Inborn errors of metabolism

I Gusti Lanang Sidiartha

Divisi Nutrisi dan Penyakit Metabolik
FK UNUD – RSUP Sanglah
 Dr. Archibald Edward Garrod
The Royal College of Physician in London, 1908.
Kakak adik penderita Phenylketonuria
(PKU)
 Introduction and pathophysiology
• Single gene defect causes blocking in a metabolic pathway
and resulting either accumulation of substrate behind the
block or deficiency of the product.

• All IEMs genetically transmitted in an autosomal recessive or

X-linked recessive
Lanpher et al. Nature Reviews Genetics 7, 449–459 (June 2006) | doi:10.1038/nrg1880
PROTEIN GLYCOGEN FAT

FRUCTOSE
AMINO ACIDS GALACTOSE

GLUCOSE FREE FATTY ACIDS

ORGANIC ACIDS

AMMONIA

PYRUVATE LACTATE

ACETYL CoA
UREA CYCLE

KETONES
UREA KREBS CYCLE

NADH ATP

An integrated view of the metabolic pathways

 Incidence of IEMs
Class No. of disorders Incidence
known

Critical, life threatening disorders of infancy 70-80 1 : 5000

Serious disorders compromising health in >300 1 : 1000
infant/adult
Common disorders of any age >300 1 : 50
 Suggestive IEMs…..
• Every child with unexplained …..
• Neurological deterioration
• Metabolic acidosis
• Hypoglycemia
• Inappropriate ketosis
• Hypotonic
• Cardiomyopathy
• Hepatocellular dysfunction
• Failure to thrive
….. should be suspected of having a metabolic
disorder
 Clinical symptomatology of IEMs
• Symptoms indicating possibility of an IEMs:
• Infant becomes acutely ill after period of normal behavior and feeding; this may occur
within hours or weeks
• Neonate or infant with seizures and/or hypotonic, especially if seizures are intractable
• Neonate or infant with an unusual odor

• Symptoms indicating strong possibility of an IEMs, particularly when

coupled with the above symptoms:
• Persistent or recurrent vomiting
• Failure to thrive
• Apnea or respiratory distress (tachypnea)
• Jaundice or hepatomegaly
• Lethargy
• Coma (particularly intermittent)
• Unexplained hemorrhage
• Family history of neonatal death, or similar illness, especially in sibling
• Parental consanguinity
• sepsis
 Major categories of IEMs
Disorders of:
• Organic acids
• Fatty acids
• Amino acids
• Carbohydrates
• Lysosomal and peroxisomal function
 Major categories of IEMs
• Organic acidemias:
• Methylmalonic or propionic acidemia, multiple carboxylase
deficiency
• Abnormal metabolism of CH, protein and fats
• Marked metabolic acidosis, ketosis, elevated lactate,, mild to
moderate hyperammonemia
• Signs: vomiting, encephalopathy, neutropenia, thrombocytopenia.
 Organic Acids
Anabolic Catabolic
ATP

propionic methylmalonic
Isoleucine acidemia acidemia
Valine
biotin B12
Methionine
Propionyl CoA Methylmalonyl CoA Succinyl CoA
Cholesterol
Odd chain fatty Bicarb is used to buffer the
acids propionic acid, leading to
increased anion gap Krebs
Cycle
isovaleric
acidemia
leucine Isovaleryl CoA 3MCC HMG CoA Acetyl CoA

ETS
Even chain fatty acids

Lysine glutaric ATP

acidemia Acetyl
Tryptophan Glutaryl CoA Crotonyl CoA CoA

Organic acids are the intermediates in the catabolism

of amino acids, lipids and other compounds; specific
enzyme deficiencies lead to characteristic urine organic
acid profiles
• Fatty acid oxidation defects = beta-oxidation
defects
• Short, medium, and long-chain acyl-CoA
dehydrogenase deficiencies
• Hypoketotic hypoglicemia, hyperammonemia,
cardiomyopathy
• MCAD is the most common
 Diagnosis of fatty acid oxidation disorders
by acylcarnitine analysis
Long chain Fatty
fatty acid acid Detected by
acylcarnitine
MCAD
Fatty acyl-CoA analysis
deficiency
Fatty acyl-carnitine

(C6-C12) (C6-C12)
Free + fatty acyl Fatty acyl-carnitine
carnitine CoAs
Fatty acyl-carnitine
acetyl
CoA
Fatty acyl-CoA
SCAD
18 16 14 12 8 6 4
MCAD ketones

Mitochondrion
Plasma Cytoplasm
 Fatty acid oxidation
Brain
CPT1/CPT2

Fatty VLCAD LCHAD MCAD SCAD

ketones
acids +
fasting acetyl CoA
*key pathway for
adaptation to fasting Krebs
cycle

•Distinguishing feature of FAOD is

hypoketotic hypoglycemia
•Medium chain acyl CoA dehydrogenase
deficiency(MCAD) is most common and
has a 25% risk of death with first episode
•LCHAD, VLCAD and carnitine uptake
disorder are variably associated with,
hepatomegaly, liver disease, hypertrophic
cardiomyopathy and potential
arrythmias
•All are autosomal recessive
• Primary lactic acidosis
• Pyruvate dehydrogenase, pyruvate carboxylase and
cytochrome oxidase deficiencies
• Severe lactic acidosis

• Aminoacidopathies
• Phenylketonuria, tyrosinemia, nonketotic hyperglicemia,
maple syrup urine disease, homocystinuria
• Similar presentation to the organic acidemia
• Bleeding diathesis or fanconi syndrome (tyrosinemia);
feeding difficulties, lethargy, coma, seizure (MSUD).
• Urea cycle defects
• Citrullinemia, ornithine transcarbamylase deficiency, arginino
succinic aciduria
• Inability to detoxify nitrogen
• Severe hyperammonemia
• Respiratory alkalosis
• Typical onset after 24 hours of age

• Disorder of carbohydrate metabolism

• Galactosemia, hereditary fructose intolerance, fructose 1,6-
diphosphatase deficiency and glycogen storage disease
• Inability to metabolize specific sugars, aberrant glycogen synthesis,
disorder of gluconeogenesis
• Hypoglycemia, hepatosplenomegaly, lactic acidosis or ketosis
 Urea Cycle Disorders
DIET
Protein NH4+ + HCO3 Carbamoyl
Phosphate

Hyperammonemia
without metabolic
acidosis (usually have OTC
Ornithine
respiratory alkalosis) Citrulline
UREA
Urea cycle disorders:
•Ornithine Arginine CYCLE Asp
transcarbamylase
deficiency (X-linked) (N)
•Carbamoyl phosphate
urea(2N)
synthase deficiency (AR) Argininosuccinic
•Citrullinemia (AR) Acid
•Argininosuccinic acidemia
(AR)
•Argininemia (AR)
OTC deficiency is the
most common and is X-
linked
• Lysosomal storage disorders
• Mucopolysaccaridosis, Tay-sachs, Nieman-Pick disease, Gaucher’s
disease
• Accumulation of glycoproteins, glycolipids, or glycosaminoglycans
within lysosomes.
• Organomegaly, facial coarseness and neurodegeneration.

• Peroxisomal disorders
• Zellweger syndrome, neonatal adrenoleukodystrophy
• Zellweger: large fontanel, organomegaly, down like facies, seizure,
chondrodysplasia punctata
• Steroidogenesis: congenital adrenal hyperplasia or smith-lemli-
opitz
• Disorder of metal metabolism: menkes syndrome, neonatal
hemochromatosis.
Clinical finding: suggestive of an IEMs
• History:
• consanguinity, mental retardation, SIDS
• Symptom onset with institution of feeding or formula change
• Growth disturbance, lethargy, recurrent emesis, poor feeding,
rashes, seizures, hiccoughs, apnea, tachypnea
• Physical findings
• Tachypnea, apnea, lethargy, hyper tonicity, hypotonicity,
hepatosplenomegaly, ambiguous genetalia, jaundice, dysmorphic,
coarse facial, rashes or patchy hypopigmentation, cataract, lens
dislocation, pigmentary retinopathy, unusual odors.
• Laboratory findings
• Metabolic acidosis with increase anion gap, primary respiratory
alkalosis, hyperammonemia, hypoglycemia, ketosis or ketonuria,
low BUN, hyperbilirubinemia, lactic acidosis, elevated livr function
test, neutropenia, thrombocytopnemia
Initial approach
• Rule out non-metabolic causes of symptoms such
as infection or asphyxia

• Laboratory assessment prior to therapy:

– Blood: glucose, CBC with diff, pH, paCO2, electrolyte
for anion gap, LFT, bilirubin, PT, PTT, uric acid,
ammonia, lactate.
– Urine: color, odor, pH, glucose, ketones, ferric chloride
reaction (for MSUD, PKU, dll),
– CSF: glycine for nonketotic hyperglycemia, lactate
Initial management
• Hydration/nutrition/acid-base management:
• Rehydrate infant
• Stop all oral intake to eliminate protein, galactose and
fructose for 48-72 hours
• Give glucose iv at 8-10 mg/kg/min: normal glucose level
(insulin if needed)
• Treat acidosis (pH < 7,22) with continuous infusion of
NaHCO3

• Elimination of toxic metabolites:

• Treatment of hyperammonemia is urgent
• Using antidotum or hemodialysis
• Treatment of coexisting/precipitating factors:
• Infection, thrombocytopenia

• Cofactor replacement:
• Vitamin-responsive form of propionic acidemia, beta-
methylcrotonyl deficiency, holocarboxylase synthetase
deficiency, and biotinidase deficiency: biotin 5 mg daily, oral
or parenteral
• Vitamin-responsive methylmalonic acidemia: vitamin B12 1
mgdaily, im
• Vitamin-responsive maple syrup urine disease: thiamine 50
mg daily, oral
Post-mortem
• It is important to make a specific diagnosis, even
in a dying child, to help parents understand and
next reproductive planning.
• Specimens:
• Blood (frozen plasma)
• Urine, refrigerated
• Spinal fluid, refrigerated
• Sterile skin biopsy (fibroblast culture), 1-2 hours after death.
• Liver, skeletal muscle, cardiac muscle, brain kidney
• If there are dysmorphic features, consider a full skeletal
radiological series
 ….. message …..
“Waiting until sepsis and other more common
causes of illness are ruled out before initiating a
specific diagnostic evaluation is inadvisable, as is
indiscriminate study of all ill newborns for
metabolic disorders”
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