What is the diagnostic workup for an inborn error of metabolism?

From the Guidelines

The diagnostic workup for an inborn error of metabolism should begin with a comprehensive clinical assessment followed by targeted laboratory testing, including plasma amino acids, urine organic acids, and acylcarnitine profile, as recommended by the American College of Medical Genetics 1. The initial evaluation should include a basic metabolic panel, complete blood count, liver function tests, ammonia level, lactate, pyruvate, and blood gases, glucose, ketones, and urine ketones. For suspected specific disorders, more specialized testing may be needed, such as enzyme assays, genetic testing, or tissue biopsies. Timing is critical, with samples ideally collected during acute decompensation before treatment begins. Newborn screening results should be reviewed when available. Neuroimaging (MRI) may reveal characteristic patterns in certain IEMs, as suggested by the Journal of the American Academy of Child and Adolescent Psychiatry 1. A multidisciplinary approach involving geneticists, metabolic specialists, neurologists, and dietitians is essential for proper diagnosis and management. Early diagnosis is crucial as many IEMs have specific treatments that can prevent irreversible damage, including dietary modifications, cofactor supplementation, substrate reduction therapy, or enzyme replacement therapy. Family genetic counseling should be offered once a diagnosis is established, as many IEMs follow autosomal recessive inheritance patterns. The most recent guidelines from the Journal of the American Academy of Child and Adolescent Psychiatry 1 support the use of a stepwise approach to additional testing, including focused metabolic testing such as serum amino acids and urine organic acids, and consideration of an electroencephalogram (EEG) if seizures or paroxysmal events are suspected. The American College of Medical Genetics recommends a chromosomal microarray in all individuals with ID of undetermined etiology, with a diagnostic yield of 7.8% in subjects with GDD/ID/IDD and 10.6% in those with syndromic features 1. Overall, a comprehensive and targeted diagnostic workup is essential for the early diagnosis and management of inborn errors of metabolism.

From the Research

Diagnostic Workup for Inborn Errors of Metabolism

The diagnostic workup for inborn errors of metabolism (IEM) typically involves a combination of clinical evaluation, laboratory tests, and confirmatory testing.

• Newborn screening (NBS) is a crucial step in the diagnosis of IEM, using tandem mass spectrometry (MS/MS) to detect numerous conditions on a single sample 2.
• In the case of a screened positive result, follow-up analytical tests such as amino acids and acylcarnitine analysis in plasma and organic acid analysis in urine are performed for confirmation 2.
• Clinical metabolomics is a new field of study that allows for comprehensive metabolite profiling of biological systems, providing insight into the mechanism of action and gene function in patients with IEM 3.
• Laboratory testing for metabolic disorders should be performed in any infant who exhibits symptoms such as lethargy, poor feeding, apnea or tachypnea, and recurrent vomiting, as these may be indicative of an IEM 4.
• Specific patterns of dysmorphic features and congenital anomalies can also characterize certain IEM, and the appropriate evaluation of affected infants is necessary 4.
• Primary care physicians should be familiar with the early signs and symptoms of IEM to initiate appropriate diagnostic and therapeutic interventions, and make referrals to specialists as needed 5.
• In acute conditions of IEM, knowledge of the main signs and symptoms is crucial, and nonspecific biochemical markers may suggest the underlying condition, but appropriate biochemical and molecular tests are required to establish the diagnosis 6.

Laboratory Tests

• Amino acids and acylcarnitine analysis in plasma
• Organic acid analysis in urine
• Tandem mass spectrometry (MS/MS)
• Metabolomics for comprehensive metabolite profiling

Clinical Evaluation

• Recognition of early signs and symptoms of IEM
• Familiarity with specific patterns of dysmorphic features and congenital anomalies
• Awareness of the importance of early intervention and routine measurement of diagnostic biochemical markers in suspected cases 6