Homocystinuria, more precisely termed classical homocystinuria or cystathionine beta-synthase (CBS) deficiency, is a rare autosomal recessive metabolic disorder characterized by elevated levels of homocysteine in the blood and urine. This condition results from deficient activity of the enzyme cystathionine beta-synthase, which is essential for the transsulfuration pathway of methionine metabolism. The disease has significant neurological manifestations and represents one of the most common inherited causes of hyperhomocysteinemia.
Classical homocystinuria is caused by mutations in the CBS gene (cystathionine beta-synthase) located on chromosome 21q22.3. Over 200 pathogenic variants have been identified, with certain mutations being prevalent in specific populations:
- p.I278T — common in European populations
- p.G307S — prevalent in Irish ancestry
- p.A114V — found in various populations
- p.R125Q — observed in multiple ethnic groups
- Autosomal recessive inheritance
- Both copies of the CBS gene must be mutated for disease expression
- Carrier parents have a 25% chance of having an affected child
- Approximately 1 in 200,000-300,000 births worldwide
¶ Biochemistry and Pathophysiology
The methionine cycle involves:
- Methionine → S-adenosylmethionine (SAM)
- SAM → S-adenosylhomocysteine (SAH)
- SAH → Homocysteine
- Homocysteine → Methionine (via remethylation) OR → Cystathionine (via transsulfuration)
CBS deficiency disrupts the transsulfuration pathway, leading to:
- Accumulation of homocysteine — toxic to vascular endothelium and neurons
- Accumulation of methionine — due to impaired conversion to cystathionine
- Reduced cysteine production — affecting glutathione synthesis
- Impaired methylation reactions — due to elevated SAH
- Endothelial dysfunction — homocysteine damages vascular endothelium
- Oxidative stress — increased reactive oxygen species production
- ER stress — protein misfolding due to impaired disulfide bond formation
- Excitotoxicity — altered glutamate metabolism
- Impaired one-carbon metabolism — affecting DNA synthesis and repair
- Ectopia lentis — dislocation of the lens (most characteristic finding)
- Severe myopia
- Glaucoma
- Retinal detachment
- Optic atrophy
- Marfanoid habitus — tall stature, long limbs, arachnodactyly
- Osteoporosis
- Scoliosis
- Pectus excavatum or carinatum
- Genu valgum
- High-arched palate
- Intellectual disability — ranging from mild to severe
- Seizures — various types
- Psychiatric disorders — depression, anxiety, schizophrenia
- Peripheral neuropathy
- Cerebrovascular disease — stroke, transient ischemic attacks
- Thromboembolism (venous and arterial)
- Deep vein thrombosis
- Pulmonary embolism
- Myocardial infarction
- Stroke (particularly in young adults)
- Elevated methionine on newborn screening
- Follow-up plasma amino acid analysis shows:
- Elevated homocysteine
- Elevated methionine
- Low cysteine
- Note: Some variants (pyridoxine-responsive) may be missed
- Plasma amino acid analysis — elevated homocysteine and methionine
- Urinary organic acid analysis — elevated homocysteine
- Enzyme activity assay — reduced CBS activity in cultured fibroblasts
- Genetic testing — CBS gene sequencing
- Slit-lamp examination to detect lens dislocation
- Fundoscopic examination for retinal changes
- MRI may show:
- White matter abnormalities
- Cerebral atrophy
- Stroke-like lesions
- Ventricular enlargement
- Methionine-restricted diet — limits natural protein intake
- Special medical formulas — methionine-free amino acid supplements
- Betaine supplementation — promotes homocysteine remethylation
- Folic acid supplementation — supports remethylation pathway
- High-dose pyridoxine (vitamin B6) — approximately 50% of patients respond
- Betaine (Cystadane) — FDA-approved for homocystinuria
- Folic acid — 1-5 mg daily
- Vitamin B12 — if deficient
- Ocular — lens surgery for ectopia lentis, management of glaucoma
- Skeletal — physical therapy, orthopedic intervention for scoliosis
- Neurological — antiepileptic drugs, psychiatric care
- Vascular — antiplatelet therapy, anticoagulation when indicated
- Regular plasma homocysteine levels
- Ocular examinations
- Bone density studies
- Neurological assessments
- Vascular imaging