Homocystinuria

Classical homocystinuria is an autosomal recessive disorder of methionine metabolism, due to cystathionine beta synthase (CBS, 21q22.3) deficiency, which leads to elevated homocysteine and methionine, and low cysteine. Incidence is about 1 in 200,000 to 335,000 (higher in Ireland, Qatar and Norway; newborn screening detected incidence about 1 in 60,000 to 100,000). It is pyridoxine (vitamin B6)-responsive in about 50% (milder phenotype).

Other causes of homocystinuria include remethylation defects: MTHFR deficiency, cobalamin disorders (cblC, cblD, cblE, cblF, cblG), and MTR deficiency (which cause low or normal methionine).

• Eye: ectopia lentis (lens dislocation, usually downward and nasal; starts at 3 to 10 years; in about 90% by age 15 years), severe myopia, glaucoma, and cataract
• Skeletal: marfanoid habitus (tall, long limbs, arachnodactyly), osteoporosis, scoliosis, pectus deformity, genu valgum, and pes cavus
• Vascular: thromboembolic events (venous and arterial; the major cause of morbidity and mortality), stroke, myocardial infarction, pulmonary embolism, and portal and cerebral venous thrombosis (about 25% by age 16 and 50% by age 30 in untreated pyridoxine-non-responsive patients)
• Neurological and psychiatric: intellectual disability (variable; IQ about 55 to 80 in pyridoxine non-responders), seizures, psychiatric disease (depression, OCD, psychosis), extrapyramidal signs
• Others: malar flush, livedo reticularis, and thin fair hair; fatty liver
• Distinguish from Marfan syndrome (lens dislocation is upward in Marfan, with aortic dilation; intelligence is normal)

1. Plasma total homocysteine (above 100 micromol/L; markedly elevated) with elevated methionine and low cystine; urinary homocystine (detected by nitroprusside test, confusable).
2. Newborn screening by methionine measurement (misses pyridoxine responsive cases).
3. CBS enzyme assay in fibroblasts (and molecular analysis of CBS).
4. Exclude remethylation defects: methylmalonic acid, vitamin B12, folate, and MTHFR studies.
5. Pyridoxine challenge: 100 to 500 mg/day orally for 1 to 2 weeks with folate (and, in infants, a dose of 100 mg IV or oral for 1 week; up to 500 mg/day in older patients), measuring total homocysteine. Reduction of at least 20 to 30% from baseline suggests responsiveness.
6. Ophthalmology, echocardiography, DXA, brain imaging, and thrombophilia assessment.

• Pyridoxine 100 to 500 mg/day (up to 1,000 mg/day, with neuropathy risk above 500 mg/day) for responders, with folic acid 5 mg/day and vitamin B12 1 mg IM monthly or 1 to 2 mg/day orally if deficient.
• Dietary methionine restriction with cysteine supplemented, methionine free amino acid formula (for non-responders and partial responders), guided by plasma amino acids.
• Betaine (trimethylglycine) 100 to 250 mg/kg/day (6 to 9 g/day in adults in two to three divided doses), which remethylates homocysteine to methionine; monitor methionine for cerebral oedema (levels above 1,000 micromol/L).
• Target plasma total homocysteine: below 100 micromol/L in non-responders; below 50 micromol/L in the pyridoxine responsive; free homocysteine below 1 micromol/L.
• Antithrombotic prophylaxis: aspirin 75 to 100 mg/day with dipyridamole or anticoagulation if previous thrombosis; avoid oestrogen containing contraceptives, smoking, prolonged immobilisation, nitrous oxide anaesthesia, and dehydration; perioperative hydration and thromboprophylaxis.
• Ophthalmological surgery for ectopia lentis (lensectomy, with expertise needed), and orthopaedic and bone health care (calcium, vitamin D, bisphosphonates).
• Psychiatric and educational support.
• Pregnancy: continue therapy, with thromboprophylaxis (enoxaparin) peripartum.
• Genetic counselling: 25% recurrence risk; carrier detection and prenatal diagnosis.