Homocystinuria

Key Features

• Consider in a child of any age with a marfanoid habitus, dislocated lenses, or thrombosis

• Diagnosis is suggested by elevated total homocysteine and methionine

• Newborn screening allows early diagnosis and treatment resulting in a normal outcome

• Most often due to deficiency of cystathionine β-synthase (CBS)

• May also be due to deficiency of methylenetetrahydrofolate reductase (MTHFR) or to defects in the biosynthesis of methyl-B₁₂, the coenzyme for methionine synthase

• All inherited forms of homocystinuria are autosomal recessive traits

Clinical Findings

• Mental retardation in about 50% of patients with untreated CBS

• Most patients have arachnodactyly, osteoporosis, and a tendency to develop dislocated lenses and thromboembolic phenomena

• Mild variants of CBS deficiency present with thromboembolic events

• Patients with severe remethylation defects usually exhibit failure to thrive and a variety of neurologic symptoms, including

  • Brain atrophy

  • Microcephaly

  • Hydrocephalus

  • Seizures in infancy and early childhood

Diagnosis

• Diagnosis is made by demonstrating elevated total serum homocysteine or by identifying homocystinuria in a patient who is not severely deficient in vitamin B₁₂

• Plasma methionine levels

  • Usually high in patients with CBS deficiency

  • Often low in patients with remethylation defects

• Cystathionine levels are low in CBS deficiency

• When the remethylation defect is due to deficiency of methyl-B₁₂, megaloblastic anemia or hemolytic uremic syndrome may be present and an associated deficiency of adenosyl-B₁₂ may cause methylmalonic aciduria

• Mutation analysis or studies of cultured fibroblasts can make a specific diagnosis

Treatment

• Large oral doses of pyridoxine effective in about 50% of patients with CBS deficiency

• Pyridoxine nonresponders are treated with dietary methionine restriction and oral administration of betaine, which increases methylation of homocysteine to methionine and improves neurologic function

• Early treatment prevents mental retardation, lens dislocation, and thromboembolic manifestations

• Large doses of vitamin B₁₂ (eg, 1–5 mg hydroxocobalamin administered daily intramuscularly or subcutaneously) are indicated in some patients with defects in cobalamin metabolism