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Prenatal and Genetic Magnesium Deficiency in Cardiomyopathy: Possible Vitamin and Trace Mineral Interactions
Published in Fima Lifshitz, Childhood Nutrition, 2020
Additional Nutritional Treatment of Homocystinuria: Folate B12,Amino Acid Intake Modification and Possibly Magnesium and Zinc: Patients with deficiency of cystathionine synthase, accompanied by abnormally low serum folate levels have the folate level further lowered by pyridoxine treatment, and folate repletion is necessary for the chemical response to pyridoxine.220,224 Vitamin B12 supplements are necessary for those whose metabolic block is after formation of cystathionine. Those with methionine accumulation also require methionine restriction and cysteine or choline supplements. Perhaps vitamin B6 treatment from infancy might be effective.222
Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Multiple infarcted areas are seen in the brain of homocystinuric patients. Cystathionine, present normally in high concentrations, is absent, indicating the local involvement of the missing enzyme. Primary structural changes are found in blood vessels independent of their diameter. Intimal thickening and fibrosis are mostly characteristic and major branches with fraying elastic fibers are also found in the aorta. Arterial and venous thomboses occur in many organs. It may be that homocysteine is responsible for the vascular lesion although the mechanism has not been revealed. The mental defect can be associated with cystine or cystathionine deficiency or excess methionine. The way how brain damage develops is still obscure since it is not yet clear what the role of cystathionine is, other than as intermediate in cysteine synthesis.
Hereditary and Acquired Causes of a Hypercoagulable State
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Homocysteine (Hey) is a sulfhydryl-containing amino acid, an intermediary metabolite derived from methionine and involved in several key transmethylation reactions. It is metabolized by a transulfuration pathway to cystathionine and cysteine, or by two transmethylation routes to methionine (Fig. 1). Severe homozygous forms of hyperhomocysteinemia are well known (30). In these cases plasma levels are markedly increased (>100 μM) resulting in urinary excretion, from which the name of the disorder, homocystinuria, derives. Clinically, these patients present in early childhood and eventually develop severe mental retardation, ectopic lens, skeletal abnormalities, and, importantly, premature arterial vascular disease and venous thromboembolism. The disorder is rare, with an estimated frequency of 1:200,000, and is most commonly due to a defect in the CBS enzyme (Fig. 1, step 1).
Givosiran for the treatment of acute hepatic porphyria
Published in Expert Review of Clinical Pharmacology, 2022
Some authors have reported, together with homocysteine, a concurrent increase in methionine levels [64,67], which may hint at a specific dysfunction of cystathionine beta-synthase (CBS), a vitamin B6–dependent enzyme that relies on heme for regulatory functions (the trans-sulfuration pathway of homocysteine catabolism starts with CBS). In principle, the inhibitory action of givosiran on the first and rate-limiting enzyme of heme biosynthesis could have an impact on the non-erythropoietic routes of heme utilization. In this case, even though vitamin B6 supplementation, used alone, may be effective in increasing CBS activity, a more complete supplementation therapy may provide a beneficial enhancement of both routes of homocysteine catabolism (trans-sulfuration and remethylation). Moreover, as the metabolism of amino acids and heme biosynthesis are complexly intertwined, it cannot be excluded that hyperhomocysteinemia is the result of more complex interactions that may benefit from a more complete integration of vitamins and cofactors. While further studies are needed before reaching consensus recommendations, it should be considered that all patients eligible for givosiran be screened for basal homocysteine levels and hyperhomocysteinemia-related vitamin status before starting treatment and periodically while on treatment with givosiran [65,68]. Adequate supplementation therapy can be considered in cases of hyperhomocysteinemia.
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).