Metabolic Disorders or Inborn Errors of Metabolism

Genetic metabolic disorders, also known as inborn errors of metabolism, are disorders in which certain molecules in the body are incorrectly processed. They are caused by mutations in the genes that code for certain enzymes, enzyme cofactors, and chemical transporters. Almost all such metabolic disorders are recessive. Partial enzyme deficiency can cause attenuated or later-onset disease.

The hundreds of metabolic conditions have a vast range of phenotypes. Disorders of energy metabolism can cause metabolic “crises” when a patient becomes catabolic (e.g., from viral illness or fasting). Metabolic crises often feature hypoglycemia, acidosis, encephalopathy, and damage to the liver, muscles, and heart. A crisis can be fatal if catabolism is not reversed in a timely manner.

Many metabolic disorders are detected by the newborn metabolic screen, specifically disorders that are treatable and more common (see Newborn Screening in this rotation guide). However, many metabolic disorders are not detected at birth but are diagnosed later in childhood.

Main Categories of Metabolic Disorders

Family of Disorder	Description	Example(s)	Typical Presenting Signs/Symptoms
Disorders of carbohydrate metabolism	Problem metabolizing sugars or glycogen	Galactosemia: failure to metabolize galactose (a component of lactose) Glycogen storage disorders: problem mobilizing glucose from glycogen during fasting, or a problem storing it as glycogen in the first place	Galactosemia: liver dysfunction, cataracts Glycogen storage disorders: hypoglycemia/fasting intolerance, hepatomegaly
Urea cycle disorders	Problem detoxifying ammonia (an intermediate of protein breakdown) into urea (excretable in urine)	Ornithine transcarbamylase (OTC) deficiency	Hyperammonemia, lethargy, encephalopathy, coma, death
Amino acid disorders	Problem metabolizing one or a few amino acids	Phenylketonuria: problem metabolizing phenylalanine	Variable, but includes encephalopathy
Organic acidemias	Problem metabolizing downstream products of amino acids	Propionic acidemia Methylmalonic acidemia	Acidosis, hyperammonemia (from organic acids disrupting the urea cycle), cognitive effects over time
Fatty acid oxidation disorders	Problem turning free fatty acids into energy currency and ketones	Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency	Hypoketotic hypoglycemia during fasting/stress
Lysosomal storage disorders	Molecules fail to be digested/recycled, accumulating in the lysosome and causing cellular toxicity	Tay-Sachs disease Gaucher disease Mucopolysaccharidoses	Hepatomegaly, splenomegaly, neurological problems, skeletal abnormalities
Mitochondrial disorders	Dysfunction of the mitochondria leading to impaired energy production	Leber hereditary optic neuropathy Leigh syndrome Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome)	Fatigue/weakness, lactic acidosis, neurological problems

Treatments exist for many metabolic disorders. Therapies follow several strategies:

substrate avoidance (e.g., limiting phenylalanine in phenylketonuria)
supplementing deficient downstream compounds (e.g., levodopa in dopa-responsive dystonia)
eliminating toxic metabolites (e.g., ammonia scavengers in urea cycle disorders)
enzyme replacement (e.g., alpha-glucosidase for Pompe disease)
cofactor supplementation (e.g., vitamin B6 in vitamin B6-responsive homocystinuria)
reversal of catabolism with high-calorie fluids or feeds

Research

Landmark clinical trials and other important studies

Research

In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe Disease

Cohen JL et al. N Engl J Med 2022.

The first documented prenatal enzyme replacement therapy to prevent the development of infantile-onset Pompe disease in a family that had already lost two previously affected children.

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy

Eichler F et al. N Engl J Med 2017.

The results of this clinical trial demonstrated that autologous transplant of gene-corrected hematopoietic stem cells was safe and effective for treatment of X-linked adrenoleukodystrophy, a fatal metabolic disease.

Read the NEJM Journal Watch Summary

Untargeted Metabolomic Analysis for the Clinical Screening of Inborn Errors of Metabolism

Miller MJ et al. J Inherit Metab Dis 2015.

Proof-of-concept study with the finding that mass spectroscopy-based analysis of hundreds of compounds can detect dozens of metabolic diseases in a single test; however, the sensitivity is inferior to established specific metabolic tests