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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Cystathionine β-synthase deficiency (CBS) is the classic and most severe form of homocystinuria. CBS can be differentiated from other forms of homocystinuria by elevated methionine levels. Patients have symptoms related to elevated homocysteine.
Prenatal and Genetic Magnesium Deficiency in Cardiomyopathy: Possible Vitamin and Trace Mineral Interactions
Published in Fima Lifshitz, Childhood Nutrition, 2020
Homocystinuria and Cardiomyopathy; Interaction of Nutrient Deficiencies?—Pyridoxine-Dependence of Homocystinurics: One of the conditions listed as being associated with CMP is homocystinuria,99 predominantly a vitamin Independent disorder.220–222 There are several metabolic abnormalities that give rise to homocystinuria, the most common of which is a Mendelian recessive trait that causes deficient activity of cystathionine beta-synthase, an enzyme that contains pyridoxal phosphate.220 Almost half of the patients respond to very high dosage pyridoxine (up to 300 times more pyridoxine than is needed for correction of a simple deficiency; they may have slight (residual) activity of this enzyme.220–221 Those with a more complete deficiency of the enzyme, or with a metabolic block after formation of cystathionine, also require additional dietary modification and/or supplementation.
Amino acid disorders and urea cycle disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
This disorder belongs to a group of conditions known as the amino acid disorders, in which there is an absence or deiciency of an enzyme that is needed to break down proteins into amino acids, which prevents the body from using proteins for growth and repair. The amino acid methionine is converted into homocysteine, which is in turn converted into cysteine. In homocystinuria there is a deiciency or absence of an enzyme called cystathionine beta-synthase (CBS), which is required to break down homocysteine into cysteine. This leads to a build-up of homocysteine in the body, especially in the blood (homocysteinaemia) and the urine (homocystinuria). In addition, there are increased levels of methionine.
Cystathionine β-synthase Deficiency Impairs Vision in the Fruit Fly, Drosophila melanogaster
Published in Current Eye Research, 2021
Marycruz Flores-Flores, Leonardo Moreno-García, Felipe Castro-Martínez, Marcos Nahmad
Classic homocystinuria is a metabolic disease mainly caused by inherited deficiency of Cystathionine-β-synthase (CBS), a vitamin B6-dependent enzyme that catalyzes the flux of sulfur from methionine to cysteine in the transsulfuration pathway.1 In humans, genetic variants causing low CBS expression lead to the accumulation of toxic levels of homocysteine and methionine in urine and plasma, affecting skeletal, visual, the central nervous system,2,3 and also poses an independent risk factor for thrombosis and vascular disease.4,5 One of the most common clinical manifestations of homocystinuria is severe myopia followed by ectopia lentis that affects about 90% of patients with a CBS deficiency.6,7 Despite the high prevalence of eye-related abnormalities caused by this disease, the molecular mechanisms that relate CBS deficiency to vision problems are poorly understood. Murine models of genetic deficiency of cbs have been used as a model of homocystinuria,8,9 including visual manifestations. For instance, studies using cbs-mutant mice have reported alterations of retinal vasculature,10 retinal ganglion cell death,11,12 and visual function.13 However, the widespread use of this experimental model is challenging due to a large degree of neonatal lethality.9
Ocular manifestations in classic homocystinuria
Published in Ophthalmic Genetics, 2021
Patrícia Ioschpe Gus, Karina Carvalho Donis, Diane Marinho, Tiago Franco Martins, Carolina Fischinger Moura de Souza, Rafael Barboza Carloto, Gabriel Leivas, Ida Vanessa Doederlein Schwartz
Classic homocystinuria (HCU) is a rare inborn error of methionine metabolism caused by cystathionine beta-synthase deficiency (CBS deficiency, OMIM 236200), an enzyme that catalyses the conversion of homocysteine to cystathionine. The minimum worldwide prevalence of HCU was estimated to be ~0.38:100,000 (1) and the pathophysiology of CBS deficiency is not fully understood. In addition to homocysteine (Hcy) accumulation, the defect leads to increased concentrations of S-adenosylhomocysteine (SAH), enhanced remethylation to methionine, and depletion of cystathionine and cysteine (2). High levels of Hcy concentrations modify sulfhydryl groups on proteins and interfere with the cross-linking of sulfhydryl groups in proteins such as elastin, which modify intracellular signaling and cause endoplasmic reticulum stress with vascular endothelial dysfunction (3).
The association between homocysteine and systemic sclerosis: A review of the literature and meta-analysis
Published in Modern Rheumatology, 2018
Yan-Jie Zhang, Li Zhang, Xiao-Lei Huang, Yu Duan, Li-Juan Yang, Jing Wang
Hcy’s metabolic process is affected by many nutrients (folate and vitamin B12) and various metabolic enzymes (MTHFR and CBS), so HHey is caused either by genetic defects of enzymes involved in Hcy metabolism or by reduced vitamin intake. For example, a previous study suggested that both of serum levels of folate and vitamin B12 were lower in SSc patients than that in controls [24]. This showed that their deficiencies may lead to elevated plasma Hcy level in SSc. However, in addition to dietary vitamin deficiency, genetic defects of enzymes involved in Hcy metabolism may also lead to the rise of plasma Hcy level [16]. Szamosi et al. [16] have found that the frequent mutation (C677T) in the gene encoding for MTHFR may lead to moderate HHey and influence the incidence of macrovascular abnormalities in SSc patients. Beyond that, CBS deficiency may also lead to severe HHey. We all know that homocystinuria is a rare genetic disorder, and it is mainly characterized by HHey that is caused by mutations in CBS, and leads to early-onset atherosclerosis and arterial and venous thromboses [25], and the main treatment strategy to lower cellular and plasma Hcy levels includes vitamin B6 intake, dietary methionine restriction, betaine supplementation, folate and vitamin B12 administration. At the same time, some new strategies to treat homocystinuria have also been made in recent years, and these mainly include functional restoration to mutant CBS, enhanced clearance of Hcy from the body and so on. These suggest that again HHey is mainly provoked by nutritional deficiency and genetic defects of enzymes involved in Hcy metabolism (Figure 2).