What is homocystinuria?
Several gene defects (autosomal, recessive) may be involved:
Cystathionine-β-synthase (CBS) gene defect (transsulfuration pathway)
CBS deficiency is the most common one. Patients have elevated homocysteine and methionine levels and can be distinguished according their responsiveness pyridoxine.
Methylenetetrahydrofolate reductase (MTHFR) gene defect (remethylation pathway)
Patients have elevated homocysteine but decreased or normal methionine concentrations.
Cobalamine (cbl) genes defect (remethylation pathway)
Patients have elevated homocysteine but normal or decreased methionine concentrations
due to a reduction of the activity of the methyl transferase.
What are the symptoms of homocystinuria?
A variety of symptoms involving mainly the eye, the nervous and the vascular systems as well as the bones and growth may affect patients. The great variability in clinical presentation may result in some cases being recognized too late, only after the occurrence of several complications such as thromboembolic events.
A developmental delay may be an early warning sign. Early distinctive symptoms can be severe myopia and ectopia lentis. Other symptoms are not specific and include mental retardation, seizures, psychiatric disturbances, osteoporosis, scoliosis, Marfanoid features and thromboembolic complications. The latter may lead to stroke, seizures, permanent neurologic sequellae and even death.
Siblings of an affected patient should be screened as early diagnosis is crucial to prevent clinical manifestations of the disease by appropriate treatment.
How can homocystinuria be treated?
Three treatment options are available and a combination of these options is often applied to optimize the reduction of homocysteine levels.
Methionine restricted diet:
This is amongst the most restrictive diets for metabolic diseases, therefore many children or late diagnosed patients cannot comply with it. Furthermore, though it can stop further progression of complications, it does not lead to reversal of major abnormalities (Mudd et al. 1985).
Vitamin B6 + Folate + Vitamin B12:
Supplementation with Vitamin B6+Folate+Vitamin B12 optimizes the remethylation of homocysteine via the folate-dependent remethylation pathway. However, it cannot always restore normal levels of homocysteine.
Betaine:
Betaine activates an alternative remethylation pathway via the betaine-homocysteinemethyltransferase. Activation of this pathway was proven to further reduce the homocysteine concentration in all types of homocystinuria.
Reduction of the excessive homocysteine levels in patients with homocystinuria is often followed by clinical improvement and prevention of disease progression or its complications. Non-compliance with a prescribed treatment may not have immediate consequences but long-term effects may be serious and irreversible. Therefore, regular clinical check-ups and biochemical monitoring are necessary. |
