Homocystinuria refers to increased urinary excretion of the oxidized form of homocysteine called homocystine.

Note that the laboratory tests that measure “homocysteine” levels report the total of both the reduced form (homocysteine) and the oxidized form (homocystine) when measured in plasma and urine.

The most common form of homocystinuria is due to an autosomal recessive defect in the enzyme, cystathionine β-synthase.

Over 90 mutations of this gene, located on chromosome 21, have been described. The enzyme is involved in the transsulfuration pathway from homocysteine to cystathione (homocystinuria I).

Other less common forms are due to defective remethylation of homocysteine to methionine caused by either a deficiency of methionine synthase (homocystinuria II) or due to a defect of the enzyme methylenetetrahydrofolate reductase (MTHFR; homocystinuria III).

  • Autosomal recessive disorder caused by pathogenic variants of CBS gene resulting in cystathionine β-synthase deficiency; disorder is characterized by ectopia lentis, severe myopia, skeletal abnormalities, variable intellectual disability, propensity for intravascular thrombosis and thromboembolic events, and high incidence of coronary atherosclerosis 
  • Common features include skeletal abnormalities (eg, excessive height and limb length, pectus deformity, scoliosis, high-arched palate), mitral valve prolapse, hernia, ectopia lentis, and severe myopia
  • Differentiated clinically by frequent development of intravascular thrombosis, seizures, and intellectual disability of variable severity; many patients have improvement after administration of vitamin B₆, and patients typically do not have aortic enlargement or dissection 
  • Diagnosis is made by analysis of plasma and urine for elevated homocysteine and homocystine concentrations and measuring amino acid levels in fasting blood; diagnostic thresholds for untreated older adults are as follows: 
    • Plasma homocysteine level is greater than 3 mg/dL
    • Urine homocystine level is detectable
    • Plasma methionine level is greater than 0.7 mg/dL
  • Confirm diagnosis with molecular sequence analysis of CBS gene; the most common pathogenic variants are p.Ile278Thr and p.Gly307Ser, found in exon 8 

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