DISORDERS OF AROMATIC AMINO ACIDS

Disorder
Phenylketonuria

Deficiency
Phenylalanine hydroxlase
(Classical)
Tetrahydrobiopterin (BH4)new variant

Description
Disorder of aromatic amino
acid metabolism due to a
deficiency in the activity of the
liver enzyme, which catalyzes
the conversion of
phenylalanine to tyrosine.
Phenylalanine and its products
accumulate causing an
imbalance resulting to
neurologic, dermatologic and
behavioral symptoms
Autosomal recessive

Pathogenesis

2 out of 87,005 neonates were detected

using newborn screening (local data)

Prognosis
Rarely seen because of early detection and
subsequent therapy
Mental deficiency is prevented when
treatment is initiated before 2 months of life
The rule here is you have to continue
restriction in the diet because in the long
term outcome, patient would again
deteriorate in cognitive function

Clinical Features

Diagnosis

Management

1. Mentally retarded
- If not detected earlier
- Seen in 90% patients
- Occurs in 99% of untreated patients; 50
points loss from IQ if untreated.
- Can be prevented if treatment is
initiated before 2 months of life
2. Stunted
- Generally short but weight is normal for
age
3. Light skinned, light colored hair (blond)
many are fair skinned
4. Musty smelling (due to accumulation of
phenylacetate)
5. Eczematoid rash or intractable itching
6. Behavioural disorders hyperactivity,
rhythmic purposeless movements,
stereotypy, tremors and athetosis are
common

Newborn screening by method of

Guthrie or by fluorometric
methods
A positive newborn screen result
warrants repeat Confirmatory
Testing:

Dietary
restriction
of
phenylalanine intake
Continuous phenylalanine
restricted diet
Plasma phenylalanine is
maintained at 150-600
umol per Liter
Phenylalanine free milk
formulas are commercially
available

Other Manifestations:
Cerebral palsy quadrispastic
- Spastic hypertonic cerebral palsy occurs
in 30%, seizures in 20% and EEG
abnormalities in 80% of pts.

Quantitative phenylalanine and

tyrosine levels in the blood
- Classic PKU is confirmed by:
a. Phenylalanine levels > 1200
umol/L
b. low tyrosine level
Ferric Chloride Test
-- Another useful diagnostic test
- Urine is tested with 10% ferric
chloride o Positive result: green
precipitate formed
in the presence of phenyl pyruvic
acid
Residual Phenylalanine
hydroxylase
- in the liver tissue activity of less
than 10% through an assay

Abnormal movements (stereotypy)

Tyrosinemia

Fumaryl Acetoacetate
Hydrolase

Alkaptonuria

Homogentisic Acid Oxidase

Hawkinsinuria

4-Alphahydroxyphenylpyruvate
hydroxylase deficiency

-last step in the degradation of

tyrosine
-fumaryl acetoacetate builds
up
- Autosomal recessive
Relatively benign inborn error of
phenylalanine -tyrosine
catabolism
Homogentisic acid accumulates
AUTOSOMAL RECESSIVE

AUTOSOMAL DOMINANT

-CABBAGE ODOR URINE

(TYSON CHICKEN, TYROSINEMIA)

inborn error of tyrosine metabolism; excretion

of the unusual cyclic amino acid metabolite,
hawkinsin
Deficiency in enzyme that catalyses the
conversion of hydroxyphenylpyruvate to
homogentisate

Discoloration of cartilage and connective

tissues
Ochronoticpigments (ochronosis)
-Often leads to severe arthritis
-Due to oxidation of excess metabolite
May lead to severe arthritis later in life

Darkening of urine on standing

Inidividuals with this disorder are

symptomatic only during infancy. Symptoms
usually appear after weaning from
breastfeeding with the introduction of a
high-protein diet.

characteristic tyrosine metabolites

by organic acid analysis of the urine

Dietary restriction of Phe&

Tyrosine may reduce
deposition of
homogentisicacid

DISORDERS OF BRANCHED CHAIN AMINO ACID

MSUD

branched-chain
alpha ketoacid
dehydrogensae
complex

Dr. Cavans Lec:

MSUD: Manifestations

First symptoms in an infant at

about 3-5 days

Poor appetite/feeding

Irritability or high pitched

incessant crying

Characteristic odor of urine

After a few days, the baby:
becomes limp with episodes of
rigidity
has seizures
loses his/her sucking reflex
has increased sleeping
become comatose
MSUD: Management - rapid
removal of toxic substances
Temporary removal of CHON
from diet/ low protein using a
special formula
Ensure that baby hascalories
from other sources
Add VCO (medium chain) to
diet for long term mgt
MSUD: management -long term
maintain low levels of
dangerous amino acids - LOW
PROTEIN DIET
balance between growth
needs dietary intake
branched chain amino acids
minimal needs
Artificial formula of the other
essential amino acids
provision of vitamins and
minerals
regular monitoring of blood
and acid levels
regular monitoring of growth and
development

MetylMalonic Aciduria

methylmalonylCoA
mutase deficiency

AUTOSOMAL RECESSIVE

Five Clinical phenotypes:

Accumulation of 3 branched chain ketoacids

o Alpha ketoisocaproic acid
o Alpha ketoisovaleric acid
o Alpha keto B methylvaleric acid
o Derivatives of leucine, valine, isoleucine
(leucine causes more severe neurologic
symptoms)
Accumulation of BCAA ad 2-hydroxy acids in the
plasma, urine, CSF
Leucine and 2-oxoisocaproic acid are the most
toxic to the brain
Brain injury is due to neurotransmitter deficiency
and growth restriction associated with branched
chain amino acid accumulation and energy
deprivation through Krebs cycle disruption
Manifestations
Normal newborn who initially does well for a
few days and suddenly on days 5-7 develops
lethargy and high pitched cry, feeds poorly, and
becomes opisthotonic and comatose
Seizure and hypoglycaemia are also common

Classic MSUD
a characteristic sweet odor resembling
burnt sugar (maple syrup) can be
detected in the patients urine , sweat,
hair and cerumen
Birth: newborns appear healthy
Overwhelming illness in the first few
days of life. Lethargy, quickly
progressing to convulsions and coma, is
a common manifestation.
5th -7th day: develop lethargy, feeding
difficulty and hypotonia after ingestion
of protein
2nd week: seizures because of cerebral
edema
Within 1 month: coma and death
Intermittent MSUD
Milder manifestation compared to
classic form
Patients are generally well but become
really sick when they are under stress
such as in infection or surgery
Intermediate MSUD
Seen in patients whose enzyme activity
is about 15-25% of normal
Symptoms are milder than the classic
form

Plasma amino acid analysis elevated branched amino

acids (leucine, isoleucine and
valine)
Urine Organic Analysis
increased levels of branched
chain keto-acids
Definitive
diagnosis:
measuring the activity of
BCKD enzyme of fibroblast,
leukocyte or amniotic fluid
levels
o Classic forms have 02% residual enzyme
activity
Presumptive
Diagnosis:
presence
of
2,4
dinitrophenylhydrazine
(DNPH) which precipitates the
keto-acids in the urine
forming a yellow precipitate
Diagnosis
measurement/ detection of
BCAA in urine or plasma
NBS using TMS
Activity of the BCKD enzyme
DNA testing for the known
genes

Neonatal ketoacidosis, lethargy,

vomiting and profound hypotonia, and
profound metabolic acidosis

Chronic Management
o Restriction of intake
of BCAA to levels
necessary for growth
For Classic MSUD
o Special diet MSUD
powder
o Restriction
of
proteins are vital
For Milder Forms
o Protein limitation of
1-1.5 g per kg per
day
Trial of high dose thiamine
(B1) is recommended (10100 mg per day)

Thiamine responsive MSUD

Same clinical features as intermediate
MSUD
Biochemical abnormality maybe
corrected with the intake of high doses
of thiamine

The success of therapy is

largely dependent on strict
adherence to the diet and
prevention of metabolic
crises

E-3 Deficient MSUD

Patient present with lactic acidosis
Symptomatology may parallel that of
classic MSUD or may show a more rapid
neurologic deterioration
defects in the metabolic pathway
where methylmalonyl-coenzyme A (CoA) is
converted into succinyl-CoA by the

Removal of toxic
metabolites and restoring
the mental alertness and
capacity of the patient
o Peritoneal
dialysis
and hemodialysis are
efficient
o Adequate
calories
should be provided
o A small amount of
protein is necessary
to help lower the
levels of branched
chain amino acids
(BCAA)

Frequent measurement of
plasma BCAA
Increased amount of
methylmalonic acid and
metabolites of PA

Correction of acidosis
and prevention of further
catabolism

enzymemethylmalonyl-CoA mutase
Vitamin B12 is also needed for the conversion of
methylmalonyl-CoA to Succinyl-CoA. Mutations
leading to defects in vitamin B12 metabolism or
in its transport frequently result in the
development of methylmalonic acidemia.
Isovaleric Acidemia

Glutaric Aciduria

isovaleryl CoA
dehydrogenase

Glutaryl-CoA
dehydrogenase

AUTOSOMAL RECESSIVE

AUTOSOMAL RECESSIVE

First week of life after onset of protein

feeding
Defect in methylmalonyl CoA mutase
Hematologic: Anemia, leukopenia and
thrombocytopenia
Renal Failure in the second decade

The deficient enzyme plays an essential role in

breaking down proteins from the diet.
Specifically, the enzyme is responsible for the
third step in processing leucine, an essential
amino acid.
If a mutation in the IVD gene reduces or
eliminates the activity of this enzyme, the body
is unable to break down leucine properly.
As a result, isovaleric acid and related
compounds build up to toxic levels, damaging
the brain and nervous system.

Stale perspiration, sweaty feet or ripe

cheese odor
First week: acidosis, coma
Infants who survive acute phase will go
on to have the chronic intermittent form
later on in life.
Chronic: lethargy, vomiting, ataxia and
ketoacidosis
Death may occur if proper therapy is not
initiated.

body is unable to break down completely

the amino acids lysine, hydroxylysine
and tryptophan.
Excessive levels of their intermediate
breakdown products (glutaric acid, glutarylCoA, 3-hydroxyglutaric acid, glutaconic acid) can
accumulate and cause damage to the brain and
other organs, but particularly the basal ganglia,
which are regions that help regulate movement
GA1 causes secondary carnitine deficiency,
as glutaric acid, like other organic acids, is
detoxified by carnitine. Mental retardation may
also occur

Neurodegenerative after the first year

of life
Hypotonia, dystonia, choreoathetosis
and seizures
Resemble extrapyramidal cerebral
palsy
Macrocephaly, loss of appetite, profuse
sweating and hypoglycemia

Molecular testing

Mass spectrometry: screening of

urine of newborns-> early
diagnosis
Elevations of isovalerylglycine in
urine and of isovalerylcarnitine in
plasma are found

Acrid urine

Restriction of isoleucine,
methionine, valine and
threonine (medical food
available)
Trial of Vitamin B12
Growth Hormone tried in
suboptimal growth

Low protein
L-carnitine
Glycine and carnitine

DISORDERS OF UREA CYCLE ENZYMES

Urea Cycle Defects

5 BiochemicalReactions and
catalyzed by a different enzyme
1. Carbamyl
palmytoyl
synthetase deficiency (CPS)
2. Ornithine transcarbamylase
deficiency (OTC)
3. Arginosuccinate synthetase
deficiency (Citrullinemia)
4. Arginosuccinase defieciency
(arginosuccinic aniduria)
5. Arginase (Ornithemia)

Prognosis
92% 1 year survival rate
The IQ however is severely
affected
The duration of coma
correlates with the severity
of mental deficiency
Patients who remain in
hyperammonemic coma
beyond 5 days are more
developmentally
handicapped

All are Autosomal recessive

inheritance (except OTC
deficiency which is X-linked
recessive)

Clinical Manifestations
In the neonatal period, signs and symptoms are mostly related to brain
dysfunction, and are similar regardless of cause of hyperammonemia
Patients do well in the immediate postnatal period until 2-4 days of life when
regular milk intake is established
Become sick and deteriorate fast unless therapy is instituted
Progressive lethargy, apnea, and/or seizures
Hyperammonemia without metabolic acidosis can trigger increased
intracranial pressure that may be manifested by bulging fontanel and dilated
pupils
In patients with partial enzyme deficiencies, the presentation is episodic and
occurs beyond the neonatal period
Unexplained vomiting, intermittent headaches, behavioural changes or acute
encephalopathy
Due to ammonia intoxication
After 1st day of delivery and even before initiation of protein feeding:
o Progressive lethargy
o Vomiting
o Hypotonia

Subsequent days:
o progressive loss of consciousness
o Seizures

Presentation is episodic and patients in partial enzyme deficiency

Occurs late in infancy, childhood and adulthood

The oldest reported patient with partial OTC deficiency was 58 years old

Unexplained or cyclic vomiting, intermittent headache, behavioral changes and

acute encephalopathy

Suspect in a newborn with hypermmonemia without organic acidemia

Clinical presentation and

presence
of
hyperammonemia
Specific plasma amino acid
and urine organic acid profiles
Plasma
ammonia
concentration of 150 mmol
per Liter or higher
Associated with a normal
anion gap Vs Organic aciduria
abnormal anion gap
Normal
serum
glucose
concentration
Definitive Diagnosis: enzyme
activity assay done on liver
tissue (Liver Biopsy)

Removal of ammonia by
peritoneal dialysis or
hemodialysis
Reduce
the
plasma
ammonia concentration
by limiting nitrogen intake
to 1.2 to 2 gram per
kilogram per day and
using essential amino
acids for protein
Allowing
alternative
pathway excretion of
excess nitrogen with
sodium benzoate and
phenylacetic acid
Reduce the amount of
nitrogen in the diet
Reduce
catabolism
through introduction of
calories
supplied
by
carbohydrates and fats
Reduce the risk of
neurological
complications

DISORDERS OF FATTY ACID OXIDATION

Fatty Acid Oxidation Defects

3 clinical presentations:
1. Hepatic presentation
- Uric acid
- Liver enzymes dehydrogenase
(MCAD) deficiency
- Characterized by acute life
threatening attacks of coma
precipitated by fasting
- Anion gap and acidosis may be
present
- Biochemical abnormalities:
a. Hypoketotic hypoglycemia
b. Hyperammonemia
c. Elevations in serum urea, uric
acid and liver enzymes

Diagnosis
Urinary organic acid analysis
- C6-C10 dicarboxylic
acids and absence of
ketosis
Definitive diagnosis:
Measurement
of
specific enzyme activity
in liver tissue

Treatment of FAO
During
infancy,
prevention
of
hypoglycemia is vital
to survival
Frequent feeding to
avoid fasting
With age, other
alternative metabolic
pathways are
activated to provide
for fuel to meet the
bodys requirements
Carnitine in cases of
secondary carnitine
deficiency states
Riboflavin
in

2. Symptoms referable to the muscles

- Carnitine palmitoyl-transferase II
deficiency
- Sudden muscle weakness in young
adults associated with
myoglobinuria and renal failure
following strenuous exercise

megadoses

3. Cardiac manifestations
- Patients present with
progressive heart failure
between ages 2-3 years
- Cardiomyopathy may
accompany acute hepatic
syndrome
- Exemplified by the muscle-kidney
plasma membrane carnitine
transporter defect
DISORDERS OF SULFUR CONTAINING AMINO ACIDS
Homocystinuria

cystathionine beta synthase

deficiency

Autosomal recessive
Homocystinuria represents a
group of hereditary metabolic
disorders characterized by an
accumulation of the amino
acidhomocysteine in
the serum and an increased
excretion of homocysteine in
the urine. Infants appear to
be normal and early
symptoms, if any are present,
are vague.

Pathogenesis
primary defect defect is in the
enzyme cystathionine B
synthetase which catalyzes the
formation of cystathionine from
homocysteine and serine
Accumulation of homocysteine
and other cysteine
homocysteine residues causes
symptoms referable to the
connective tissue and vascular
systems.

Clinical Manifestations
Developmental delay and mental
retardation between 18-24 months
Eye problems: glaucoma, cataracts,
optic atrophy, myopia or astigmatism
Bony Changes: spinal osteoporosis and
pectus excavatum
Malar flush
Vascular
systems:
Arteriovenous
thromboembolism phenomenon is
common and usual cause of death
stroke-like symptoms, later onset

This defect leads to a multisystemic disorder of

the connective
tissue, muscles, central nervous
system (CNS), and cardiovascular
system.

Diagnosis
Cyanide nitroprusside test
o Used to screen the urine
o A red purple color develops
in
the
presence
of
homocysteine
Plasma amino acid analysis
used to document the elevated
homocysteine and methionine
levels
Enzyme activity can be measured
in the fibroblast, liver and brain
tissue
Newborn screening: elevated
blood methionine as marker for
the disorder

Trial of high dose

pyridoxine (100-500 mg
per day) - standard
Dietary restriction of
methionine
in
the
neonatal period
Folate(1-15 mg per day)
adjunct therapy
Betaine (6mg per day) for unresponsive to
pyridoxine
Methyl donor and will
convert homocysteine to
methionine
Aspirin and dipyridamole
decreased platelet
adhesiveness; prevent
thromboembolic
phenomenon

Prenatal diagnosis available by

assay of cystathione synthase in
amniocytes

DISORDERS INVOLVING DEGRADATION PATHWAYS

Mucopolysacchridoses

Autosomal recessive trait

except for Hunter syndrome
(MPS II) which is x-linked
recessive

abnormal accumulation of
glycosaminoglycans (GAG) or
mucopolysaccharides (MPS)
secondary to a basic defect in their
sequential degradation in

Hurler syndrome: (MPS IH) from

deficiency of alpha-L-iduronidase
prototype of MPS rapidly deteriorating
look physically normal at birth but
th
develops course features by the 18

Indirect way of screening:

o Look for presence of
dyostosis multiplex
o Long bones of the
upper extremities look

No effective therapy
Supportive
measures: surgical
fusion
of
the
cervical spine to

lysosomes
GAG are major components of
connective tissue mainly in
cartilage, bone, skin, tendon,
cornea, heart valves, less in liver
and brain
GAG are polymeric carbohydrates
composed of more than a single
type of building block: a
carbohydrate backbone with
amino acid or sulfate residues

month of life: large bulging

scaphocephalic head with frontal
bossing, hypertelorism (increased orbital
distance), depressed nasal bridge, wide
nostrils, large tongue, and thickened lips.
Patients are hirsute. Clouding of cornea
is characteristic. Nystagmus and
strabismus occur later. Deafness is
common. Spine is kyphotic with lumbar
gibbus. Rib cage is broad. Cardiac
valvular disease leads to CHF, angina
pectoris and MI.

o
o

short and stubby with

tapering ends and
enlarged middle shaft
portions
Indirect
way
of
screening:
skeletal
survey radiographs
Look for the presence of
dyostosis multiplex
Large skull with a Jshaped sella turcica and
shallow orbits
Confirmatory:
Specific enzyme assays
on
fibroblasts
or
leukocytes

prevent spinal cord

compression
Osteotomies
Hearing
aids
are
useful