single peroxisomal enzyme or protein (the single enzyme Clinically, RCDP symptoms include characteristic proximal
defects). shortening of the limbs (rhizomelia), cataracts, facial
dysmorphism, microcephaly, small stature, and psychomotor
Clinical presentation retardation. For all of the peroxisomal biogenesis disorders
treatment is largely symptomatic and supportive.
The peroxisomal biogenesis defects include the Zellweger
spectrum which accounts for approximately 80% of patients,
while rhizomelic chondrodysplasia punctata (RCDP) accounts Single enzyme defects
for the remaining patients with peroxisomal biogenesis disor-
The single enzyme defects result in the loss of a single protein
ders. RCDP is clinically and genetically distinct from the Zell-
and subsequently the loss of a single peroxisomal function.
weger spectrum.
Although over 50 peroxisomal matrix and numerous membrane
The clinical phenotype of Zellweger spectrum, also known
proteins have been identified only about 10 disorders associated
as cerebrohepatorenal syndrome, consists of three over-
with single enzyme defects have been described, indicating that
lapping phenotypes. The most severe phenotype being Zell-
there are many more unrecognized disorders. The known single
weger syndrome (ZS) followed by an intermediate form,
peroxisomal enzyme/protein defects are summarized in Table 1,
neonatal adrenoleukodystrophy (NALD), which is not to be
the more common/frequently encountered defects are summa-
confused with X-linked ALD, and the mildest form infantile
rized below.
Refsum disease (IRD). The overall frequency of ZS is
The most common single enzyme defect is X-linked adreno-
approximately 1:50,000. ZS classically presents with charac-
leukodystrophy. The inheritance is X-linked with approximately
teristic craniofacial features including large anterior fonta-
50% of female carriers eventually presenting with clinical
nelle, full forehead, shallow orbital ridges, epicanthal folds,
symptoms. The clinical phenotypes vary from the severe child-
high arched palate, broad nasal bridge and small nose with
hood cerebral presentation through to a mild adult form. There is
anteverted nares. Ocular abnormalities such as cataracts,
a form presenting solely with Addison Disease Severe childhood
glaucoma and corneal clouding are common. In addition there
disease takes the form of a progressive demyelination of the
is encephalopathy, seizures, severe hypotonia, hepatorenal
cerebral neurones and adrenal insufficiency. This early onset
abnormalities including renal cysts and skeletal abnormali-
male disease usually starts between 3 and 10 years of age with
ties. Patients usually succumb to the disorder within the first
behavioural abnormalities. Initial referral is often to a psychia-
few months of life and survival is extremely rare beyond
trist or psychologist. There is further progression to dementia,
a year. Patients with the milder forms of the Zellweger spec-
speech difficulty with loss of hearing & vision and finally
trum have similar but less severe symptoms to ZS and
relentless progression to decorticate spastic quadriparesis, with
survival varies from four months to several decades. For
pigmentation of the skin secondary to adrenal insufficiency. The
example, virtually all IRD patients have moderate dysmorphic
most effective treatment is haematopoietic stem cell trans-
features and sensorineural hearing loss with pigmentary
plantation which is only effective if carried out in pre-symp-
retinopathy. Early hypotonia and deranged liver function are
tomatic or early symptomatic patients. There is also late onset
common. However most IRD patients learn to walk, although
adolescent and adult cerebral forms of X-ALD which follow
their gait is frequently ataxic and their mental function is in
a similar but delayed course. The milder adult onset X-ALD
the severely retarded range as compared to profound retar-
presents with peripheral neuropathy and Addison disease
dation in NALD and ZS.
(adrenomyeloneuropathy), with or without cognitive decline,
RCDP is clinically distinct from the Zellweger spectrum and
may affect both male and female carriers. A small cohort of X-
also has severe classical presentations and milder phenotypes.
ALD patients will present with isolated adrenal insufficiency
(Addison only X-ALD).
Refsum disease, which should not be confused with infantile
Summary of the single peroxisomal protein/enzyme Refsum disease, is also a single enzyme defect and is due to
defects defective phytanoyl-CoA hydroxylase. The enzyme is required
for the a-oxidation of phytanic acid to pristanic acid. Patients
Defective peroxisomal function Disorder with Refusm disease accumulate large amounts of phytanic
b-Oxidation of very long-chain X-linked adrenoleukodystrophy acid in plasma and tissues. The clinical features include;
fatty acids Acyl-CoA oxidase deficiency pigmentary degeneration, peripheral neuropathy and cerebella
D-bifunctional protein deficiency ataxia usually presenting before the second decade of life.
Sterol carrier protein deficiency However, the age of onset and clinical severity varies according
a-methyl-acyl-CoA-racemase to the degree of residual enzyme activity. Effective treatment
deficiency can be achieved by strict avoidance of dietary phytanic acid
a-Oxidation of phytanic acid Refsum disease and plasmapheresis.
Hydrogen peroxide metabolism Catalase deficiency D-bifunctional enzyme deficiency is a single enzyme defect
Glyoxylate metabolism Hyperoxaluria type I due to defective bifunctional enzyme which is required for
Etherphospholipid biosynthesis DHAP-AT deficiency peroxisomal b-oxidation. Bifunctional enzyme deficiency is rare
Alkyl-DHAP synthase deficiency and classically presents with neonatal hypotonia, dysmorphic
features, seizures, hepatomegaly and developmental delay. The
Table 1 degree of severity is however highly variable.
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SYMPOSIUM: INBORN ERRORS OF METABOLISM
VLCFA’s Phytanic acid Pristanic acid Bile acids Plasmalogens DHAP-AT activity Catalase
(C22:C26) (plasma) (plasma) (urine & plasma) (red blood cell) (fibroblasts expression
(plasma) & platelets) (fibroblasts)
Zellwegers syndrome þþþ N/þ N/þ þþþ Low Low Low
Neonatal adrenoleukodystrophy þþ N/þ N/þ þþ Low Low Low
Infantile Refsum disease þþ N/þ N/þ þþ Low Low Low
RCDP type 1 N N/þ N/Low N Low Low N
X-Linked adrenoleukodystrophy þþ N N N N N N
D-bifunctional protein deficiency þþ N/þ N/þ N/þ N N N
a-Methyl-acyl-CoA-racemase N N/þ þ þþ N N N
deficiency
Refsum disease N þþþ Low N N N N
Hyperoxaluria type 1 N N N N N N N
Acyl-CoA oxidase deficiency þþ N N N N N N
Catalase deficiency N N N N N N Low
DHAP-AT deficiency N N N N Low Low N
Alkyl-DHAP synthase deficiency N N N N Low Low N
Table 2
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SYMPOSIUM: INBORN ERRORS OF METABOLISM
Classification of LSDs based on the nature of the Disorders that have presented with hydrops foetalis
defective protein
C Mucopolysaccharidosis type VII (Sly disease) e common
1. Defects of specific lysosomal hydrolases C Mucopolysaccharidosis type IV
a. Mucopolysaccharidoses C Neuraminidase deficiency (sialidosis type II)
i. Types IeIX C Galactosialidosis
b. Sphingolipidoses, other lipidoses and glycogen storage C Infantile sialic acid storage disease
diseases C Acute neuronopathic Gaucher disease (GD II)
i. Fabry disease C GM1 gangliosidosis (b-galactosidase deficiency)
ii. Farber disease C Mucolipidosis II (I cell disease)
iii. Gaucher disease C NiemannePick disease type A (sphingomyelinase deficiency)
iv. GM1 gangliosidosis C NiemannePick disease type C
v. GM2 gangliosidosis C Wolman disease (acid lipase deficiency)
vi. Krabbe disease C Farber disease (ceramidase deficiency)
vii. MLD
viii. NiemannePick disease types A & B Table 2
ix. NiemannePick disease type C1
x. Wolman and cholesterol ester storage disease
a “Hurler-phenotype” at birth almost certainly does not have
xi. Pompe disease (GSD II)
mucopolysaccharidosis type IH (MPS IH). Galactosialidosis, GM1
c. Glycoproteinoses
gangliosidosis and mucolipidosis II (I cell disease) are far more
i. Aspartylglucosaminura
likely. The characteristic facial appearance seen in MPS IH evolves
ii. Fucosidosis
over the first year of life and it is rare to make a diagnosis on dys-
iii. a and b mannosidoses
morphic grounds before the age of 9 months except in populations
iv. Neuraminidase deficiency
where this disorder is very common such as within the Irish trav-
v. Schindler disease
elling community.
2. Defects in post-translational modification of lysosomal proteins
Patients with acute neuronopathic Gaucher disease (GD II) can
a. Multiple sulphatase deficiency
present with severe ichthyosis (“collodian baby”), unusual facies,
b. Mucolipidosis II (I cell disease)
arthrogryposis, enlargement of the liver and spleen and hernias.
c. Mucolipidosis III
Another dermatological clue to the presence of underlying LSD is
3. Defects in activator proteins
the abundant Mongolian blue spots seen in children with muco-
a. GM2 gangliosidosis AB variant
polysaccharidoses and GM1 gangliosidosis.
b. Prosaposin deficiency
c. Saposin A deficiency Cardiac disease
d. Saposin B deficiency In infantile Pompe disease (glycogen storage disease type II, acid
e. Saposin C deficiency maltase deficiency), cardiac failure, cardiac arrhythmia and car-
4. Defects in structural lysosomal membrane proteins, protective diomegaly may all be present at birth. Indeed in a number of
proteins, transporters and trafficking affected infants cardiomegaly has been demonstrated on foetal
a. LAMP 2 ultrasounds performed in the last trimester of pregnancy. Affected
b. LIMP 2 infants also have macroglossia with a protruding tongue and are
c. Cathepsin A deficiency generally hypotonic. In addition to the cardiomyopathy demon-
d. Mucolipidosis IV strated on echocardiography (usually hypertrophic, occasionally
e. Cystinosis dilated) there is also elevation of liver enzymes and CPK on
f. Infantile sialic acid storage disease and Salla disease biochemical testing and the blood film will reveal vacuolated
g. NiemannePick disease type C1 lymphocytes in the vast majority of affected patients.
5. Miscellaneous
a. Cathepsin K deficiency (Pycnodysostosis) Hepatosplenomegaly and liver disease
Hepatosplenomegaly at birth has very many different causes and
Table 1 the common ones such as bacterial and viral infections or
anatomical abnormalities need to be diagnosed quickly as
specific treatment may be available. A number of LSDs can also
DNA mutation studies. In infants that survive physical and
be present with enlargement of the liver and spleen and in
radiological examinations may provide further clues to the correct
a number of affected patients ascites will also be present. Careful
diagnosis.
clinical and radiological examinations for other abnormalities
may be helpful and in some circumstances bone marrow or liver
Other neonatal presentations
biopsy may suggest underlying LSD. In contrast to this non-
Dysmorphism specific presentation some infants with NiemannePick disease
A number of disorders have dysmorphic features that can be type C (NP-C) have a very evocative clinical presentation with
identified at or soon after birth. In fact the infant that has liver disease in the newborn period. In these affected infants
PAEDIATRICS AND CHILD HEALTH 21:2 77 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
metacarpals and when present the radiologist will often give the
Therapy first clue to diagnosis.
In mucolipidosis II (I cell disease) severe bone disease can be
Modality Disorders treateda present from before birth with severe osteopenia and patholog-
Haematopoietic stem MPS IH (Hurler syndrome) ical fractures. This presentation is often associated with a tran-
cell therapy (includes Alpha-mannosidosis sient hyperparathyroidism demonstrated by an increased serum
bone marrow Presymptomatic Krabbe parathyroid hormone and alkaline phosphatase activity with
transplantation, disease a normal calcium concentration.
umbilical cord blood Juvenile MLD (other disorders
transplantation and less commonly treated
Presentation in infancy and childhood
peripheral blood stem but where there is good
cell transplantation) theoretic chance of success: Neurological presentation
Aspartylglucosaminuria, Unfortunately a great majority of LSDs have a significant neuro-
Farber disease, Wolman disease, logical component. In many disorders it is by far the dominating
NiemannePick disease type C2) clinical effect of the disease (e.g. most sphingolipidoses) whereas
Enzyme replacement therapy in others it is merely one element of a more generalized disorder
AldurazymeÒ MPS I (e.g. mucopolysaccharidosis type I).
ElapraseÒ MPS II In infantile TayeSach’s disease the onset of the neurological
NaglazymeÒ MPS VI disorder can seem very acute, with an explosive onset of seizures
FabrazymeÒ Fabry disease starting towards the end of the first year of life in a patient initially
ReplagalÒ Fabry disease thought to be following a normal pattern of development. Rapid
CerezymeÒ Gaucher disease neurodegeneration follows with visual loss, spasticity and even-
VprivÒ Gaucher disease tually loss of all skills culminating in death before the age of 5
UplysoÒ Gaucher disease years in most affected infants. In these patients clinical examina-
MyozymeÒ Pompe disease tion reveals the classical macular “cherry red spot” secondary to
Substrate reduction therapy storage within the retinal cells.
ZavescaÒ Gaucher disease type I in The typical developmental pattern seen in LSDs is one of
patients for whom ERT regression. After a period of apparently uneventful progress,
is unsuitable development slows and peers start to acquire skills at an increas-
ZavescaÒ NiemannePick disease type C ingly faster rate. Eventually development plateaus and then
a
acquired skills are lost in a pattern. The most recently acquired
Many conditions have been treated but this table indicates only those disorders
skills are lost first and eventually the child becomes dependent on
where significant numbers of patients are routinely referred for transplanta-
tion. For a comprehensive list of conditions that have been treated see Vellodi, its carers for all needs.
2004. By far the largest group of patients have MPS IH (Hurler syndrome). For some disorders characteristic patterns can be seen. In
mucopolysaccharidosis type III (Sanfilippo syndrome) most of the
Table 3 affected children are normal until the age of 12e18 months and then
fail to develop normal speech. Initially this is usually ascribed to
(about a quarter of all patients with NP-C seen in our clinic) associated middle ear disease and deafness. However, when this is
severe liver dysfunction often associated with conjugated corrected speech fails to improve and developmental progress is
hyperbilirubinaemia suggests a diagnosis of biliary atresia and further impaired. Children with this disorder have only mild
a number of NP-C infants have had surgical procedures to somatic abnormalities and the facial features of an MPS disorder are
exclude this diagnosis. A significant number of these patients will often not appreciated in this group. Diagnosis is usually established
go onto develop liver failure and die (about one third) whilst the when the patients develop the characteristic challenging behaviour
others will slowly improve over months (and even years in some seen in MPS III. This is characterized by severe insomnia and often
patients) and eventually make a full recovery from their liver extreme hyperactivity making management extremely difficult. As
disease only to present with the neurological manifestations of the disease progresses skills are lost and the children become
the disease often many years later. unsteady and fall and also develop neurological dysphagia. By mid-
Hepatosplenomegaly in older patients may be the presenting teenage years most affected patients are dependent on their carers
manifestation of Gaucher disease (types I and III) and Nie- for all needs before death occurs towards the end of the second or
mannePick disease. There are often haematological abnormalities early in the third decade of life.
secondary to hypersplenism and bone marrow infiltration. Neuronal ceroid lipofuscinoses (NCL) is a group of disorders
Respiratory infiltration is often under recognized in these patients said to be the commonest neurodegenerative disorder of child-
who on rare occasions will present with respiratory failure. hood. The neurodegeneration occurs at a differing age of onset and
speed of progression depending on the type of NCL present. The
Skeletal disease (mesenchymal presentation) group as a whole is characterized by difficult to control seizures
The skeletal manifestations of LSDs known as dysostosis multi- and progressive visual loss. Enzyme assay and DNA mutation
plex (DM) usually present for the first time in the second 6 analysis have made diagnosis of NCL more readily available.
months of life depending on the nature of the underlying NiemannePick disease type C (NP-C) can present with two
disorder. DM is best seen in the vertebral bodies, hips, pelvis and unusual but specific neurological abnormalities. The first involves
PAEDIATRICS AND CHILD HEALTH 21:2 78 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
an abnormality of voluntary eye movement due to a failure to leading to misfolding of the lysosomal enzymes the chaperones,
initiate ordinary saccades. This supra-nuclear gaze palsy initially which are usually enzyme inhibitors, can bind to the enzyme
affects vertical movements and affected patients often blink inducing stability and aid transport to the lysosome where the
excessively in an attempt to initiate eye movement. This is often chaperone dissociates. As long as the mutation does not involve the
the first neurological abnormality detected in affected patients. active site of the enzyme a small increase in residual enzyme
Over time the horizontal movements are also affected and the eyes activity will result. This may, in some disorders, be sufficient to
become virtually immobile. (In Gaucher disease type III horizontal convert a serious disorder to a more attenuated form. Chaperone
gaze palsy develops and in these patients rapid head movements therapy for Fabry disease and Pompe disease is under development
(head thrusting) are used to stimulate eye movement.) and early clinical trials have been completed in both disorders.
The second neurological abnormality seen commonly in NP-C is
cataplexy, a sudden transient loss of muscular tone precipitated by Conclusions
emotion, usually humour. Patients have bouts of laughter culmi-
Although rare most paediatricians will encounter one or more
nating in sudden hypotonia and will fall to the ground if not sup-
LSD in their career. As treatment options are increasing, at least
ported. The attacks last seconds but can recur in bouts and can be
for some of these disorders, it is important to make a timely
very disabling. Cataplexy is closely related to narcolepsy another
diagnosis. A combination of clinical presentation, radiology and
neurological complication seen in NP-C patients. It is important to
appropriate biochemical testing will lead to a diagnosis in most
recognize cataplexy for what it is and not diagnose the episodes as
affected patients. After diagnosis patients should be referred to
epilepsy as cataplexy does not usually respond to standard anti-
metabolic centres that have expertise in the management of these
convulsants and is most responsive to tricyclic antidepressants such
conditions so that treatment options can be explored. A
as imipramine.
PAEDIATRICS AND CHILD HEALTH 21:2 79 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Mitochondrial disease e membrane. Each complex has multiple subunits (46 for complex
I). When fuels are burnt in the mitochondria, ‘co-factors’ are
Pathology
Mitochondrial biochemistry: the mitochondrial respiratory
chain consists of five ‘complexes’ floating in the mitochondrial
Elisabeth Jameson MBBCh BSc MRCPCH is a ST7 in Paediatric Inherited Unaffected female due to low heteroplasmy
Disorders of Metabolism at the Biochemical Genetics Unit, Genetic
Medicine, 6th Floor, St Mary’s Hospital, Oxford Road, Manchester M13 Affected female/male respectively
9WL, UK. Conflict of interest: none. Unaffected female/male respectively
PAEDIATRICS AND CHILD HEALTH 21:2 80 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Mutations preceded with m. are located in mtDNA. Other genes, e.g. POLG1, SURF1, Tafazzin are nuclear.
Table 1
PAEDIATRICS AND CHILD HEALTH 21:2 81 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Normal development
Detailed history, family tree and clinical examination
Baseline investigations, e.g. liver function, echocardiography,
lactate Baseline imaging if indicated, e.g. MRI head
Stepwise decline in
age-appropriate skills
Skills
No Yes
Negative
MUSCLE BIOPSY Test for common
± skin biopsy, CSF lactate mutations in blood
Episode of
Histochemistry Biochemistry decompression
Time (years)
Molecular Genetics
MRI: magnetic resonance imaging, MELAS: mitochondrial encephalopmyopathy, Figure 3 Stepwise progression of Leigh syndrome.
lactic acidosis and stroke like episodes, MERRF: myoclonic epilpesy, ragged red
fibres, NARP: neurogenic weakness, ataxia, retinitis pigmentosa, LHON: Leber’s
hereditary optic neuropathy, CSF: cerebrospinal fluid is relatively small containing 16 569 base pairs. This allows
molecular studies to be performed relatively easily. Interpretation
Figure 2 The investigation of suspected mitochondrial disease. can be difficult due to the high percentage of benign sequence
variants and the varying degrees of heteroplasmy.
Occasionally, a patient with a mitochondrial disorder may have
c) Histochemistry. For complexes II and IV, this can show the normal respiratory chain results in muscle. This may be due to tissue
activities in individual muscle fibres. Sometimes complex IV specific disease, e.g. only affecting liver, or a low level of heteroplasmy
activity is present in some muscle fibres but absent in others, in the sample. Conversely, abnormal results may be due to artefact if
giving a patchwork appearance; this suggests that the under- samples are not processed correctly or they may be secondary, e.g.
lying defect may involve mtDNA. due to some drugs used for HIV (human immunodeficiency virus).
When arranging muscle biopsy it is worthwhile coordinating it
with simultaneous skin biopsy and cerebrospinal fluid Management and prevention
sampling. It is essential to make the correct diagnoses as some of the
differential diagnoses respond well to treatment, e.g. fat oxidation
Mutation analysis: some syndromes are associated with partic- disorders, biotinidase deficiency. Unfortunately, mitochondrial
ular genetic defects, see Table 1, and it is worth looking for these in disease seldom responds to specific treatment. A small number of
blood before doing a muscle biopsy. In other patients, molecular patients have ubiquinone deficiency but even these patients may
studies are determined by the muscle biopsy results. In a patient show little clinical response to treatment with ubiquinone.
with Leigh syndrome due to complex IV deficiency, it may be Consequently, for most patients management is a supportive care
appropriate to sequence SURF1, a nuclear gene. In other patients, package. This may involve anti-convulsants for seizure control,
results may point to an mtDNA defect. The mitochondrial genome ptosis surgery, gastrostomy feeding and home care packages. At
times of acute illness, bicarbonate replacement can be used to
correct metabolic acidosis secondary to raised lactate levels. The
lack of treatment contrasts with the great progress made in iden-
Causes of raised lactate tifying the underlying genetic defects. This allows genetic coun-
selling and sometimes prenatal diagnosis (if mutations are found
C Artefact due to difficult venesection in a nuclear gene but it is not usually possible for mtDNA defects).
C Hypoxia
C Hypotension due to sepsis Prognosis and explanation to family
C Cardiac disease Explanation and predictions regarding prognosis are difficult due
C Organic acidaemias to the rarity of these diseases, multi-system involvement,
C Fat oxidation defects unpredictability and complicated genetics. Explanation is even
C Gluconeogenesis defects harder when there is uncertainty about the diagnosis or the
C Pyruvate dehydrogenase and pyruvate carboxylase underlying genetic defect. The prognosis depends on the clinical
deficiencies presentation but even within one syndrome it is unpredictable.
C Mitochondrial disorders Patients, especially those with Leigh syndrome, tend to run
a relapsingeremitting course with periods of stability followed
by a decompensation from which there is a failure to recover to
Box 1 their previous ability and thus a stepwise decline, see Figure 3.
PAEDIATRICS AND CHILD HEALTH 21:2 82 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Follow-up Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease.
Most patients profit from seeing a specialist (in inherited metabolic Nat Rev Genet 2005; 6: 389e402.
disease or neurology) and a community paediatrician, who can liaise
with local services. The pattern of disease will guide the role of the
allied health professionals. Genetic counselling for the parents, unaf-
fected siblings and the wider family is also a key part of management.
Practice points
Funding
C Mitochondrial disease has a diverse spectrum
None. A C Phenotype and genotype do not closely correlate
C Have a low threshold for considering mitochondrial disease in
a child with multi-system pathology
FURTHER READING C Treatment is largely symptomatic
McFarland R, Taylor RW, Turnbull DM. The neurology of mitochondrial C Prognosis is difficult to predict.
disease. Lancet Neurol 2002; 1: 343e51.
PAEDIATRICS AND CHILD HEALTH 21:2 83 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Glycogen storage disease variants. Over time it has become clear that they don’t share the
same pathology and there are some conceptual differences and for
that reason many of these disorders were renamed on a few
Christian J Hendriksz
occasions causing even more confusion. With this caveat in mind
Paul Gissen it is still useful for the generalist to remember that the lower
numbered disorders do represent the more severe end of the
spectrum and generally fasting tolerance time increases as the
numbers increase. For example Glycogen storage disorder type 1 is
Abstract usually associated with severe fasting intolerance with fasting
Glycogen storage disorders are a group of inborn errors of metabolism
times as short as 45 min compared to case affected by Glycogen
characterized by accumulation of glycogen in various tissues. This accumu-
storage disease type IX who may have completely normal fasting
lation is the histological hallmark of these disorders although the pheno-
times and frequently being diagnosed by the finding of incidental
type shows variable overlap. Hepatomegaly, hypoglycaemia, elevated
hepatomegaly.
lactate and urate with or without neutrophil dysfunction are the classical
presentations for the commonest disorders namely GSD types I a, 1b
and III. Elevated creatine kinase, weakness, hypertrophic cardiomyopathy Glycogen storage disease type I
with or without rhabdomyolysis represent the commonest muscle subtypes Type I glycogen storage disease (GSD I) is the commonest most
with the best known ones being GSD II, III and V. Control of glucose defi- severe childhood form and typically presents in early infancy. First
ciency by added calories, tube feeding or modified cornstarch is frequently report of patients was by von Gierke in 1929, when he described
the main basis of treatment. Supportive therapies are needed to establish enlarged liver and kidneys containing excessive amount of
near normality. Potential curative therapies are enzyme replacement thera- glycogen seen at autopsy. GSD I is inherited as an autosomal
pies by mode of liver transplantation, bone marrow transplantation or use recessive condition and although there are no accurate estimates
of recombinant enzyme. of the incidence for GSD I, for the GSDs as a group it is approxi-
mately one in 20,000 infants.
Keywords bone marrow transplantation; cornstarch; enzyme replace-
ment therapy; GSD or glycogen storage disease; hypertrophic cardiomy- Pathophysiology
opathy; inborn error of glycogen metabolism; liver transplantation; Deficiency of hepatic glucose-6-phosphatase enzyme, which
rhabdomyolysis catalyses the final step of both gluconeogenesis and glycogen
breakdown operates inside the lumen of the endoplasmic retic-
ulum and must cross the endoplasmic membrane to be effective,
was found in the initial patients with GSD I (MIM232200). In
Introduction 1959 a subgroup of patients without the classical glucose-6-
phosphatase defect was described and later the defect in the
Glycogen storage diseases are a group of disorders characterized as transport of gucose-6-phosphate was demonstrated. Thus the
the name states by the accumulation of Glycogen in various tissues. name glycogen storage disease type Ia (GSD Ia) designates
Glycogen is a branched chain polymer of glucose and is one of the the true enzyme defect, and glycogen storage disease type Ib
dynamic sources of glucose storage in muscle and liver. This is the (GSD Ib) designates the transport defect. GSD Ic and GSD Id
natural pattern but when there is excessive storage of glycogen in disease subtypes had also been proposed caused by an abnormal
these tissues due to enzyme deficiencies it will manifest with clin- inorganic phosphate transport, however most of the described
ical symptoms and signs that is associated within these two main patients were later found to have mutations in the gene encoding
storage areas. For this reason the glycogen storage disorders are the glucose-6-phosphate translocase and therefore also belong to
frequently divided into those affecting primarily the liver and those the GSD Ib group (MIM232220).
affecting muscle. This division is clinically useful as long as it is In GSD I liver is unable to generate free glucose in response
remembered that there is some overlap and some other tissues and to neuro-endocrine stimuli caused by hypoglycemia. The
organs are also affected. defect results in an accumulation of glucose-6-phosphate that
The disorders were numbered as they were discovered and enters glycolysis, which results in increased lactate
assumed that they would be similar in their pathology and that the production.
most severe variants were discovered first followed by milder
Clinical and biochemical features
Children with of GSD I may be identified in the neonatal period with
Christian J Hendriksz MBChB MSc FRCPCH is a Consultant in Paediatric hypoglycemia and lactic acidosis but it is more common for the
Metabolic Medicine in the department of Clinical Inherited Metabolic patients to first present at 3e4 months of age with hepatomegaly
Disorders at the Birmingham Children’s Hospital NHS Foundation Trust, and/or hypoglycaemic seizures. GSD I patients typically have doll-
Steelhouse lane, Birmingham B4 6NH, UK. Conflict of interest: none. like facies (due to fat deposits in the cheeks), short stature and
protuberant abdomen due to liver enlargement although final
Paul Gissen MRCPCH PhD is a Consultant in Paediatric Metabolic Medicine height is frequently normal. Kidneys are also enlarged but there is
in the department of Clinical Inherited Metabolic Disorders at the no increase in the size of other organs.
Birmingham Children’s Hospital NHS Foundation Trust, Steelhouse The characteristic features of GSD I are fasting lactic acidosis and
lane, Birmingham B4 6NH, UK. Conflict of interest: none. short fasting tolerance, which may be less than 2 h, however the
PAEDIATRICS AND CHILD HEALTH 21:2 84 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
PAEDIATRICS AND CHILD HEALTH 21:2 85 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
early death and the later onset form with significant morbidity and
mortality. Both forms are at increased risk of death during Practice point
anaesthesia and this is particularly true for the infantile form
where arrhythmias are frequently uncovered. C Some patients with hypoclycaemia may developed muscle
Supportive therapy for infections and assisted ventilation and symptoms so consider these disorders.
wheelchair use is common in older patients. Other new treatments
are in development but not commercially available at present.
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SYMPOSIUM: INBORN ERRORS OF METABOLISM
coloured urine and as it is painless it is hardly ever offered in the Clinical and biochemical features
list of concerning features in the clinical history. The condition is This condition usually present with hepatomegaly and growth
also classically associated with second wind phenomena where retardation early in childhood. Ketotic hypoglycaemia and hyper-
the patient would start an activity and then stop due to pain but lipidaemia are usually mild, if present. Lactic acid and uric acid are
after a short period of rest is able to complete the activity. This is typically normal. The heart and skeletal muscles are not involved
also a progressive disorder so with increasing age the symptoms and the hepatomegaly improves with age and usually disappears
and signs becomes more prominent starting from muscle aches around puberty.
and pains to muscle cramps, myoglobinuria and then ultimately Although these patients have greatly diminished activity of
rhabdomyolysis and renal failure during the acute episode. phosphorylase in the liver, the number of patients with primary
Persistent weakness and increasing disability represents the full defect in phosphorylase is small whereas deficiency in phos-
blown picture in older patients. Some incidental findings may phorylase kinase activity (GSD IX) is much more common.
also lead to diagnosis and creatine kinase levels are mildly Mutation analysis of liver phosphorylase gene is available for
elevated in most cases. Electromyography may show non specific the diagnosis.
myopathic changes or increased muscle irritability.
Diagnosis is by measuring the specific enzyme deficiency in Treatment and prognosis
muscle biopsy samples or by molecular analysis. The histological A high-carbohydrate diet and frequent feeding are effective in
changes in muscle biopsy tissue may also point towards this preventing hypoglycaemia, but most patients require no specific
diagnosis and the presence of subsarcolemmal normal looking treatment and incidental finding of asymptomatic hepatomegaly
glycogen in vacuoles will alert the astute histopathologist. Vacu- is the commonest finding.
olar myopathic changes are associated with many conditions and
only by specific staining techniques can the different chemicals be Glycogen storage VII
distinguished. GSD VII also called Tarui’s disease caused by deficiency of
Differential diagnosis can be wide especially in the young where phosphofructokinase (MIM 232800) is a very rare disorder with
muscle aches and pain and elevated creatine kinase is associated about 100 cases described in the literature since first reported in
with muscular dystrophies, other glycogen storage disorders, 1965.
disorders of fatty acid metabolism and other rare disorders like
Danon’s disease. Weakness and disability in the older patients Clinical and biochemical features
share many similarities with other muscular disorders and rhab- The clinical features are a combination of exercise induced
domyolysis is associated with certain drugs or viral infections. muscle cramps, weakness and haemolytic anaemia. It is also
associated with myoglobinuria, rhabdomyolysis and growth
Treatment and prognosis delay. Cataracts, gall stones and increased uric acids have also
There is no specific treatment at present and life style modifica- been described.
tion supported by some dietary measures may be useful. Exces-
sive weight gain lowers the aerobic threshold and gentle exercise Treatment and prognosis
will have beneficial effect on this as well. There is no specific treatment and ingestion of glucose before
This disorder has a relatively benign long-term outcome as exercise can sometimes exacerbate symptoms or the so called
significant morbidity and mortality is associated with rhabdo- “out of wind phenomena”. Great clinical variability exits with
myolysis and acute multi organ failure and a rare neonatal form severe fatal neonatal form to asymptomatic late onset variants
causing respiratory failure but both these two complications are that may not be diagnosed.
rarely seen. More frequently the symptoms and loss of function
over time is controlled by ability. There is increased risk with Glycogen storage disease IX
certain anaesthetic agents and anaesthetist should be made aware Patients with GSD IX have a deficiency in phosphorylase b kinase,
of this condition and change the drugs as needed. which can be demonstrated in leukocytes and erythrocytes. These
Genetic counselling is possible in most cases and the condi- patients were initially described as GSD IV when deficient phos-
tion carriers no increased risk during pregnancy. phorylase activity was found. This condition can be inherited in an
autosomal recessive or X-linked form (initially classified as GSD-VIII).
The cause of the confusing numerical classification was due in
Practice point part to a lack of understanding of the genetics of phosphorylase
activating system. Phosphorylase kinase consists of four subunits
C When investigating fatigue always ask for history suggesting encoded by different genes on different chromosomes and
second wing phenomena. differentially expressed in different tissues.
PAEDIATRICS AND CHILD HEALTH 21:2 87 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
and mild elevation of liver transaminases. These abnormalities cells where it facilitates bilateral glucose transport. FanconieBickel
gradually disappear with age, and most adult patients are practi- disease is characterized by proximal renal tubular dysfunction,
cally asymptomatic despite a persistent phosphorylase kinase abnormal regulation of glucose homeostasis, and accumulation of
deficiency. Hypoglycemia is variable and usually is mild, if present. glycogen in liver and kidneys. Patients present in the first year of life
with failure to thrive, rickets, and a protuberant abdomen due to
Autosomal recessive GSD IX: autosomal phosphorylase kinase hepato- and renomegaly. Moon-shaped facies and fat deposition in
deficiency can be present in (1) liver-specific, (2) liver and the shoulders and abdomen are seen and puberty is delayed.
muscle and (3) muscle-specific forms (MIM261750). As with the Hypophosphataemic rickets and osteoporosis are constant features.
X-linked form, in (1) hepatomegaly and growth retardation are These patients may exhibit intestinal malabsorption and diarrheoa.
the predominant symptoms in childhood. In addition some of Laboratory findings include fasting ketotic hypoglycaemia,
these patients are hypotonic. Some cases of phosphorylase proximal renal tubular acidosis, hypophosphataemia, increased
kinase deficiency restricted to muscle have been reported and in serum alkaline phosphatase levels, and radiologic findings of
whom onset of symptoms was late (adolescence or adulthood), rickets. Liver transaminases, plasma lactate, and uric acid are
however GSD IX patients with childhood presentation of myop- usually normal. Fasting hypoglycaemia and hepatomegaly may be
athy have been described. Muscle-specific phosphorylase kinase explained by an altered glucose transport out of the liver, resulting
deficiency could be inherited in an X-linked or autosomal in an increased intracellular glucose level that inhibits glycogen
recessive manner. Establishing the diagnosis of type IX glycogen degradation, leading to the glycogen storage. Hypoglycaemia is
storage disease is challenging owing to underlying genetic exacerbated by renal loss of sugars across the basolateral
heterogeneity and variable expressivity. The deficiency of phos- membranes in the proximal tubular cells.
phorylase kinase is not consistently detectable by the erythrocyte Treatment is symptomatic paying attention to replacement of
assay, and liver, muscle, or heart biopsy is necessary to confirm water, electrolytes, and vitamin D, restriction of galactose intake.
some cases biochemically. The enzyme assay is also unable to Patients are managed with frequent small meals with cornstarch
differentiate between patients with X-linked and an autosomal supplementation and an adequate caloric intake, however,
recessive pattern of inheritance. Thus, in many instances, growth retardation persists despite interventions.
mutation analysis is needed for further sub typing of the disease.
PAEDIATRICS AND CHILD HEALTH 21:2 88 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
cramping has also been reported suggesting hepatic and muscle enzyme replacement therapy in the form of liver transplantation,
variants. bone marrow transplantation or recombinant enzyme gives the
Treatment is symptomatic and involves frequent high-protein greatest hope for those affected by severe phenotypes. A
feeds and nighttime supplementation with uncooked cornstarch.
Most children do not suffer neurocognitive damage. Short stature
may occur, but no other long-term complications seen in GSDs
FURTHER READING
have been described.
ELECTRONIC RESOURCES
Muscle glycogen synthase deficiency was reported recently in
http://emedicine.medscape.com/pediatrics_genetics#metabolic.
patients with muscle glycogen synthase gene mutations
http://www.agsd.org.uk/.
(MIM611556). Clinical features included hypertrophic cardio-
http://www.patient.co.uk/doctor/Glycogen-Storage-Disorders.htm.
myopathy and sudden cardiac arrest at the age of 10, and skeletal
muscle fatigability.
TEXTBOOKS
Chen YT. Glycogen storage diseases. In: Scriver CR, Beaudet AL, Sly WS,
eds. The metabolic and molecular bases of inherited disease. 8th Edn.
Practice point
New York, NY: McGraw-Hill, 2001: 1521e51.
Smit GPA, Rake JP, Akman HO, et al. The glycogen storage diseases and
C Postprandial hyperglycaemia is frequently missed and can
related disorders. In: Fernandes J, Saudubray JM, Berghe G, Walter JH,
point towards one of these disorders.
eds. Inborn metabolic diseases: diagnosis and treatment. New York,
NY: Springer, 2006. Chap 6.
Conclusion JOURNALS
Although the accumulation of glycogen forms the basis of most Heller S, Worona L, Consuelo A. Nutritional therapy for glycogen storage
these disorders for the clinician there are only a few important diseases. J Pediatr Gastroenterol Nutr 2008 Aug; 47(suppl 1): S15e21.
messages to take away. The combination of both muscular and Ozen H. Glycogen storage diseases: new perspectives. World J Gastro-
hepatic symptoms should make the clinicians suspect these disor- enterol 2007 May 14; 13: 2541e53.
ders. Other classical features are hypoglycaemia, increased serum Rake JP, Visser G, Labrune P, et al. European Study on Glycogen Storage
lactate and urate. Elevated creatine kinase and muscular weakness Disease Type I (ESGSD I). Guidelines for management of glycogen
with associated rhabdomyolysis are also important triggers. storage disease type I e European Study on Glycogen Storage Disease
Hypertrophic cardiomyopathy is a frequent association and post- Type I (ESGSD I). Eur J Pediatr 2002 Oct; 161(suppl 1): S112e9.
prandial hyperglycaemia is found in both GSCD 0 and GSD XI. van Adel BA, Tarnopolsky MA. Metabolic myopathies: update 2009. J Clin
Attenuated forms may present with asymptomatic hepatomegaly or Neuromuscul Dis 2009 Mar; 10: 97e121.
being diagnosed incidentally from either liver or muscle biopsy Visser G, Rake JP, Labrune P, et al. European Study on Glycogen Storage
specimens. Disease Type I. Consensus guidelines for management of glycogen
The main stay of treatment is control of hypoglycaemia and storage disease type 1b e European Study on Glycogen Storage
other associated features. Supportive treatment is important and Disease Type 1. Eur J Pediatr 2002 Oct; 161(suppl 1): S120e3.
PAEDIATRICS AND CHILD HEALTH 21:2 89 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
a review Pathology
In the normal post-absorptive state there is a fall in glucose
Elisabeth Jameson
concentration with a parallel fall in insulin. This results in a release
John H Walter of compensatory hormones and a reduction in glucose use by
muscles and peripheral tissues. Release of glucose from glycogen
(glycogenolysis) initially satisfies energy demands. However,
energy production from the oxidation of fats becomes increasingly
Abstract important both to decrease the dependency on the limited stores of
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an auto-
glycogen and to produce ketones that can be used as an alternative
somal recessive disorder of fatty acid oxidation with an incidence in the
to glucose as a fuel for the brain. This is especially important in
UK of more than 1:10,000. The majority of patients are homozygous for
young children whose cerebral glucose requirements are high and
a missense mutation c.985A>G. Newborn screening for this condition
whose physiological response to periods without enteral feeds is
was implemented nationally in England and Northern Ireland in 2009
accelerated when compared with that in adolescents and adults.
and is planned for Scotland in 2011. Patients with MCADD are at risk
The oxidation of fatty acids is shown in Figure 1. Fatty acids
during periods of fasting stress, particularly during intercurrent infections,
released from triglycerides enter the mitochondria and subse-
of developing an encephalopathy associated with hypoketotic hypogly-
quently undergo b-oxidation, a process by which the fatty acyl-CoA
caemia. These can be prevented by giving high calorie drinks (the emer-
molecule is sequentially shortened by two carbon units until it is
gency regimen) during periods of illness but hospital admission is
completely converted to acetyl-CoA. Electrons released from
required for intravenous dextrose if the emergency regimen is not toler-
b-oxidation enter the respiratory chain to produce ATP whereas the
ated. No specific treatment is required at other times. This review high-
majority of the acetyl-CoA produced is converted to ketones by the
lights the pathogenesis, the presentation and management of MCADD.
liver. Acyl-CoA dehydrogenase enzymes within this b-oxidation
cycle have activities that are chain length specific: MCAD (medium-
Keywords emergency regimen; fatty acid oxidation disorder; hypo- chain acyl-CoA dehydrogenase) has maximum activity for C6eC10
glycaemia; MCADD; medium-chain acyl-CoA dehydrogenase deficiency
fatty acids. Due to a degree of overlap in chain length specificity
other b-oxidation dehydrogenases are able to oxidise medium chain
fatty acids and produce ketones when flux through the pathway is
low. This explains why patients with MCADD are generally able to
MCADD review
tolerate overnight fasting. However during periods of increased
Definition requirements for b-oxidation there is an accumulation of medium-
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is chain fatty acyl-CoA derivatives and reduced acetyl-CoA and
an autosomal recessive disorder of mitochondrial beta oxidation ketone production resulting in clinical illness.
of medium chain length fatty acids. It is caused by mutations in
the ACADM gene. Newborn screening
Newborn screening for MCADD by tandem mass spectroscopy
Epidemiology underwent evaluation in England between 2004 and 2006 and
The disorder is panethnic but more common in Caucasians with was implemented nationally in England and Northern Ireland in
an incidence of one in 6000e10,000. 60e80% of symptomatic 2009. Screening is planned for Scotland in 2011. See ‘diagnosis’
patients are homozygous for the c.985A>G missense mutation. A section for further detail on newborn screening.
further 15e20% are compound heterozygous for c.985A>G in
combination with another mutation. The prevalence of the Clinical presentation
common mutation likely reflects a founder effect and is thought The classic presentation is of encephalopathy with hypoketotic
to have originated in northwest Europe. The genotypes in those hypoglycaemia. It is important to recognize that the child may
detected by newborn screening are more diverse suggesting that have developed an acute encephalopathy prior to the fall in blood
glucose, which can lead to diagnostic confusion. It typically
presents between the ages of 3 and 24 months when the child
Elisabeth Jameson MBBCh BSc MRCPCH is an ST7 in Paediatric Inherited experiences their first ‘fast’ associated with an intercurrent infec-
Disorders of Metabolism in the Biochemical Genetics Unit, Genetic tion (often gastroenteritis) or being placed nil by mouth prior to
Medicine, 6th Floor, St Mary’s Hospital, Oxford Road, Manchester, M13 a surgical procedure. The child will typically become increasingly
9WL, UK. Conflict of interest: none. lethargic with nausea or vomiting which rapidly progresses to
coma. Hepatomegaly and hypotonia are often present. Tests done
John H Walter MD FRCPCH is a Consultant in Paediatric Inherited at the time will show evidence of hepatocellular dysfunction,
Disorders of Metabolism in the Biochemical Genetics Unit, Genetic hypoglycaemia, hypoketosis (the presence of ketones does not
Medicine, 6th Floor, St Mary’s Hospital, Oxford Road, Manchester, M13 exclude the diagnosis) and mild-moderate hyperammonaemia. If
9WL, UK. Conflict of interest: none. the low blood sugars are not detected the child may suffer
Cytoplasm
Triglyceride stores
Mitochonrial membrane
Mitochonrion
Carnitine
Figure 1 Fatty acid oxidation. Triglycerides are mainly composed of long chain fatty acids which require transfer across the mitochondrial membrane as an
acylcarnitine. Medium chain fatty acids can cross the mitochondrial membrane directly. Within the mitochondrion fatty acids then undergo b-oxidation in
which the fatty acid molecule is sequentially shortened by two carbon units releasing acetyl-CoA. Certain enzymes involved in b-oxidation, including
MCAD, are chain length specific. Deficiency of this enzyme prevents the normal catabolism of both long and medium chain fatty acids and results in an
increase in medium chain acylcarnitines in blood, increased u-oxidation to form dicarboxylic acids, and a reduction in ketone body production.
a seizure, permanent neurological damage secondary to cerebral Where MCADD screening is undertaken the large majority of
oedema and in the worst-case scenario death. In unscreened affected infants are now detected within 2 weeks of birth.
populations up to 25% of patients with MCADD have died in their However, there are three groups of children who may still present
first episode. Sudden unexpected death in infancy (SUDI) may be symptomatically and in whom the diagnosis must be considered:
caused by undiagnosed MCADD but it is not a cause of true 1. Newborns prior to the result of the newborn screening (due
Sudden Infant Death Syndrome (SIDS); generally there is always to inadequate breast-feeding or neonatal infection), see case
a preceding illness associated with poor feeding. example below in Box 1.
Diagnosis
Newborn screening: newborn screening relies on tandem mass
Case example of early neonatal death resulting from
spectrometry to detect raised C8 (octanoylcarnitine). C8 has been
MCADD
found to be both a specific (low number of false positives) and
sensitive (low number of false negatives) marker for MCADD,
Baby 1 was born at term following an uneventful pregnancy. He
particularly if combined with measurement of the C8/C10 acyl-
was observed on the post-natal for 24 h in view of prolonged
carnitine ratio. In addition to raised C8 there is also an increased
rupture of membranes. He was discharged home the next day on
urine hexanoyl glycine. Table 1 highlights the key biochemical
breast feeds. On day 2 of life he appeared pale, though was
findings in MCADD.
feeding well. Later that day he became apnoeic and required
In the UK the newborn screening programme specifies that
resuscitation and transfer to a paediatric intensive care unit. A CT
blood should be collected on filter paper between days 5e8 of life.
head scan was consistent with hypoxic-ischaemic encephalopathy
and he remained encephalopathic. The decision to withdraw life
support was made. The cause of death was thought to be sepsis,
Biochemical findings in MCADD
however the results of a blood spot acylcarnitine analysis showed
Investigation Result a markedly increased C8 of 10.7 mmol/l. Urine organic acids
Blood sugar Normal or low showed heavy dicarboxylic aciduria with traces of abnormal
Urinary or plasma ketones Low or absent glycine conjugates but with no ketones. Mutation analysis went on
Urine organic acids Raised C6eC10 dicarboxylic acids to confirm the baby was homozygous for the common MCADD
(adipic, suberic and sebacic), mutation c.985A>G.
hexonylglycine, suberylglycine and The family’s older children will undergo mutation analysis,
phenylpropionylglycine even though their newborn screen was negative. Any future chil-
Blood acylcarnitines Raised octanoylcarnitine (C8) and dren will be treated as potential MCADD sufferers until tests
decanoylcarnitine (C10) results are back.
Table 1 Box 1
2. Children born prior to the newborn screening program. Stage 3. If the child is obviously not well, not tolerating or not
3. Children born in other countries where screening does not taking drinks or the family are worried contact or go to the hospital.
take place.
Stage 4. If the child is not tolerating or taking the emergency
Symptomatic: a child, who presents with a blood sugar less than drinks then the child will need intravenous 10% dextrose/0.45%
2.6 mmol/l, should undergo a number of investigations at the time saline. Try to re-establish normal diet within 48 h.
of the hypoglycaemia (Table 2). However this may not always be Intravenous fluids with 10% dextrose/0.45% saline must also
achieved. Characteristic abnormalities in the urine organic acids be used if the child is nil by mouth prior to a surgical procedure.
may be transient so that samples collected when patients have
recovered from an episode may not be diagnostic. Blood octa- Long term management: throughout life the emphasis is to
noylcarnitine, however, is always increased in MCADD. prevent fasting. UK recommendations for the maximum age related
fasting time are given in Table 3. MCADD is not a contraindication
Differential diagnosis to breast-feeding but bottle top-ups may be needed particularly in
The differential diagnosis includes those disorders that cause the first few days after birth. Formulas made with medium chain
encephalopathy and hypoglycaemia. Hypoketosis is associated triglycerides are contraindicated. Weaning can be commenced at
with other inherited disorders of fatty acid oxidation and with the usual time of 6 months under the guidance of a dietician. Once
hyperinsulinism. A significant ketosis is a feature of the majority toddler age is reached the child needs to have three meals a day and
of other causes. A careful clinical history and the investigations a bedtime snack. Missed meals should be replaced with a starchy
listed in Table 2 will usually confirm the correct diagnosis. snack or sugary drink. A normal diet should be encouraged as the
child grows but with inclusion of regular starchy foods. It is
Management important that the child’s school is aware of his/her disorder and is
Acute illness: it is important to emphasize that a child with able to recognize symptoms that might be related to MCADD. Once
MCADD may become seriously unwell before the blood sugar the child reaches adolescence the issue of excess alcohol should be
falls and it is imperative to treat early. All children with MCADD addressed in view of the risk of hypoglycaemia secondary to inhi-
should have an emergency regimen for use at times of illness. bition of gluconeogenesis. Individuals with MCADD are at poten-
The aim of the emergency regimen is to provide a source of tial risk from their disorder throughout life and should remain
energy and thus prevent hypoglycaemia. The emergency regimen under review when they reach adulthood.
consists of drinks usually of soluble glucose polymer (e.g. Max-
ijul or Polycal) though some families use alternatives in discus- Siblings of MCADD patients: since MCADD is an autosomal
sion with a specialist dietician. recessive condition, new siblings have a one in four risk of being
The principles of management of an unwell child with affected. A summary of the guidelines for their initial manage-
MCADD are given below, further detail can be found on the ment after birth, provided by BIMDG, is as follows:
‘British Inherited Metabolic Disease Group’ (BIMDG) website Investigations should be undertaken between 24 and 48 h of
including emergency regimes; see http://www.bimdg.org.uk/. age with blood spot acylcarnitines, urine organic acids and
DNA mutation analysis. Cord blood is not suitable because of
Stage 1. If the child is not their usual self or may be at risk of the risk of maternal contamination.
illness (for example post-immunization) give regular oral drinks A term baby should be fed every 4 h and a preterm every 3 h.
and reassess in 2e4 h. If the child is better when re-assessed then Potential problems associated with breast-fed babies are diffi-
they go back to their normal diet, if unwell then go to stage 2. culties in quantifying the amount of breast milk taken and the
low supply of breast milk in the first 72 h. These babies may
Stage 2. Regular drinks of the emergency regime to be given day need formula top-ups. If there are any concerns at all the baby
and night as per the child’s individual regime. This treatment should be transferred to the neonatal unit for blood sugar
should continue until the child improves. If the child does not monitoring with appropriate management, i.e. formula feeds
improve go to stage 3. or intravenous 10% dextrose. These measures should continue
until acylcarnitine and urine organic acid results are known.
Older siblings of patients detected by newborn screening, who
Investigations to be taken at the time of hypoglycaemia were born before screening was started or born in countries
Blood Urine
Glucose Ketones Recommended fasting times for children with MCADD
Acylcarnitines Organic acids when well
Free fatty acids and 3(OH) butyrate Reducing substances
Amino acids Age of child Maximum safe fasting time (h)
Ammonia 0e4 months 6
Lactate From 4 months 8
Growth hormone, cortisol, thyroid function, From 8 months 10
insulin, C-peptide From 12 months onwards 12
Table 2 Table 3
Box 2
FURTHER READING
without screening for MCADD should also be investigated. Occa- British Inherited Metabolic Disease Group. Available at: http://www.
sionally parents have also been found to be affected demonstrating bimdg.org.uk.
that survival into adulthood without severe illness is possible. Clarke JTR. A clinical guide to inherited metabolic disease. Cambridge:
Cambridge University Press, 2007.
Prognosis and explanation e Box 2 highlights the process UK newborn screening programme centre. Available at: http://www.
following diagnosis by newborn screening and Box 3 the key points to newbornbloodspot.screening.nhs.uk.
Box 3
PAEDIATRICS AND CHILD HEALTH 21:2 94 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Diabetes mellitus
Type 1 and type 2 diabetes mellitus are both associated with an
Figure 2 LDL-receptor synthesis and recycling. The LDL-receptor is
synthesized and trafficked to the cell surface ready to bind ApoB on LDL. increased lifetime risk of cardiovascular disease. However, well-
Once bound, the LDL/LDL-receptor complex is internalized and fusion with controlled type 1 diabetes mellitus is not typically associated
a lysosome occurs. This releases the LDL and digests it, resulting in free with significant dyslipidaemia. The obesity epidemic has driven
cholesterol efflux and recycling of the receptor back to the surface. the rate of development of type 2 diabetes mellitus, with
Mutations resulting in FH can occur at numerous points along this increasing numbers of cases diagnosed in childhood. Type 2
pathway, all resulting in inadequate clearance of LDL from the circulation. diabetes mellitus is often associated with characteristic lipid
abnormalities, typically an increase in total cholesterol and
It is important to note that when cholesterol is measured by triglycerides and a reduction in HDL-C. There is currently no
a clinical laboratory, it is derived from all the lipoproteins evidence to support lipid-lowering therapy for the vast majority
mentioned above. HDL cholesterol measurements isolate the of children with diabetes mellitus. However, given the increased
cholesterol specifically from this fraction, but LDL cholesterol lifetime cardiovascular risk attributable to the disease, treatment
concentration is often a calculated estimate based on an should be considered particularly when there are multiple risk
assumption of the ratio of triglyceride to cholesterol in VLDL. factors present, such as obesity, smoking and hypertension.
This may not always be applicable, for example when chylomi-
crons are present in the non-fasted state, or where IDL is the Thyroid disease
predominant non-HDL/non-LDL fraction. Untreated hypothyroidism may be associated with increased total
Cholesterol concentrations also vary with age. In children and LDL cholesterol. This is probably due to decreased receptor-
they show a slight rise until age 10e11, and then dip during mediated LDL catabolism. Treatment of the hypothyroidism
puberty before rising to adult levels. A steady rise then occurs almost invariably results in resolution of hypercholesterolaemia.
throughout adulthood. Use of statins in untreated hypothyroidism is associated with an
increased risk of myopathy.
Cardiovascular risk in children
Renal disease
The assessment of global cardiovascular risk is well established Nephrotic syndrome is associated with increased total and LDL-C
in adults. Calculation of cardiovascular risk is commonly used to and to a lesser extent reduction in HDL-C. The degree of dysli-
target therapies for primary prevention. Several tools may be pidaemia appears to be inversely related to the serum albumin
used, many of which use data from the Framingham study,
a long term ongoing study of cardiovascular risk. These take into
account variables such as total cholesterol, HDL-C, age and
systolic blood pressure. The output from such risk factor calcu- Laboratory investigations for the assessment of
lators is usually expressed as percentage risk of developing hyperlipidaemia
cardiovascular disease over a 10-year period. There is limited
data to support the use of these tools in paediatric practice and Investigation
the cardiovascular risk of a child over the next 10 years will Total cholesterol, LDL-C, HDL-C, triglycerides
always be low due to the influence of young age. Post-mortem Renal function and urine dipstick
studies, such as the PDAY (Pathobiological Determinants of Bilirubin, albumin, ALP, ALT or AST
Atherosclerosis in Youth) study demonstrate that atherosclerosis, Fasting plasma glucose
with the formation of fatty streaks, begins in childhood, and Thyroid function test
calculation of lifetime cardiovascular risk may therefore be more
LDL-C ¼ low-density lipoprotein cholesterol; HDL-C ¼ high-density lipopro-
applicable in the paediatric population. However, such calcula-
tein cholesterol; ALP ¼ alkaline phosphatase; ALT ¼ alanine aminotrans-
tors for children are not yet in widespread use. The American ferase; AST ¼ aspartate aminotransferase.
Academy of Paediatrics therefore recommends assessment of
lipid status in overweight and obese children, and in those with Table 1
PAEDIATRICS AND CHILD HEALTH 21:2 95 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
FH ¼ familial hypercholesterolaemia; LDL-C ¼ low-density lipoprotein cholesterol; LDL-R ¼ low-density lipoprotein cholesterol receptor; PCSK9 ¼ proprotein conver-
tase subtilisin kexin type 9.
Table 2
PAEDIATRICS AND CHILD HEALTH 21:2 96 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
valve and coronary arteries. Florid physical signs are often Familial combined hyperlipidaemia
present, such as tendon and subcutaneous xanthomata. Familial Combined Hyperlipidaemia (FCHL) is an important
disorder, but is much less clearly defined than FH. It is likely that
Diagnosis of familial hypercholesterolaemia: the diagnosis of several genes are responsible and lifestyle factors may also be
FH involves a personal and family history, physical examination, important. Typically the total and LDL-C are elevated as well as
measuring total and low-density lipoprotein cholesterol (LDL-C) serum triglycerides, although there does seem to be significant
in serum and the use of DNA diagnostics. In the UK the Simon heterogeneity in the lipid profiles of families with FCHL. The
Broome criteria (Table 2) are used as they were developed using abnormal lipid profile probably occurs due to overproduction of
a UK population and are straightforward to employ in the clinic. VLDL.
However all clinical diagnostic criteria lack specificity and
sensitivity, particularly in less severe presentations when Hypertriglyceridaemia
cholesterol concentrations may not reach the diagnostic thresh- Hypertriglyceridaemia may be seen in childhood, usually due to
olds. This is a particular issue in children and younger people a precipitating factor in a susceptible individual (see Secondary
due to the variation of cholesterol concentrations with age, and causes of hyperlipidaemia). Genetic forms also exist, such as
diagnostic physical stigmata, particularly tendon xanthomata, the rare familial lipoprotein lipase deficiency, which may result
are often absent in children. For these reasons there is an in severe hypertriglyceridaemia. Presentation with this disorder
increasing role for a DNA diagnosis in suspected FH in paediatric may be with eruptive xanthomata or acute abdominal pain,
practice. which may be recurrent. Acute pancreatitis may occur when the
triglycerides exceed 10e15 mmol/l, and may occasionally exceed
Genetics of familial hypercholesterolaemia: FH is most 100 mmol/l. In childhood this results from the failure to clear
commonly caused by mutations in the LDL-receptor gene, with chylomicrons, although in the teenage and adult years VLDL may
a smaller number of cases due to mutations in the Apo B-100 and also accumulate. Treatment for a primary hypertriglyceridaemia
PCSK9 genes. There is a higher risk of CHD in individuals with an thus focuses on restriction of fat intake.
LDL-R mutation, compared to those who are mutation negative.
Mutations may be indentified in up to 90% of individuals with Treatment
‘definite’ FH (with tendon xanthomata) and genetic testing in
Lifestyle interventions
patients with ‘possible’ FH can help clarify the diagnosis. Current
Lifestyle therapies are an important component in the treatment
National Institute for Health and Clinical Excellence Clinical
of hyperlipidaemia and involve avoidance of smoking and die-
Guidelines support early identification of FH in children from age
tary and exercise interventions. Such interventions are important
10 years and a DNA diagnosis can provide conclusive evidence of
for general long-term cardiovascular health and the prevention
a diagnosis to parents and their doctors. However, the absence of
and treatment of obesity. Lifestyle intervention alone is usually
a detectable DNA mutation does not exclude the diagnosis of FH
not effective for the prevention of cardiovascular disease in
and an individual with a clinical diagnosis of FH who does not
inherited dyslipidaemias. The role of nutritional supplements,
have a demonstrable DNA mutation should still be considered at
containing plant stanols and sterols is not clear in children, but
high risk and treated accordingly.
beneficial effects appear to be similar to those seen in adults.
Cascade testing for familial hypercholesterolaemia: in the UK
it is estimated that 85% of the estimated 120,000 people who are Drug therapy
affected by FH have not been diagnosed. Cascade testing is the Statins: they are the most commonly used class of drugs used to treat
preferred strategy for identifying these individuals. The most hyperlipidaemia in both children and adults. They work through
efficient and cost effective approach is to use DNA testing for inhibiting the rate determining step of the cholesterol biosynthesis,
those families with a known mutation or cholesterol testing in HMG-CoA reductase, and effectively reduce total and LDL choles-
those families in whom a mutation cannot be found. Cascade terol. They have limited effects upon triglyceride and HDL-C
testing commenced across Wales in 2010 with extension to the metabolism. There are few randomized placebo controlled trials of
rest of UK anticipated in the next few years. One consequence of statins in paediatric FH, but a wealth of data has confirmed the
this approach is that there will be an increase in the number of beneficial effects of statins in the reduction of cardiovascular
children and young people identified with FH who will need mortality and morbidity in non-FH adults. There are no outcome
advice and treatment. studies in children and most have used surrogate markers, such as
measures of endothelial function and carotid intima media thick-
Polygenic hypercholesterolaemia ness. These have indicated an improvement in surrogate markers
Polygenic hypercholesterolaemia is much more common than FH. with statins in the FH population. Previous concerns that statins may
An increase in total cholesterol and LDL-C is seen, but clinically the not be safe in children appear to be unfounded, as data now confirm
differentiation from FH may not be clear. DNA testing can be that statins do not have detrimental effects upon growth and
particularly helpful in this situation. The genetics of this condition development and are generally well tolerated. Therapy should be
are not as well understood as for FH. Several genes are likely to be considered in an individual child based upon LDL-C concentrations
important as well as lifestyle factors, such as obesity and poor diet. and the age of onset of cardiovascular disease in family members.
Polygenic hypercholesterolaemia is more commonly identified in Treatment with a statin should be considered in FH from the age of
adults and the risk of premature CHD is much lower than for FH 10. In the UK currently Atorvastatin is licensed in children over the
with a documented DNA mutation. age of 10 years up to a dose of 20 mg per day and Pravastatin is
PAEDIATRICS AND CHILD HEALTH 21:2 97 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
licensed at a dose of 10e20 mg per day in children aged 8e14 years Daniels SR. Greer FR and the Committee on Nutrition. Lipid screening and
and up to 40 mg in older children. cardiovascular health in childhood. Pediatrics 2008; 122: 198e208.
Datta BN, McDowell IFW, Rees JAE. Integrating provision of specialist lipid
Other drug therapy: Ezetemibe decreases intestinal absorption services with cascade testing for familial hypercholesterolaemia. Curr
of cholesterol and may be used in children. Its main use is in Opin Lipidol 2010; 21: 366e71.
combination therapy with statins, in particular for children with Durrington PN. Hyperlipidaemia diagnosis and management. 3rd Edn.
homozygous FH. It can also be used in monotherapy, for instance London: Hodder Arnold, 2007.
if statin therapy is not tolerated. National Institute for Health and Clinical Excellence. Clinical guidelines
Fibrates reduce hepatic triglyceride production and peripheral and evidence review for familial hypercholesterolaemia: the identifi-
lipolysis and have been used in children. Their main use is in the cation and management of adults with familial hypercholesterolaemia.
treatment of hypertriglyceridaemia and they have a limited effect Clinical Guidelines 71; 2008.
in reducing LDL-C. Pathobiological Determinants of Atherosclerosis in Youth Research Group.
Bile acid sequestrants and nicotinic acid are also licensed for Relationship of atherosclerosis in young men to serum lipoprotein
use in hyperlipidaemia, but are not widely used in children. cholesterol concentrations and smoking. JAMA 1990; 264: 3018e24.
Umans-Eckenhausen MAW, Defesche JC, Sijbrands EJG, Scheerder RLJM,
LDL apheresis Kastelein JJP. Review of first 5 years of screening for familial hyper-
LDL apheresis is a treatment similar to renal dialysis. Patients cholesterolaemia in the Netherlands. Lancet 2001; 357: 165e8.
usually attend fortnightly. LDL cholesterol is removed from the Wierzbicki AS, Viljoen A. Hyperlipidaemia in paediatric patients. The role
patient and absorbed onto a specific LDL absorption column and of lipid-lowering therapy in clinical practice. Drug Saf 2010; 33:
blood then returned to the patient. This invasive procedure 115e25.
effectively reduces LDL cholesterol in conjunction with drug
therapy and its use should be considered in all children with
homozygous FH.
PAEDIATRICS AND CHILD HEALTH 21:2 98 Ó 2010 Elsevier Ltd. All rights reserved.
SELF-ASSESSMENT
Self-assessment
Questions
ALT 49 U/litre (1e50)
Case 1 GGT 38 U/litre (0e78)
A 10-day-old baby girl was admitted with poor feeding, leth- Protein 50 g/litre (60e80)
argy and weight loss (Wt 3.01 kg; Birth wt 3.42 kg). She was Albumin 35 g/litre (35e50)
born at term, breast fed initially but formula fed from day 3.
PT 30.1 s (11.4e14.3)
She was apyrexial, warm and well perfused but jaundiced.
APTT 82.3 s (25.2e33.5)
Respiratory rate was 36/min and respiratory system exami-
Fibrinogen 1.4 g/litre (1.9e4.3)
nation was normal. Abdominal examination revealed soft
abdomen with a 3 cm liver edge palpable and cardiovascular CSF microscopy Negative for infection
examination revealed the presence of a systolic murmur, but CSF glucose 2.2 mmol/litre
no other abnormal findings. The peripheral pulses as well as CSF protein 1.2 g/litre
oxygen saturations were normal in all 4 limbs.
Venous gas pH 7.38, pO2 4.3 kPa, pCO2 6.0 kPa,
BE e5.1 mmol/litre
Glucose 3.4 mmol/litre
Lactate 1.0 mmol/litre
Blood results Ammonia 61 umol/litre (11.2e35.4)
Hb 16.4 g/dL (12.1e16.3)
WCC 10109/litre (5e19.5)
Neutrophils 0.7109/litre (2e9) 1. Which among the following is the most important
Lymphocytes 7.7109/litre (3.5e8.5) diagnosis to consider in this baby? Choose ONE answer
Platelet count 153109/litre (150e400) a) Neonatal sepsis
Na 133 mmol/litre (133e146) b) Metabolic illness
K 5.2 mmol/litre (3.5e5.3) c) Congenital cardiac disease
Urea 2.4 mmol/litre (2.5e7.8) d) Insufficient milk intake
Creatinine 38 mmol/litre (0e39) She was commenced on IV broad spectrum antibiotics
CRP <5 mg/litre (<5) (Benzylpenicillin and Gentamicin, later changed to Cefo-
taxime) and acyclovir (added to cover potential viral
Total bilirubin 379 mmol/litre (1e17)
infection). She was kept on 60 ml/kg/day of IV fluids (and
Direct bilirubin 38 mmol/litre (0e8)
small amounts of bottle feeds).
ALP 1028 U/litre (60e350)
At 48 h, the blood culture grew E. coli but CSF culture was
reported negative. Coagulopathy improved with adminis-
tration of fresh frozen plasma and vitamin K.
She completed 14 days of IV antibiotics, and tolerated
Ranjana Kanekal MB ChB is a Foundation year 2 Trainee in the feeds well once the formula was changed. She improved
Department of Paediatrics at James Cook University Hospital, with the above management and underwent further inves-
Middlesbrough, UK. tigations which identified the diagnosis.
Case 3
A healthy term baby girl was born with a large birth mark
involving the right side of her face. This was deep red in
colour, macular and involving the eyelid, cheek & forehead.
Newborn examination was normal.
She remained well until 5 months of age when she first
presented with seizures. Her seizures involved the left side
of the face & limbs, initially starting with facial twitching
movements, progressing to have tonic clonic movements
which started with left upper limb and subsequently
involved all four limbs. The duration and frequency
of seizures were variable with as many as five seizures in
a 24-h period.
PAEDIATRICS AND CHILD HEALTH 21:2 100 Ó 2010 Published by Elsevier Ltd.
SELF-ASSESSMENT
2. b) Galactosaemia
Classical galactosaemia is an autosomal recessive
disorder of galactose metabolism caused by the deficiency
of Gal 1 PUT enzyme, with an incidence of 1/23e44,000.
Majority presents in neonatal period after ingestion of
galactose (derived from lactose in milk), with poor feeding
& feed intolerance, jaundice, hepatosplenomegaly, hepato-
cellular insufficiency, hypoglycaemia, muscle hypotonia,
cataracts and sepsis. E coli sepsis is seen more frequently in
Figure 2 these babies.
Mitochondrial diseases have variable presentations with
2. What does the above MRI scan show (Figure 2)? Choose
some conditions presenting early with significant metabolic
ONE answer
acidosis, collapse and sudden infant death. Many present later
a) Normal scan
with hypotonia, developmental delay and neurological prob-
b) Vascular malformation on the right side
lems. Neonatal haemochromatosis is a fatal, progressive
c) Decreased in size & calcifications in the right
illness which often presents within the first few days of life,
hemisphere
characterized by hepatomegaly, hypoglycemia, coagulopathy
d) Right MCA territory infarction
(refractory to Vitamin K therapy) hypoalbuminaemia, hyper-
3. What are the associated complications commonly seen ferritinaemia and hyperbilirubinaemia. Lysosomal storage
with this condition? Choose ONE answer disorders (e.g. Gaucher’s) present later in infancy with hepato-
a) Learning difficulties splenomegaly, psychomotor retardation and evidence of bone
b) Glaucoma marrow infiltration. Fructose intolerance can present with
c) Cutaneous vascular malformations very similar clinical features following introduction of fruits
d) Intracranial & ophthalmic tubers and fruit juices. Age at presentation, absence of metabolic
e) Renal involvement acidosis and coagulopathy which responded to treatment
4. What are the most important management strategies in makes the above diagnoses less likely.
this condition? Choose THREE answers
3. a) Galactose 1 phosphate uridyl transferase (Gal-1-PUT)
a) Anti-epileptic medication
Gal-1-PUT is the enzyme that is deficient in
b) Hemispherectomy
galactosaemia.
c) Regular ophthalmology review & intraocular pressure
In view of the neonatal liver disease, coagulopathy and
monitoring
E. coli sepsis, this baby was investigated for Gal-1-PUT
d) Physiotherapy
deficiency by measuring the enzyme activity in erythrocytes
e) Laser treatment of the facial lesion
(Patient <0.5; Normal: 18e28) and a diagnosis of classical
f) Occupational therapy
galactosemia was made. This was later confirmed with
g) Long term antibiotics
DNA mutation analysis.
h) Oral anticoagulants
Classical galactosaemia is part of newborn screening
i) Regular monitoring of renal function
programmes of many countries.
j) All of the above
4. a,d,e) Regular paediatric follow-up, annual ophthal-
Answers
mology review, lactose free diet
Case 1 Successful management of galactosaemia requires
1. a) Sepsis appropriate dietary input. A galactose-restricted diet is
In a neonate presenting in this manner, three main advised. Lactose free milk (e.g. Wysoy) is advised in
diagnoses must be considered e sepsis, congenital cardiac neonatal period. After this, lactose-free diet without
diseases and metabolic illnesses. Deranged coagulation and restriction of galactose containing fruits and vegetables is
PAEDIATRICS AND CHILD HEALTH 21:2 101 Ó 2010 Published by Elsevier Ltd.
SELF-ASSESSMENT
FURTHER READING
Balasubramanian S, Ganesh R. Vitamin D deficiency in exclusively
breast-fed infants. Ind J Med Res 2008; 127: 250e255.
Singh J, Moghal N, Pearce SHS, Cheetham TD. The investigation of
hypocalcaemia and rickets. Arch Dis Child Health 2003; 88:
403e407.
Case 3
1. a) SturgeeWeber syndrome
The presence of facial capillary haemangioma involving
the ophthalmic & maxillary branch distribution of trigem-
inal nerve, and focal onset of seizures with secondary
generalization points towards this diagnosis.
SturgeeWeber syndrome is the association of angiomas of
the leptomeninges and facial skin. Many children develop
seizures, developmental delay and glaucoma. Seizures often
develop in the 1st year of life, due to associated angiomas
involving the ipsilateral cerebral hemisphere. They are typi-
cally focal tonic-clonic, contralateral to the side of facial nae-
vus. There is associated shrinkage and neuronal cell loss of the
affected hemisphere. Hemiparesis and hemiplegia can occur,
which, along with recurrent seizures can lead to develop-
Figure 3 mental delay and disability.
PAEDIATRICS AND CHILD HEALTH 21:2 102 Ó 2010 Published by Elsevier Ltd.
SELF-ASSESSMENT
2. c) Decreased size & calcifications in the right hemisphere 4. a,c,e) Anti-epileptic medication, regular ophthalmology
The ipsilateral hemisphere shows marked decrease in review & intra-ocular pressure monitoring, laser treat-
size and evidence of calcification. Isolated MCA territory ment for the facial lesion
infarction is unlikely to cause this degree of shrinking & Management depends on the severity of symptoms.
calcification of the hemisphere. Intracranial vascular mal- Physiotherapy and occupational therapy may be required if
formations leads to the presence of dilated blood vessels indicated. It is important to explain the diagnosis and
(may have evidence of haemorrhage), which is not the most prognosis to the parents and review the child regularly.
prominent feature in this image. Seizures can be difficult to manage and may require inser-
tion of vagal nerve stimulator or even surgical management
(hemispherectomy).
3. b) Glaucoma
Glaucoma of the ipsilateral eye is a common association
in SturgeeWeber syndrome. Other associations include FURTHER READING
learning difficulties, hemiplegia and protracted seizures Nowak CB. The phacomatoses: dermatologic clues to neurologic
leading to disability. anomalies. Semin Paediatr Neurol 2007; 14: 140e149.
PAEDIATRICS AND CHILD HEALTH 21:2 103 Ó 2010 Published by Elsevier Ltd.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
presenting acutely*
iting, developmental delay and episodes of drowsiness particularly
in the morning. Patients presenting with a severe acute encepha-
lopathy particularly may have had previous episodes, commonly
J V Leonard much milder precipitated by intercurrent infections or fasting.
A A M Morris
Family history
Where there is a clear history of an affected sibling (more distant
relative in the case of X-linked disorders) or highly consanguin-
Abstract eous families, these leads must be followed up carefully. There
Inborn errors of metabolism are individually rare but so many have now been may be a history of undiagnosed death or unexplained illness
described that the general paediatrician will encounter one from time to that may provide useful clues. Consanguinity, although relevant,
time. For many, early treatment is important. Unfortunately most present only increases the risk of an autosomal recessive disorder by
with non-specific symptoms and signs. It is therefore necessary to identify a modest percentage.
and investigate those at high risk. The most common problems are neurolog-
ical (including coma, seizures and stroke-like episodes), hypoglycaemia,
disorders of acidebase regulation, cardiomyopathy and acute liver disease. Modes of presentation
Treatment should be started as soon as an inborn error is suspected. Although inborn errors may present in many different ways and at
almost any age, the common presentations can be simplified into
Keywords acute liver failure; ataxia; cardiomyopathy; catabolism; five categories: (1) neurological presentation including acute
encephalopathy; hyperammonaemia; hypoglycaemia; metabolic acidosis; encephalopathy, seizures, stroke-like illness and acute ataxia, (2)
respiratory alkalosis; seizures; stroke-like illness hypoglycaemia, (3) disorders of acidebase regulation, (4)
cardiomyopathy and cardiac arrhythmias and (5) acute liver
disease. Metabolic disorders may also present at or soon after birth
with a number of different problems that include ascites/hydrops,
Introduction dysmorphic syndromes, seizures and severe hypotonia. Lists of
Inborn errors of metabolism are generally rare, although some the causes of these problems can be found in Leonard and Morris
disorders are more common in genetically isolated populations. (2006).
Many inherited metabolic conditions are now well recognized and
they may present at almost any age from the newborn period into Neurological presentation
adult life. Many disorders are now treatable and it is important to Acute encephalopathy: a common presentation of inborn errors is
recognize the underlying disorder at the earliest possible stage to an acute encephalopathy but there are very many causes of such an
prevent permanent damage. Unfortunately however for most illness. An acute metabolic encephalopathy may be very variable
disorders the early symptoms and signs are not specific so it is ranging from mild to severe. Typically the symptoms are of gradual
necessary to try to identify those at high risk of having a metabolic onset, unless the patient has a convulsion. The early symptoms are
disorder. often drowsiness, lethargy, altered behaviour and unsteady gait.
These symptoms may fluctuate and then often somewhat unex-
* pectedly the patients may deteriorate, becoming comatose. Treat-
This chapter is a short introduction and cannot cover all situa-
ment is urgent and basic metabolic investigations should always be
tions. If in doubt, consult your local specialist metabolic centre.
Detailed and free instructions on the management of acute illness of done in any patient with an undiagnosed encephalopathy. An
individual inborn errors of metabolism can be found on the British episode may be precipitated by infection and fever but evidence of
Inherited Metabolic Disease Group (BIMDG) website http://www. these does not exclude the metabolic disorder.
bimdg.org.uk/. The causes of metabolic encephalopathy and the investiga-
tions that are necessary to identify the majority of metabolic
J V Leonard PhD FRCP FRCPCH is a Former Professor of Paediatric Metabolic disorders are summarized in Table 1.
Disease at the UCL Institute of Child Health, and Consultant Paedia-
trician at Great Ormond Street Children’s Hospital, London, UK. Seizures: those disorders that may present with seizures with the
Conflicts of interest: none. investigations are listed in Table 2.
A A M Morris PhD FRCPCH is a Consultant in Paediatric Metabolic Medi- Stroke-like episodes: the most common metabolic causes of
cine at the Department of Genetic Medicine, St Mary’s Hospital, Oxford stroke-like episodes with the appropriate investigations are listed
Road, Manchester M13 9WL, UK. Conflicts of interest: none. in Table 3.
PAEDIATRICS AND CHILD HEALTH 21:2 51 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Causes of acute metabolic encephalopathy Metabolic disorders that may present with seizures
Hyperammonaemia Table 2
Plasma ammonia should be measured in every undiagnosed
encephalopathic patient since early intervention is essential.
However the interpretation of results can be problematic. Reference
values are less than 50 mmol/l but any difficulty with the ven- Metabolic disorders that may present with a stroke-like
epuncture, including a child struggling or a haemolyzed sample, illness
may increase the plasma ammonia concentration. Encephalopathic
patients usually have values >100 mmol/l although in the newborn Causes Investigations
in the threshold usually taken to be 200 mmol/l. However it must be Homocystinuria Plasma amino acids and
emphasized that the interpretation of plasma ammonia concentra- total homocysteine
tions requires careful assessment of the conditions under which the Organic acidaemias Urine organic acids
blood was collected as well as the effect of any treatment of such as Ornithine transcarbamylase Plasma ammonia
intravenous glucose. deficiency
The metabolic causes of hyperammonaemia and investiga- Mitochondrial disorders Blood mitochondrial
tions are listed in Table 5. (e.g. MELAS) DNA mutations
Congenital disorders of Serum transferrin
Disorders of acidebase regulation glycosylation isoelectric focussing
Metabolic acidosis: metabolic acidosis is a common complication Fabry disease Enzyme tests
of almost any illness and is usually secondary to tissue hypoxia.
However, if the history suggests previous episodes, there is marked Table 3
PAEDIATRICS AND CHILD HEALTH 21:2 52 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Causes of hypoglycaemia and investigations The major causes of and investigations for metabolic
(taken during hypoglycaemia) acidosis
Table 5 Table 7
PAEDIATRICS AND CHILD HEALTH 21:2 53 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
Table 8
blood glucose should always be measured in the laboratory. It
should then be corrected, either orally or intravenously, depend-
Sudden collapse ing on the patient’s condition. If corrected with intravenous
Patients with inborn errors may collapse suddenly. Patients with glucose, give 2 ml glucose 10%/kg followed by the infusion of
neurological problems including coma, those with hypoglycaemia 10% glucose approximately equal to the normal glucose utiliza-
and liver disease may all have a seizure. They may also develop tion rate (children 4e7 mg/kg/min; adults 2 mg/kg/min). Blood
cerebral oedema with consequent herniation. Patients with clot- glucose concentrations should be reviewed after approximately
ting abnormalities may have a cerebral haemorrhage. 15e30 min.
Patients with the metabolic acidosis may be able to compensate
with increased respiratory effort for a time but when they can no Metabolic acidosis: the blood pH must be monitored carefully.
longer maintain this, they may collapse. It is important to anticipate Peripheral perfusion, dehydration and infection should be corrected
this and, if necessary, start assisted ventilation at an early stage. first and appropriate steps taken if the blood pH is critical despite
Patients with cardiac disease may develop arrhythmias. assisted ventilation. A convenient cut off is pH of <7.1 (or greater
than this if the patient is clearly deteriorating). This situation is not
Management the same as diabetic ketoacidosis, as the acidosis will not respond to
insulin quickly. Hence sodium bicarbonate should be given as a half
The management of these patients is divided into two sections;
correction ((base deficit weight (kg) 0.3)/2). The sodium
firstly the management of acute illness and secondly the preven-
tion of such illness in the first place. All patients who are at risk of
decompensation should have a plan that starts at home to try to Disorders that may respond to pharmacological doses
prevent episodes of decompensation. of vitamins or cofactors
Acute illness Disorder Vitamin
After resuscitation and stabilization it is important to document Methylmalonic acidaemia Hydroxocobalamin
the clinical state. For patients with neurological illness, the Glas- Biotinidase deficiency Biotin
gow coma score should be noted. Efforts should be made to Holocarboxylase synthetase Biotin
identify the factor that has precipitated the illness such as infection deficiency
or fasting. This is not always possible as sometimes patients Homocystinuria Pyridoxine
become ill for reasons that are not clear. Pyridoxine dependency, Pyridoxine, pyridoxal phosphate
The steps that should be taken in the treatment of acute illness PNPO deficiency
are listed in Table 9, together with notes about each stage of the Vitamin deficiency, MSUD, Thiamine
process. Pyruvate dehydrogenase
Some inborn errors will improve markedly if given pharma- deficiency and others
cological doses of cofactor of the defective enzyme. The most (all rare)
important disorders that may respond are listed in Table 10. Carnitine Carnitine transporter deficiency
Riboflavin Multiple acyl-CoA dehydrogenase def
Special problems: hypoglycaemia: it is important to document and occasionally others
hypoglycaemia correctly. Bedside strip tests only give approxi-
mate value despite the apparent accuracy of the metres so that Table 10
PAEDIATRICS AND CHILD HEALTH 21:2 54 Ó 2010 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INBORN ERRORS OF METABOLISM
bicarbonate should be administered slowly and reviewed early symptoms. The factors that commonly precipitate decom-
frequently. The plasma electrolytes must also be monitored. Hae- pensation include fasting and infection. The earliest symptoms
modialysis should be considered if the plasma sodium starts to rise are usually just not feeling well, anorexia, vomiting, ataxia or, in
or if the acidosis is not controlled. some conditions, hyperventilation. Each patient is different and it
is important to identify the earliest symptoms and discuss these
Hyperammonaemia: the treatment of hyperammonaemic with the family.
encephalopathy is urgent. The same steps are followed as those for The family should have clear instructions of exactly what to do
the general patient. In addition arginine, sodium benzoate and and when to make decisions. Almost invariably the mainstay of the
sodium phenylbutyrate should be given early if these are available treatment at home is a high carbohydrate drink given frequently
and the patient transferred to a specialist centre as quickly as including during the night. The family should always carry details
possible. of their condition and the acute management. A laminated A5 sheet
has been found to be very acceptable. More details of the emergency
Cerebral oedema: it cannot be stressed too strongly that early regimens can be found in Dixon and Leonard (1992).
intervention is essential to prevent cerebral oedema as, once Anaesthesia and surgery may also cause problems. If the patient
established, it is difficult to reverse. It is commonly the cause of is due to have an elective procedure with an anaesthetic then this
death in these patients. The management once oedema is estab- requires careful planning (for more information please refer to the
lished is standard. protocols on the BIMDG website). It is essential to ensure that a high
calorie intake is given throughout and after the procedure to avoid
Catabolism: acute decompensation in patients with inborn errors the triggering decompensation.
is often precipitated by infection or fasting and triggering catabo-
lism. Every effort should be made to reverse this. A high energy Conclusions
intake is given either orally or intravenously. More calories can be
Inborn errors that present acutely are often treatable and delay
given more quickly orally which is the preferred route if at all
will worsen the outcome. It is important to have a simple strategy
possible. However if the patient cannot tolerate oral feeding,
for identifying patients at high risk. Treatment does not need to
glucose should be given intravenously, if necessary by central line.
wait for a diagnosis but can start at once. Every effort should be
Protein should always be introduced fairly early since failure to do
made to prevent or reduce episodes of decompensation. A
so will prolong the catabolic state.
PAEDIATRICS AND CHILD HEALTH 21:2 55 Ó 2010 Elsevier Ltd. All rights reserved.