Inborn errors of metabolism are genetic disorders caused by defects in enzymes or transport proteins, leading to accumulation of toxic substrates or deficiency of essential products. Although individually rare, they collectively affect a significant number of children and require prompt diagnosis and treatment.
Phenylketonuria
Phenylketonuria is caused by deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Phenylalanine accumulates and is converted to phenylpyruvate and other metabolites that are toxic to the developing brain. Untreated PKU causes severe intellectual disability, microcephaly, seizures, and reduced pigmentation.
Newborn screening for PKU is universal in developed countries. Treatment with a phenylalanine-restricted diet, using special medical formulas, prevents neurological damage if started early. Tyrosine becomes conditionally essential and must be supplemented. Tetrahydrobiopterin, the cofactor for phenylalanine hydroxylase, is effective in some patients. Maternal PKU requires strict metabolic control during pregnancy to prevent fetal damage.
Maple Syrup Urine Disease
MSUD results from deficiency of branched-chain alpha-keto acid dehydrogenase, the enzyme complex that catabolizes leucine, isoleucine, and valine. The branched-chain amino acids and their corresponding alpha-keto acids accumulate, causing the characteristic sweet odor in cerumen and urine that gives the disease its name.
Neonatal presentation includes poor feeding, lethargy, and progressive neurological deterioration. Without treatment, coma and death occur. Treatment involves dietary restriction of BCAA and careful metabolic monitoring during intercurrent illness. Liver transplantation corrects the metabolic defect by providing enzyme activity.
Urea Cycle Disorders
Urea cycle disorders result from defects in any of the six enzymes of the urea cycle. Ornithine transcarbamylase deficiency is the most common and is X-linked. Defects impair nitrogen disposal, causing ammonia accumulation. Hyperammonemia in the neonatal period causes lethargy, vomiting, cerebral edema, and coma.
Treatment includes protein restriction, arginine supplementation, nitrogen-scavenging drugs such as sodium phenylbutyrate that provide alternative pathways for waste nitrogen excretion, and hemodialysis for acute hyperammonemic crises. Liver transplantation is curative.
Glycogen Storage Diseases
GSDs result from defects in glycogen metabolism enzymes, causing abnormal glycogen accumulation. Von Gierke disease from glucose-6-phosphatase deficiency causes severe fasting hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. Treatment includes uncooked cornstarch to provide sustained glucose release.
Pompe disease from acid alpha-glucosidase deficiency causes glycogen accumulation in lysosomes, primarily affecting cardiac and skeletal muscle. The infantile form presents with cardiomyopathy and early death. Enzyme replacement therapy with recombinant alglucosidase alfa improves outcomes.
Lysosomal Storage Diseases
LSDs result from deficiencies of lysosomal hydrolases, causing accumulation of undegraded substrates. Gaucher disease, the most common, results from glucocerebrosidase deficiency, causing accumulation of glucocerebroside in macrophages. Hepatosplenomegaly, bone pain, and cytopenias are typical. Enzyme replacement therapy and substrate reduction therapy are available.
Tay-Sachs disease from hexosaminidase A deficiency causes GM2 ganglioside accumulation, primarily in neurons. The infantile form presents with developmental regression, cherry-red macular spot, and blindness, with death by age 4. No effective treatment exists. Carrier screening in high-risk populations has reduced incidence.
Mitochondrial Disorders
Mitochondrial disorders affect oxidative phosphorylation, caused by mutations in mitochondrial or nuclear DNA. They affect tissues with high energy demands, particularly brain and muscle. MELAS presents with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Leigh syndrome causes subacute necrotizing encephalopathy. Diagnosis involves muscle biopsy showing ragged red fibers and biochemical analysis of respiratory chain complexes.
Newborn Screening
Expanded newborn screening using tandem mass spectrometry detects many IEMs from dried blood spots. Acylcarnitine profiles identify fatty acid oxidation disorders and organic acidemias. Amino acid profiles identify aminoacidopathies. Early detection allows presymptomatic treatment, dramatically improving outcomes for many disorders.
Treatment Principles
Treatment strategies include substrate restriction, such as the low-phenylalanine diet for PKU. Product supplementation replaces missing compounds, as with thyroid hormone in congenital hypothyroidism. Cofactor supplementation enhances residual enzyme activity. Enzyme replacement therapy delivers recombinant enzyme for lysosomal storage diseases. Substrate reduction therapy inhibits synthesis of accumulating substrates. Liver transplantation provides functional enzyme activity for some liver-based disorders.
