What are the symptoms and management of homozygous MTR (methionine synthase) and MTRR (methionine synthase reductase) mutations?

Symptoms and Management of Homozygous MTR and MTRR Mutations

Homozygous MTR (methionine synthase) and MTRR (methionine synthase reductase) mutations cause severe hyperhomocysteinemia with megaloblastic anemia and neurological manifestations, requiring aggressive treatment with hydroxocobalamin, folate, betaine, and other B vitamins. 1, 2, 3

Clinical Presentation

Common Symptoms

• Hematological manifestations:

  • Megaloblastic anemia (may present as early as 2 months of age)
  • Persistent macrocytosis resistant to conventional B12 treatment 4
  • Bone marrow examination typically shows megaloblastic changes 3

• Neurological manifestations:

  • Developmental delay
  • Feeding difficulties
  • Cerebral atrophy
  • Neurological dysfunction 2, 3

• Biochemical abnormalities:

  • Moderate to severe hyperhomocysteinemia (plasma total homocysteine typically 44-169 μmol/L)
  • Reduced methionine levels (though not always present)
  • Absence of methylmalonic aciduria (distinguishing from other cobalamin disorders) 3, 4

Variability in Presentation

• Age of onset ranges from 2 weeks to 3 years (median 4 weeks) 3
• Some patients with specific mutations (e.g., c.1361C>T in MTRR) may present with milder phenotypes primarily showing hematological manifestations with minimal neurological involvement 4

Diagnostic Approach

1. Initial laboratory evaluation:

   • Measure plasma homocysteine levels (typically >30 μmol/L)
   • Complete blood count (looking for macrocytic anemia)
   • Serum and erythrocyte folate
   • Serum cobalamin (B12)
   • Serum/urine methylmalonic acid (normal in MTR/MTRR defects) 1

2. Confirmatory testing:

   • Genetic analysis of MTR and MTRR genes
   • Enzymatic analysis in fibroblasts
   • Complementation studies
   • Evaluation of methylcobalamin production from labeled cyanocobalamin 3, 4

3. Additional assessments:

   • Brain MRI to evaluate for cerebral atrophy or ischemic lesions
   • Neurophysiological examinations (e.g., somatosensory evoked potentials)
   • Developmental assessment 3, 4

Management

Pharmacological Treatment

1. Vitamin supplementation:

   • Hydroxocobalamin (vitamin B12): High-dose intramuscular injections
   • Folate/methylfolate: 5 mg daily (higher than standard doses)
   • Vitamin B6: 50 mg daily to support transsulfuration pathway
   • Riboflavin (vitamin B2): 10 mg daily, particularly important for MTRR function
   • Betaine: To promote alternative homocysteine remethylation 1, 2

2. Treatment goals:

   • Target reduction of homocysteine to <15 μmol/L
   • Monitor methylmalonic acid levels to detect functional B12 deficiency
   • Regular follow-up of homocysteine levels to assess treatment efficacy 1

Monitoring

• Regular assessment of homocysteine levels
• Complete blood count to monitor anemia
• Neurological and developmental assessments
• Brain imaging as indicated by clinical status 1, 3

Special Considerations

• Treatment must be lifelong
• Early diagnosis and treatment may prevent or minimize neurological complications
• Even patients with initially mild phenotypes require close monitoring as long-term neurological consequences remain possible 4

Genetic Counseling

• Autosomal recessive inheritance pattern
• Siblings of affected individuals have a 25% chance of being affected
• Carrier testing for family members is recommended
• Prenatal diagnosis is possible for at-risk pregnancies 1

Prognosis

• Variable depending on:

  • Specific mutations (some associated with milder phenotypes)
  • Age at diagnosis and treatment initiation
  • Compliance with treatment
  • Response to therapy 3, 4

• Early diagnosis and treatment may significantly improve outcomes, particularly regarding neurological manifestations

Pitfalls and Caveats

• Diagnosis may be delayed due to non-specific presentation or incomplete evaluation of megaloblastic anemia
• Standard B12 supplementation alone is insufficient; specific high-dose regimens are required
• Macrocytosis may not be present in all cases, potentially delaying diagnosis
• Neurological damage may be irreversible if treatment is delayed
• Regular monitoring is essential even in patients with initially mild presentations 3, 4