Approach to inborn errors of metabolism

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Also known as biochemical diseases, inherited metabolic disorders are mostly single gene disorders that affect one of the biochemical processes of the body.  Most are rare but some are common, for example phenylketonuria (PKU) occurs 1 in 12,000 births (1).  Every year in British Columbia, two to three children are born with PKU (2).  By detecting PKU or other biochemical diseases early, neonatal disease, mental retardation, and mental illness can be prevented.

Until recently the following diseases were detected by the newborn screening program in BC: congenital hypothyroidism, PKU, galactosemia, and medium chain acyl-CoA dehydrogenase deficiency (3).  However, now with the availability of tandem mass spectrometry, it has become possible to screen for up to 30 additional treatable metabolic diseases (4).

Current diseases screened for can be seen at:

Basic anatomy and physiology

Mostly inherited as autosomal recessive traits, biochemical diseases are due to an enzyme or transport protein defect.  This leads to a deficiency and/or a build-up of metabolites. Either the deficiency of essential products or the inability to eliminate precursors is directly responsible for disease manifestations.

Classes of metabolism diseases

Metabolic diseases can be categorized according to the different nutritional components in which the abbarrent metabolism may be found:


  • Amino acid metabolism (examples are phenylketonuria and maple syrup urine disease). There is aberrant synthesis or breakdown of amino acids. (Screened for with panels of urine organic acids and serum amino acids.)
  • Urea cycle disorders. There is an enzyme deficiency resulting in aberrant degradation of nitrogen compounds. (Screened for with serum ammonia level.)


  • Disorders of Carbohydrate metabolism
    • Glycogen storage diseases
  • Storage diseases
    • Lysosomal storage diseases
    • Peroxisomal disorders


  • Disorders of Fatty Acid metabolism – Mitochondrial disorders (example is Medium Chain Acyl Dehydrogenase deficiency)

Trace elements

  • Metal metabolism disorders (Hemochromatosis, Wilson’s disease)


Fetal development for neonates with inborn errors of metabolism may have been normal, provided that the metabolites are able to cross the placenta and may be metabolized by the mother for the fetus. Often therefore the neonate may be asymptomatic, and may only become symptomatic after the initiation of feeds or with intercurrent illness / long periods of fasting.

Although the clinical picture may vary, infants with metabolic disorders typically present with lethargy, decreased feeding, vomiting, tachypnea (from acidosis), decreased perfusion, and seizures (6).

Toddlers and preschool-aged children present with stagnation or loss of cognitive milestones; loss of expressive language skills; progressive deficits in attention, focus, and concentration; and other behavioral changes. Other non-specific indicators may be developmental regression, growth retardation and seizures. Multiple stillbirths or early childhood deaths on family history may also be suggestive.

Specific disorders are suggested by signs as listed below:

symptom/signs biochemical disease
vomiting and acidosis after starting on breast milk or formula amino acid or carbohydrate metabolism
unusual odor of urine or sweat (e.g. burnt sugar smell) e.g. maple syrup urine disease
hepatosplenomegaly accumulation of metabolites within the cells of liver and spleen
mental retardation due to 1) brain atrophy due to harmful circulating metabolites such as PKU or 2) enlarged brain due to inability to metabolize intracellular substances
severe acidosis with high anion gap abnormal metabolites of amino acid and organic acid metabolism
hyperammonemia urea cycle and organic acid disorders


Initial workup when an inborn error of metabolism is suspected usually includes electrolytes, glucose, lactate, serum ammonia, serum amino acids and urine organic acids. Based on these results and after consulting metabolic diseases specialists, further investigations may be sought. These may include CSF analyzed for the metabolite in question.

Approach to treatment

Treatment is obviously dependent on the disorder suspected. General principles however are:

1) Removal of toxic compounds – hemodialysis, hemovenovenous filtration, chelators, and compounds that serve as ammonia trapping agents

2) Enhancement of the activity of the deficient enzyme

3) Decreasing the flux through the deficient pathway by restricting precursors in the diet. If an inborn error of metabolism is suspected in a neonate they should be kept NPO but given IV fluids containing dextrose so as to keep the infant anabolic.

Examples of Inborn Errors of Metabolism by Disorder (7)




Metabolic error

Key manifestation

Key laboratory test

Therapy approach

Amino acid metabolism
Phenylketonuria 1:15,000 Autosomal recessive Phenylalanine hydroxylase (> 98 percent)Biopterin metabolic defects (< 2 percent) Mental retardation, acquired microcephaly Plasma phenylalanine concentration Diet low in phenylalanine hydroxylase
Maple syrup urine disease 1:150,000(1:1,000 in Mennonites) Autosomal recessive Branched-chain a-keto acid dehydro-
Acute encephal-
opathy, metabolic acidosis, mental retardation
Plasma amino acids and urine organic acidsDinitrophenyl-
hydrazine for ketones
Restriction of dietary branched-chain amino acids
Carbohydrate metabolism
Galactosemia 1:40,000 Autosomal recessive Galactose 1-phosphate uridyltransferase (most common); galactokinase; epimerase Hepatocellular dysfunction, cataracts Enzyme assays, galactose and galactose 1-phosphate assay, molecular assay Lactose-free diet
Glycogen storage disease,
type Ia (von Gierke’s disease)
1:100,000 Autosomal recessive Glucose-6-
Hypoglycemia, lactic acidosis, ketosis Liver biopsy enzyme assay Corn starch and continuous overnight feeds
Fatty acid oxidation
Medium-chain acyl-CoA dehydrogenase deficiency 1:15,000 Autosomal recessive Medium-chain acyl-CoA dehydrogenase Nonketotic hypoglycemia, acute encephal-
opathy, coma, sudden infant death
Urine organic acids, acylcarnitines, gene test Avoid hypoglycemia,
avoid fasting
Lactic acidemia
Pyruvate dehydrogenase
1:200,000 X-linked E1 subunit defect most common Hypotonia, psychomotor retardation, failure to thrive, seizures, lactic acidosis Plasma lactateSkin fibroblast culture for enzyme assay Correct acidosis; high-fat,
low-carbohydrate diet
Lysosomal storage
Gaucher’s disease 1:60,000; type 1-1:900 in
Ashkenazi Jews
Autosomal recessive b-glucocere-
Coarse facial features, hepatospleno-
Leukocyte b-glucocere-
brosidase assay
Enzyme therapy, bone
marrow transplant
Fabry’s disease 1:80,000 to 1:117,000 X-linked a-galactosidase A Acropares-
thesias, angio-
keratomas hypohidrosis, corneal opacities, renal insufficiency
Leukocyte a-galactosidase A assay Enzyme replacement therapy
Hurler’s syndrome 1:100,000 Autosomal recessive a-l-iduronidase Coarse facial features, hepatospleno-
Urine mucopoly-
saccharidesLeukocyte a-l-iduronidase assay
Bone marrow transplant
Organic aciduria
Methylmalonicaciduria 1:20,000 Autosomal recessive Methylmalonyl-
CoA mutase, cobalamin metabolism
Acute encephalo-
pathy, metabolic acidosis, hypera-
Urine organic acidsSkin fibroblasts for enzyme assay Sodium bicarbonate, carnitine, vitamin B12, low-protein diet, liver transplant
Propionic aciduria 1:50,000 Autosomal recessive Propionyl-CoA carboxylase Metabolic acidosis, hypera-
Urine organic acids Dialysis, bicarbonate, sodium benzoate, carnitine, low-protein diet, liver transplant
Zellweger syndrome 1:50,000 Autosomal recessive Peroxisome membrane protein Hypotonia, seizures, liver dysfunction Plasma very-long-chain
fatty acids
No specific treatment available
Urea cycle


1. Phenylketonuria.  Accessed Monday, August 06, 2007 16:41

2. BC Children’s hospital’s Biochemical Diseases Clinic.  Accessed Monday, August 06, 2007 13:14

3.  Newborn Screening – Diseases detected. Accessed Monday, August 06, 2007 14:29

4. Biochemical Diseases – For professionals.  Accessed Monday, August 06, 2007 13:43

5. Dworkin, P.  NMS Pediatrics. 4e.New York, Lippincott Williams & Wilkins, 2000.

6. Raghuveer, Garg, and Graf.  Inborn Errors of Metabolism in Infancy and Early Childhood: An Update.  American Family Physician.  Vol. 73 No. 11. June 2006

7. Raghuveer, Garg, and Graf.  Inborn Errors of Metabolism in Infancy and Early Childhood: An Update.  American Family Physician.  Vol. 73 No. 11. June 2006

8. Nelson’s Essentials of Pediatrics – 5E.   Overview of treatment p.252

9. Polin and Spitzer.  Fetal and Neonatal secrets, 2e.


Written by: Esther Lee

Edited by: Elmine Statham

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