Residency · Residency · Medicine Pediatrics
Inborn Errors of Metabolism: Newborn Screening and Adult Presentations
Introduction
Inborn errors of metabolism (IEM) encompass over 1,000 genetic disorders affecting biochemical pathways. While traditionally considered pediatric diseases, improved newborn screening and treatments have created a growing population of adults living with IEM. Med-peds physicians are uniquely positioned to bridge the gap between pediatric metabolic care and adult medicine, recognizing both neonatal presentations and late-onset or surviving-into-adulthood phenotypes.
Newborn Screening
Principles and Methods
The Recommended Uniform Screening Panel (RUSP) includes over 35 core conditions and 25 secondary targets. Tandem mass spectrometry (MS/MS) revolutionized screening by enabling simultaneous detection of amino acids and acylcarnitines. Screening is performed on dried blood spots collected at 24-48 hours of life. Point-of-care screening for critical congenital heart disease (pulse oximetry) and hearing loss complement metabolic panels. False positives are common; confirmatory testing is essential before initiating treatment.
Categories of Screened Conditions
| Category | Examples | Detection Method | Acute Presentation |
|---|---|---|---|
| Amino acid disorders | PKU, MSUD, homocystinuria | Elevated amino acids on MS/MS | Encephalopathy, seizures |
| Fatty acid oxidation | MCADD, VLCADD | Abnormal acylcarnitine profile | Hypoketotic hypoglycemia, cardiomyopathy |
| Organic acidemias | Propionic, methylmalonic, isovaleric | Abnormal acylcarnitines + organic acids | Metabolic acidosis, hyperammonemia |
| Urea cycle disorders | OTC deficiency, citrullinemia | Elevated citrulline or low citrulline | Hyperammonemia, respiratory alkalosis |
| Other | Galactosemia, biotinidase deficiency, congenital hypothyroidism | Specific analytes | Variable |
Amino acid disorders: Phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria. Fatty acid oxidation disorders: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD), very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) Organic acidemias: Propionic acidemia, methylmalonic acidemia, isovaleric acidemia. Urea cycle disorders: Ornithine transcarbamylase (OTC) deficiency, citrullinemia. Other: Galactosemia, biotinidase deficiency, congenital hypothyroidism, sickle cell disease, cystic fibrosis.
Clinical Presentations Across Ages
Neonatal Presentations
Acute metabolic crisis: Poor feeding, lethargy, vomiting, seizures within the first days of life. Key laboratory findings: metabolic acidosis, hyperammonemia, hypoglycemia, elevated lactate. Urea cycle defects classically present with respiratory alkalosis and markedly elevated ammonia. Organic acidemias present with anion gap metabolic acidosis and ketonuria.
Childhood Presentations
Developmental delay, failure to thrive, hepatomegaly. Recurrent episodes of metabolic decompensation triggered by illness, fasting, or dietary indiscretion. Lysosomal storage diseases (Gaucher, Fabry, mucopolysaccharidoses) may present with organomegaly, skeletal abnormalities, and neurodegeneration.
Adult Presentations
Late-onset OTC deficiency: Episodic confusion, psychiatric symptoms, hyperammonemia triggered by stress, surgery, or high-protein meals. Fabry disease: Neuropathic pain, angiokeratomas, progressive renal failure, cardiomyopathy. Wilson disease: Hepatic and neuropsychiatric symptoms in adolescents and young adults. Acute intermittent porphyria: Abdominal pain, neuropsychiatric symptoms, autonomic dysfunction. Adult-onset MSUD: Episodic encephalopathy during metabolic stress.
Diagnostic Approach
Plasma amino acids: Elevated phenylalanine (PKU), branched-chain amino acids (MSUD), methionine (homocystinuria) Urine organic acids: Characteristic profiles for organic acidemias. Acylcarnitine profile: Identifies fatty acid oxidation and organic acid disorders. Ammonia and lactate: Critical in acute presentations. Genetic testing: Next-generation sequencing panels, whole exome/genome sequencing for definitive diagnosis. Enzyme assays: Confirmatory for lysosomal storage diseases and specific enzyme deficiencies.
Management Principles
Acute Management
Stop catabolism: Provide high-concentration IV dextrose (D10 or higher) with appropriate electrolytes. Ammonia scavengers: Sodium benzoate and sodium phenylacetate for hyperammonemia. Dialysis: Hemodialysis for ammonia >500 mcmol/L or rapidly rising levels. Avoid prolonged fasting; maintain anabolism with sufficient calories. Specific cofactor therapy: Carnitine supplementation, biotin, hydroxocobalamin as indicated.
Chronic Management
Dietary therapy: Phenylalanine-restricted diet for PKU; protein-restricted diets for urea cycle defects and organic acidemias. Enzyme replacement therapy (ERT): Available for Fabry, Gaucher, Pompe, and select mucopolysaccharidoses. Substrate reduction therapy: Miglustat for Gaucher type 1 and Niemann-Pick C. Liver transplantation: Curative for some urea cycle defects, MSUD, and propionic acidemia. Gene therapy: Emerging for several conditions including aromatic L-amino acid decarboxylase deficiency.
Transition to Adult Care
Structured transition programs improve outcomes and adherence. Adult providers must understand dietary restrictions, emergency protocols, and monitoring schedules. Pregnancy planning is critical: maternal PKU syndrome causes intellectual disability, microcephaly, and heart defects in offspring of women with uncontrolled phenylalanine.
Clinical Pearls
Any neonate with unexplained lethargy, poor feeding, or metabolic acidosis should have ammonia, lactate, and newborn screening results checked urgently. Hyperammonemia with respiratory alkalosis points toward a urea cycle defect; with metabolic acidosis, consider organic acidemia. Adults with unexplained episodic encephalopathy, cardiomyopathy, or renal failure should be evaluated for late-onset IEM. Maternal PKU requires preconception phenylalanine control to prevent teratogenic effects. The growing population of adults with IEM demands internists who understand these conditions.
References
- Wasserstein MP, Andriola M, Arnold G, et al. Clinical outcomes of children with abnormal newborn screening results for IEM. Genet Med. 2021;23(5):816-826.
- Saudubray JM, Baumgartner MR, Walter J. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Springer; 2022.
- Berry SA, Brown C, Grant M, et al. Newborn screening 50 years later: access issues faced by adults with PKU. Genet Med. 2013;15(8):591-599.
- Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2019;14(1):32.