Homocystinuria and Hyperhomocysteinaemia
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Direct answer
Homocystinuria is an inherited disorder of methionine metabolism, most often caused by cystathionine beta-synthase deficiency, that produces very high plasma homocysteine. Hyperhomocysteinaemia is the wider term for raised homocysteine from genetic or acquired causes, most commonly folate, vitamin B12 or vitamin B6 deficiency. The classic examination clue is ectopia lentis displaced downwards, accompanied by thrombosis and intellectual disability.
What you must remember
- Inheritance: classical homocystinuria is autosomal recessive, caused by cystathionine beta-synthase deficiency on chromosome 21.
- Ectopia lentis: the lens dislocates downwards and inwards, the opposite of the upward displacement seen in Marfan syndrome.
- Clinical features: marfanoid habitus, intellectual disability, osteoporosis, malar flush and arterial or venous thrombosis.
- Pyridoxine responsiveness: only a subset responds to vitamin B6, the cofactor of cystathionine beta-synthase, so a trial forms part of the workup.
- Diagnosis: raised total plasma homocysteine and methionine on amino acid analysis, with homocystine detectable in urine.
- Treatment: pyridoxine where responsive, methionine restriction with cysteine supplementation, betaine and folate, with antithrombotic cover.
- Nutritional causes: folate, vitamin B12 or vitamin B6 deficiency, chronic kidney disease and hypothyroidism all raise homocysteine, and these are far more common than the inherited form.
- Outcome evidence: lowering homocysteine with vitamins has not consistently prevented cardiovascular events in large randomised trials.
High-yield traps in homocystinuria
Homocystinuria is a favourite source of eye-sign and treatment questions.
- Trap: choosing Marfan syndrome for any lens displacement Correct: Marfan lenses move upwards and temporally, while homocystinuria lenses move downwards and nasally, and the direction usually decides the question.
- Trap: treating every raised homocysteine as classical homocystinuria Correct: nutritional deficiency and renal failure are far commoner, and amino acid analysis separates the inherited form.
- Trap: assuming vitamin B6 cures all patients Correct: only a subset of patients with cystathionine beta-synthase deficiency responds, so methionine restriction remains necessary for non-responders.
Frequently asked questions
Which eye finding points towards homocystinuria rather than Marfan syndrome?
Downward and medial displacement of the lens, known as ectopia lentis, points towards homocystinuria. Marfan syndrome usually displaces the lens upwards and temporally, so the direction of displacement is the classic discriminator in examinations.
What are the commonest causes of raised homocysteine in adults?
Folate, vitamin B12 or vitamin B6 deficiency, together with chronic kidney disease and hypothyroidism, are among the commonest causes of raised homocysteine in adults. These acquired causes are far more frequent than classical homocystinuria, which is a rare inherited disorder.
Why is cysteine given in classical homocystinuria?
Cystathionine beta-synthase deficiency blocks the step that converts homocysteine into cystathionine and then cysteine. Cysteine supplementation, given together with methionine restriction, replaces the missing cysteine supply in classical homocystinuria.
Does lowering homocysteine with vitamins prevent heart attacks and strokes?
Vitamin supplementation lowers plasma homocysteine, but large randomised trials have not consistently shown fewer cardiovascular events. Homocysteine is therefore regarded as a marker of vascular risk rather than a proven treatment target in the general population.
Which vitamin is the cofactor for cystathionine beta-synthase?
Cystathionine beta-synthase uses pyridoxal phosphate, the active form of vitamin B6, as its cofactor. Some patients with a mutant enzyme improve on high-dose pyridoxine, which is why a pyridoxine trial forms part of the workup for homocystinuria.