What are the clinical features, diagnosis, and management steps for inborn errors of metabolism?

Inborn Errors of Metabolism: Clinical Features, Diagnosis, and Management

Early recognition and prompt intervention are essential for inborn errors of metabolism (IEMs), as timely diagnosis and treatment can significantly reduce morbidity and mortality while improving health outcomes. 1

Clinical Features

Age-Specific Presentations

• Neonatal period (0-7 days)
  • Severe urea cycle defects and organic acidemias present immediately after birth
  • Amino acid disorders and organic acidemias typically present 24-72 hours after protein feeding begins
  • Fatty acid oxidation defects and galactosemia usually present 3-7 days after establishing feeding 1

Key Clinical Manifestations

• Neurological

  • Lethargy, seizures, movement disorders
  • Developmental delay or regression (particularly during illness)
  • Unexplained encephalopathy 1

• Gastrointestinal

  • Cyclic vomiting, poor feeding
  • Gastroparesis
  • Hepatomegaly 1

• Other Physical Findings

  • Coarse facial features (in lysosomal storage disorders)
  • Hepatosplenomegaly
  • Multisystem involvement (cardiac, hepatic, renal) 1

High-Risk Factors

• Family history of unexplained infant deaths or IEMs
• Parental consanguinity
• Previous siblings with similar presentations 1

Diagnostic Approach

Initial Evaluation

• First-line laboratory tests (GALAK panel) 2
  • Glucose
  • Arterial blood gas
  • Lactate (levels >3 mmol/L are more likely clinically significant)
  • Ammonia
  • Ketones

Specialized Testing

• Plasma acylcarnitine profile analysis

  • Gold standard for detecting disorders of fatty acid oxidation and organic acid metabolism
  • Uses tandem mass spectrometry (MS/MS) 1, 3

• Urine organic acid analysis

  • Essential for diagnosing organic acidemias
  • Should be interpreted based on overall pattern of metabolites rather than individual abnormalities 3

• Plasma amino acids

  • Critical for detecting amino acid disorders 1

• Additional tests

  • Urine glycosaminoglycans for lysosomal storage disorders
  • Enzyme assays or genetic tests for definitive diagnosis 4

Newborn Screening

• Verify positive newborn screening results
• Remember that not all IEMs are included in screening panels
• False negatives can occur if samples are collected too early 1, 3

Management Principles

Emergency Management

• Don't wait for all test results before initiating treatment in critically ill infants 1
• Four key principles of therapy 2:
  1. Substrate reduction (e.g., protein restriction in urea cycle disorders)
  2. Provision of deficient metabolites
  3. Disposal of toxic metabolites
  4. Increase in enzyme activity

Disease-Specific Management

• Tyrosinemia Type I

  • Early treatment with NTBC (nitisinone) and diet can prevent progression to hepatocellular carcinoma 3

• Fatty Acid Oxidation Disorders

  • Avoid fasting
  • Medium-chain triglyceride supplementation for specific disorders 3

• Organic Acidemias

  • Dietary protein restriction
  • Carnitine supplementation
  • Management of acute metabolic decompensation 3

Long-term Considerations

• Pubertal transition

  • Hormonal fluctuations may affect metabolic control
  • Growth hormone surges and sex steroid activity require careful monitoring 5

• Dietary management

  • Balance nutritional needs during growth spurts
  • Monitor for complications like obesity and insulin resistance 5

Pitfalls and Caveats

• Diagnostic challenges

  • IEMs can mimic sepsis in neonates - always consider metabolic disorders in the differential diagnosis of a full-term infant with unexplained symptoms 6
  • Some disorders may have intermittent presentations with normal laboratory values between episodes 3

• Treatment considerations

  • Collect diagnostic samples before initiating treatment whenever possible
  • Recognize that some IEMs have variable enzyme deficiency, affecting the clinical presentation and response to treatment 1

• Laboratory interpretation

  • Proficiency testing programs are essential for accurate organic acid analysis 3
  • Interpretation should be performed by qualified specialists with appropriate board certification 3

By maintaining a high index of suspicion and following a systematic approach to diagnosis and management, clinicians can significantly improve outcomes for patients with inborn errors of metabolism.