Our patient, born in 1986, was the second son of a woman who had had progressive loss of vision during the first 7 years of her life, related to bilateral dislocated lenses. She was diagnosed with homocystinuria when both lenses were surgically removed when she was 7 years old. Plasma free homocystine and methionine were 48 μmol/l (N = 0) and 670 μmol/l (N = 19–25), respectively. She had moderate learning difficulties, a depressed sternum, pes cavus, high arched palate, fair skin with easily seen veins and signs of osteoporosis on spinal X-rays. She had neither arachnodactyly nor thromboembolic events. She was initially and successfully treated with pyridoxine 500 mg/day, which was reduced to 100 mg/day and then 50 mg/day.
At age 24 years, she had a normal pregnancy giving birth to an unaffected child, without post-partum complications. At age 29 years, she had a male child by a different unrelated partner. The plasma total homocysteine (tHcy) in this child was elevated at 107 μmol/l (N = 5–15). Follow-up of the mother between the ages of 29 and 48 years showed satisfactory metabolic control (plasma tHcy 21 – 112 μmol/l, plasma methionine 45–48 μmol/l) with therapy including pyridoxine 50 mg/day, folic acid 5 mg/day, cyanocobalamin 50 μg/day and an unrestricted diet. No new clinical events have occurred, despite the fact she was a mild smoker. Molecular study of the CBS gene showed the mutations c.374 G>A (R125Q) in exon 3 and c.671 G>T (R224L) in exon 6.
The second child of our patient was seen at the age of 17 days for homocystinuria screening. His father had no family history of homocystinuria. At the age of 17 days, free Hcy was not detected but 8 months later plasma tHcy and methionine were 107 and 1999 μmol/l, respectively. A methionine-restricted diet was started, with pyridoxine 50 mg/day and folic acid 5 mg/day. Between the age of one and nine years, metabolic control was good with plasma tHcy less than 5–13 μmol/l, methionine 46–53 μmol/l, growth was normal and no lens dislocation was observed. The patient had no arachnodactyly, no bone deformities and his neurological development was normal. At age 10 years, betaine 3 g/day was started. From age 13 to 19 years, plasma tHcy and methionine mostly remained high, at 100–201 and 636–708 μmol/l respectively, despite increasing doses of pyridoxine to 300 mg/day, betaine to 4.5 g/day and adding cyanocobalamin 50 μg/day. No clinical events were reported and eye examination remained normal despite suspected non-compliance with therapy. At age 19 years, his DEXA lumbar spine Z-score was -2.7. Molecular analysis of the CBS gene showed the mutations c374 G>A (R125Q) and c.689 insC, which predicts a frameshift and downstream stop codon.