Cystathionine β‐Synthase ( CBS ) Deficiency: Genetics

Abstract

Abstract Cystathionine β‐synthase (CBS) catalyses condensation of homocysteine and serine to cystathionine, and by alternative reactions also synthesis of hydrogen sulfide. CBS deficiency, an autosomal recessive trait with estimated worldwide frequency of 0.82–1.09 per 100 000 births, manifests usually by thromboembolism, and in severe forms also by lens dislocation, marfanoid features, osteoporosis and neuropsychiatric complications. Laboratory findings include grossly elevated plasma total homocysteine and mildly to grossly elevated blood methionine, which is analysed in neonatal screening. CBS binds three cofactors: pyridoxal‐5′‐phosphate, an allosteric activator S ‐adenosylmethionine and haem with as‐yet‐unresolved function. In the CBS gene, more than 160 different mutations have been described to date. Most of the mutations are missense yielding misfolded enzymes, which can potentially be rescued by chaperones. CBS deficiency is efficiently treated by combination of large doses of pyridoxine, methionine‐restricted diet and betaine; experimental enzyme replacement therapy is efficient in mouse models of disease. Key Concepts Cystathionine β‐synthase catalyses the first step in the transsulfuration of homocysteine to cysteine, and also synthesis of hydrogen sulfide from cysteine. Cystathionine β‐synthase is a modular enzyme composed of a haem‐binding N ‐terminal domain, the active core with pyridoxal‐5′‐phosphate involved in catalysis and the C ‐terminal autoinhibitory domain, which binds S ‐adenosylmethionine. More than 160 different pathogenic mutations have been described in the CBS gene, almost 90% of all mutant CBS alleles carry missense mutations. Mutant CBS subunits often misfold, and their conformation and activity may be rescued by chaperones. Deficient CBS activity leads to gross elevation of plasma total homocysteine, often to elevated blood methionine levels, and decreased blood cystathionine. Phenotypic consequences of mutations in the Cbs gene include thromboembolism and vascular occlusion, which is accompanied in severe forms of the disease by lens dislocation, marfanoid features, osteoporosis and neuropsychiatric involvement. CBS deficiency can be managed by administration of pyridoxine, low‐methionine diet and betaine; treatment is efficient when started early after birth. Population frequency of patients with CBS deficiency ascertained clinically and by newborn screening is one to two orders of magnitude lower than the frequency calculated from the prevalence of heterozygotes for pathogenic mutations; this observation indicates an ascertainment bias or lack of symptoms in many CBS‐deficient individuals. Various murine models of CBS deficiency recapitulate the organ involvement observed in human patients, and experimental enzyme replacement therapy corrects efficiently these complications.