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Classical homocystinuria due to cystathionine beta-synthase (CbS) deficiency is characterized by the multiple involvement of the eye, skeleton, central nervous system, and vascular system. According to data collected from countries that have screened over 200,000 newborns, the cumulative detection rate of CbS deficiency is 1 in 344,000. In some areas, the reported incidence based on clinical cases is approximately 1 in 65,000. More recently, screening based on CbS mutations has led to reported incidences as high as 1 in 20,000. Patients are normal at birth and, if left untreated, the disease course is progressive. Eye anomalies include ectopia lentis (85% of the cases), with high myopia. Skeletal changes include genu valgum and pes cavus, followed by dolichostenomelia, pectus excavatum or carinatum and kyphosis, or scoliosis and osteoporosis. Thromboembolism, affecting both large and small arteries and veins, is the most striking cause of morbidity and mortality. Intellectual deficiency rarely manifests before the first to second year of life. Clinically significant psychiatric illness is found in 51% of cases. Involvement of the liver, hair, and skin has also been reported. The disease is an autosomal recessively inherited disorder of methionine metabolism, caused by mutations in the CBS gene (21q22.3). CbS normally converts homocysteine to cystathionine in the transsulfuration pathway of the methionine cycle and requires pyridoxal 5-phosphate as a cofactor. The other two cofactors involved in methionine remethylation include vitamin B12 and folic acid. Clinical diagnosis of CbS deficiency is confirmed by blood amino acid analysis (including total homocysteine measurement), assays of CbS enzyme activity, or by screening for CBS mutations. If the disease is diagnosed in the newborn infant, as ideally it should be, the aim of treatment must be to ensure the development of normal intelligence and prevent the development of other complications. Later, it aims at preventing life-endangering thromboembolic events and further escalation of the complications. There are currently three recognized modalities of treatment. For those that are pyridoxine responsive, the treatment includes pyridoxine in pharmacological doses in combination with folic acid and vitamin B12 supplements. In pyridoxine nonresponsive individuals, the recommended treatment is a methionine-restricted, cystine-supplemented diet in combination with the pyridoxine, folic acid and vitamin B12 supplementation. Betaine anhydrous is a methyl donor that may lead to lowering of homocysteine levels in these individuals and can be used as an adjunct to such a diet. It obtained EU marketing authorization as an orphan drug for the treatment of homocystinuria in 2007.
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