Cobalamin/Propionate/Homocysteine Metabolism Related Disorders Panel

Disorders of cobalamin (vitamin B₁₂)/propionate/homocysteine metabolism result from defects in the vitamin B₁₂ metabolic pathway. Age of disease onset ranges from the perinatal period to adulthood. Multiple organ systems are affected. Molecular testing is used to confirm suspected cobalamin/propionate/homocysteine metabolism-related disorder in individuals with clinical symptoms and/or biochemical findings.

Findings

• Cardiovascular
• Gastrointestinal
• Hematological
• Immunological
• Neurological
• Neuromuscular/skeletal
• Ocular
• Renal
• Respiratory
• Dysmorphic features
• Failure to thrive
• Metabolic decompensation

Etiology

• Defects of absorption, transport, and intracellular metabolism of cobalamin/propionate/homocysteine lead to accumulation of methylmalonic acid, methionine, and/or homocysteine in blood and urine.
• Elevated propionylcarnitine level and/or propionyl/acetylcarnitine ratio are usually detected in plasma, and increased methylmalonic acid is detected in blood, despite normal or elevated vitamin B₁₂ levels.

Prevalence

• Methylmalonic aciduria from all causes – 1/48,000-61,000 in North America
• Isolated methylmalonic acidemia – 1/50,000-100,000
• Combined malonic/methylmalonic aciduria – ~1/30,000
• Methylmalonic aciduria, vitamin B₁₂-responsive, cblA type – 1/50,000-100,000
• Methylmalonic aciduria, vitamin B₁₂-responsive, cblB type – 1/50,000-100,000
• Methylmalonic aciduria and homocystinuria, cblC type – up to 1/67,000
• Methylmalonic aciduria, and homocystinuria, cblD type – 1/50,000-100,000
• Methylmalonic aciduria, mut (0) type – 1/50,000-100,000
• Methylmalonyl-CoA epimerase deficiency – 1/50,000-100,000
• Homocystinuria due to cystathionine beta-synthase deficiency – 1/1,800 in Qatar; 1/6,400 in Norway; 1/17,800 in Germany

• Methionine adenosyltransferase deficiency – 1/22,000 in Spain; 1/26,000 in Portugal

• Homocystinuria, B₆-responsive and nonresponsive types, combined – 1/58,000-1,000,000

• Propionic acidemia – 1/50,000-100,000; 1/1,000-2,000 in Inuit in Greenland; 1/5,000 in Saudi Arabia

• Rare for other disorders included in the panel

Inheritance

Autosomal recessive for all genes tested, except for HCFC1 (X-linked) and MAT1A (autosomal dominant or autosomal recessive)

Genotype-Phenotype Correlation

• Variants in multiple genes cause overlapping and highly variable phenotypes.

• Other genetic and/or biochemical/dietary factors may influence severity of clinical phenotype.

• Clinical features and age of onset are highly variable.

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

Variable, dependent on condition

Limitations

• A negative result does not exclude a heritable form of cobalamin metabolism disorders.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of the targeted genes
  • Regulatory region variants and deep intronic variants
  • Breakpoints of large deletions/duplications
  • Deletions/duplications in the ADK, AHCY, and GNMT genes
  • Non-coding transcripts
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Deletions/duplications less than 1 kb in the targeted genes by array
  • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants
  • Single exon deletions/duplications in the following exons:
    • ABCD4 (NM_005050) 1; HCFC1 (NM_005334) 26; MTHFR (NM_001330358) 1; PCCB (NM_001178014) 4; SUCLA2 (NM_003850) 11

Analytical Sensitivity

For massively parallel sequencing:

Genes Tested