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Homocystinuria
Published in Charles Theisler, Adjuvant Medical Care, 2023
Homocystinuria is an inherited disorder that prevents the full breakdown of methionine and the proper use of its breakdown product, homocysteine. This leads to an abnormal and harmful buildup of homocysteine in the blood and urine and may also cause low levels of cysteine. The disorder is characterized by myopia, dislocation of the lens in the eye, an increased risk of abnormal blood clots, brittle bones, Marfan-like features, and sometimes problems with development and learning. One type of homocystinuria results in poor metabolism of folate (vitamin B9) which also leads to excess homocysteine levels. Nutritional causes of hyperhomocysteinemia are vitamin B6 or B12 deficiency and, less often, folate deficiency.1 These disorders can cause intellectual disability, seizures, problems with movement, and megaloblastic anemia. Homocystinuria usually does not show symptoms in a newborn baby. A goal of treatment is to decrease elevated homocysteine blood levels. In general, there are three possible therapeutic approaches to homocystinuria: (1) restriction of substrate (low methionine diet), (2) replacement of missing products (e.g., cystine), and (3) supplementation with coenzymes (pyridoxine, betaine anhydrous).1 Nutritional causes should be handled appropriately or ruled out.
Recurrent pregnancy loss
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Christine E. Ryan, Danny J. Schust
Hyperhomocysteinemia may be caused by MTHFR mutation (heritable) and/or low levels of vitamin B6 or B12, or folate (acquired). Random homocysteine levels are considered mildly elevated at 16 to 24 μmol/L, moderately elevated at 25 to 100 μmol/L, and severely elevated at >100 μmol/L. Dietary supplementation with vitamins B6, B12, and folate can normalize homocysteine levels, but has not yet been show to decrease thrombotic risk (56).
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).
Plasma homocysteine levels and handgrip strength in postmenopausal women
Published in Climacteric, 2022
P. García-Alfaro, I. Rodriguez, F. R. Pérez-López
Homocysteine is a non-essential sulfur-containing amino acid produced in the liver by the transmethylation of methionine. It is degraded into cysteine through the irreversible trans-sulfuration pathway, and under normal circumstances, some 50% follow the re-methylation pathway to regenerate methionine. These reaction pathways require the presence of vitamin B6, vitamin B12 and folate as cofactors [1,2]. Plasma homocysteine increases significantly with age and there are gender differences, levels being higher in men than in women [3]. Also, there are lifestyle factors, like smoking and physical inactivity, that may influence their levels [4]; elevated homocysteine levels are associated with oxidative stress, endothelium dysfunction, smooth muscle cell proliferation, reduced Von Willebrand factor and increased fibrinogen levels [5]. Hyperhomocysteinemia has been related to a greater risk for developing acute coronary syndrome, stroke and cardiovascular mortality [6]. Also, it has been associated with cognitive impairment, dementia and Alzheimer’s disease [7], increased bone fragility [8] and bone fractures [9]. Other factors associated with hyperhomocysteinemia are chronic kidney disease and the effect of medications such as isoniazid, cyclosporine, methotrexate, phenytoin and theophylline [1]. Recent studies have reported the relationship between plasma homocysteine levels and muscle strength and sarcopenia, although with controversial results [10–13]. Differences in results between studies might be due to the use of different cut-off values of muscle strength and homocysteine, and the ages of studied populations.
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.
Methylenetetrahydrofolate reductase gene polymorphisms are not associated with embryo chromosomal abnormalities and IVF outcomes
Published in Systems Biology in Reproductive Medicine, 2021
Ruth Morales, Belén Lledó, José A. Ortiz, Alba Cascales, Helena Codina, Adoración Rodríguez-Arnedo, Joaquin Llácer, Andrea Bernabeu, Rafael Bernabeu
Deficiency of MTHFR may lead to an increase in plasma homocysteine levels (Jacques et al. 1996), a vasculotoxic, embryotoxic and neurotoxic molecule (Lucock 2006). In some individuals, the concentration of circulating homocysteine is so high that they develop hyperhomocysteinemia (Frosst et al. 1995; Van Der Put et al. 1998). This is a risk factor for myocardial infarction, venous thrombosis, recurrent miscarriage, and other problems during pregnancy (Wouters et al. 1993; Frosst et al. 1995; Nelen et al. 1997, 1998; Quere et al. 1998; Van Der Put et al. 1998; Alam et al. 2008). In comparison, the presence of MTHFR mutations, especially if there is an additional folate deficiency, causes a decrease in S-adenosyl-methionine level leading to DNA hypomethylation, which could affect embryo development. Moreover, MTHFR mutations have also been associated with chromosomal non-disjunction and fetal aneuploidies (Melnyk et al. 2000; Hassold et al. 2001).