Definition: a group of inherited genetic disorders characterized by impaired homocysteine metabolism
Epidemiology
Etiology
- Autosomal recessive
- Cause deficiencies in one or more of the following enzymes
- Methionine synthase
- Cystathionine synthase: an enzyme that catalyzes the conversion of homocysteine and serine to cystathionine, using vitamin B6 as a cofactor.
- Methylenetetrahydrofolate reductase (MTHFR): an enzyme involved in folate metabolism that reduces N5,10-methylenetetrahydrofolate to methyltetrahydrofolate.
- Impaired affinity of cystathionine synthase for pyridoxal phosphate
Pathophysiology
- Methionine synthase (homocysteine methyltransferase) deficiency → impaired conversion of homocysteine into methionine
- Cystathionine synthase deficiency → impaired conversion of homocysteine into cystathionine
- All forms result in the accumulation of homocysteine.
Clinical features
- Nonspecific features in infancy: growth faltering, developmental delay
- Eyes
- Downward and inward subluxation of the ocular lens (ectopia lentis) after 3 years of age (in Marfan syndrome, the lens usually luxates upwards and outwards)
- Myopia and glaucoma later in life
- Downward and inward subluxation of the ocular lens (ectopia lentis) after 3 years of age (in Marfan syndrome, the lens usually luxates upwards and outwards)
- Progressive intellectual disability
- Psychiatric and behavioral disorders
- Light skin
- Marfanoid features
- Tall, thin
- Pectus deformities (e.g., pectus excavatum)
- Scoliosis
- Elongated limbs (↑ arm:height ratio; ↓ upper:lower body segment ratio), arachnodactyly
- Hyperlaxity of joints and hyperelasticity of the skin
Tip
Marfan syndrome and homocystinuria both present with marfanoid habitus. Distinguishing features include intellectual disability, which is only seen in homocystinuria, and the direction of lens dislocation (downwards in homocystinuria and upwards in Marfan syndrome).
- Osteoporosis
- Cardiovascular complications like thromboembolism, premature arteriosclerosis, and coronary heart disease increase the risk of myocardial infarction and stroke
Diagnostics
- ↑ Homocysteine in urine and serum
- Urine sodium nitroprusside test: Urine changes color to an intense red in the presence of homocysteine.
- Serum methionine levels
- Increased in cystathionine synthase deficiency
- Decreased in methionine synthase deficiency and methylenetetrahydrofolate reductase deficiency
Treatment
- Some patients respond to large doses of pyridoxine (vitamin B6).
- Methionine synthase deficiency: high-methionine diet
- Cystathionine synthase deficiency
- Low-methionine, high-cysteine diet
- Supplementation of vitamin B12 and folate
- Impaired affinity of cystathionine synthase for pyridoxal phosphate: high-cysteine diet
- MTHFR deficiency: supplementation of folate