This article includes discussion of homocystinuria due to cystathionine beta-synthase deficiency, classical homocystinuria, CBS deficiency, cystathionine beta-synthase deficiency, and homocystinuria due to cystathionine beta-synthase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Dislocation of the optic lens, osteoporosis, thinning and lengthening of the long bones, intellectual disability, and thromboembolism are the most common features in homocystinuria due to cystathionine beta-synthase deficiency. There are multiple causes for homocystinuria. This overview will focus on homocystinuria due to cystathionine beta-synthase deficiency. Despite manifestation of symptoms in childhood some affected individuals were discovered in the second to fourth decade only when presenting with severe thromboembolic complication. In this article, the author reviews this disease and explains why homocystinuria, particularly the pyridoxine-responsive and most readily treatable form of the disease, is still underrecognized.
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• Dislocation of the optic lens, osteoporosis, thinning and lengthening of the long bones, intellectual disability, and thromboembolism affecting large and small arteries and veins are the most common clinical features of homocystinuria.
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• Homocystinuria is a rare inborn error of metabolism caused by mutations in the cystathionine beta-synthase gene.
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• There are 2 major types of homocystinuria due to cystathionine beta-synthase deficiency based on their response to B6 (pyridoxine).
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• Homocystinuria due to cystathionine beta-synthase deficiency is screened for in some newborn screening programs.
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• Total homocysteine in plasma, often higher than 200 µmol/L (normal < 15 µmol/L), and increase of plasma methionine allows diagnosis of cystathionine beta-synthase deficiency.
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• Early and lifelong consequent treatment with diet and vitamins leads to significantly better outcome in affected patients.
Historical note and terminology
Homocystinuria caused by cystathionine beta-synthase deficiency is an inborn error of the transsulfuration pathway. The disorder is biochemically characterized by accumulation of homocysteine, methionine, and a variety of other metabolites of homocysteine in the body and, ultimately, excretion in the urine. The disease was discovered in 1962 by Carson, Neill, and colleagues when individuals with intellectual disability were screened for abnormal urinary amino acids (10; 17). Two years later, the enzymatic defect was identified by Mudd and colleagues (54). Since then, considerable experience has defined the clinical phenotype, the abnormal biochemistry, and the natural history of the disease (57). Dislocation of the optic lens, osteoporosis, thinning and lengthening of the long bones, intellectual disability, and thromboembolism affecting large and small arteries and veins are the most common clinical features (57).
In 1967, Barber and Spaeth reported that 3 cystathionine beta-synthase-deficient patients responded to high doses of pyridoxine (vitamin B6), with decrease of plasma methionine levels to normal and virtual elimination of homocysteine from plasma and urine (04). This observation has since been extended to many additional patients by many authors. It became obvious that there are 2 distinct populations of patients with homocystinuria, one of which responds to treatment with pyridoxine and one that does not (24; 53; 57; 28). The autosomal recessive inheritance of cystathionine beta-synthase deficiency was reported by Finkelstein and colleagues in 1964 (18). The gene has been cloned and mapped to chromosome 21 in the subtelomeric area q22.3 (58). The human cystathionine beta-synthase cDNA sequence was published in 1993 (38). Crystallization and preliminary crystallographic analysis of a protein construct that contains the full-length cystathionine beta-synthase from Homo sapiens and crystallization of the catalytic core of this enzyme from Saccharomyces cerevisiae has been achieved (60; 15), and the structure of the human enzyme has been published (16).
Homocystinuria presents with elevated urinary homocysteine and plasma homocysteine. There are multiple causes that include genetic forms of inborn errors of metabolism related to interference with conversion of homocysteine to methionine and abnormalities of cobalamin transport or metabolism. In addition to genetic etiologies, homocystinuria can also be caused by acquired forms of secondary to severe cobalamin (B12) deficiency. Therefore, adding the enzyme to the end of the term “homocystinuria” provides the most accurate nomenclature, eg, homocystinuria due to cystathionine beta-synthase deficiency.