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Concept: Homocystinuria


Considering that hyperhomocysteinemia is an independent risk factor for cardiovascular disease, the purpose of this study was to determine the kinetics of serum homocysteine (tHcy) and the vitamins involved in its metabolism (folates, B(12), and B(6)) in response to acute exercise at different intensities. Eight sedentary males (18-27 yr) took part in the study. Subjects were required to complete two isocaloric (400 kcal) acute exercise trials on separate occasions at 40% (low intensity, LI) and 80% VO(2peak) (high intensity, HI). Blood samples were drawn at different points before (pre4 and pre0 h), during (exer10, exer20, exer30, exer45, and exer60 min), and after exercise (post0, post3, and post19 h). Dietary, genetic, and lifestyle factors were controlled. Maximum tHcy occurred during exercise, both at LI (8.6 (8.0-10.1) µmol/L, 9.3% increase from pre0) and HI (9.4 (8.2-10.6) µmol/L, 25.7% increase from pre0), coinciding with an accumulated energy expenditure independent of the exercise intensity. From this point onwards tHcy declined until the cessation of exercise and continued descending. At post19, tHcy was not different from pre-exercise values. No values of hyperhomocysteinemia were observed at any sampling point and intensity. In conclusion, acute exercise in sedentary individuals, even at HI, shows no negative effect on tHcy when at least 400 kcal are spent during exercise and the nutritional status for folate, B(12), and B(6) is adequate, since no hyperhomocysteinemia has been observed and basal concentrations were recovered in less than 24 h. This could be relevant for further informing healthy exercise recommendations.

Concepts: Nutrition, Obesity, Cardiovascular disease, Vitamin, Folic acid, Negative feedback, Homocysteine, Homocystinuria


Classical homocystinuria (homocysteinemia type 1, MIM# 236200) is a rare inherited disorder in Mainland China. This study aimed to identify mutations in the cystathionine β-synthase (CBS) gene which are associated with classical homocystinuria in nine Chinese patients.

Concepts: Genetics, China, People's Republic of China, Mainland, Mainland China, Chinese Civil War, Homocysteine, Homocystinuria


We present the results of the 45-year clinical observation of 27 Russian homocystinuria patients. We made a mutation analysis of theCBSgene for thirteen patients from eleven unrelated genealogies. All patients except for the two were compound heterozygotes for the mutations detected. The most frequent mutation in the cohort investigated was splice mutation IVS11-2a->c. We detected one new nonsense mutation, one new missense-mutation and three novel small deletions. We also report the clinical case of the B6-responsive patient genotyped as Ile278Thr/Cys109Arg.

Concepts: DNA, Mutation, Point mutation, Missense mutation, Nonsense mutation, Homocystinuria, Cystathionine, Cystathionine beta synthase


We report on the 1st case of ischemic priapism secondary to poorly controlled homocystinuria. Homocystinuria is a rare, autosomal recessive, inherited disorder of metabolism that is caused by a deficiency of cystathionine synthase, leading to marked hyperhomocysteinemia. Arterial and/or venous thromboemboli are a major cause of mortality and morbidity in patients with homocystinuria. Untreated patients have a 50% chance of having a vascular event by 30 years of age. Increased homocysteine levels have been reported to upregulate prothrombotic factors and downregulate antithrombotic factors; in particular, increased homocystinuria has been found to downregulate nitric oxide (NO). Mice that are deficient in NO synthase in the cavernosal smooth muscles have a higher incidence of priapism. Decrease in NO synthase causes downregulation of cyclic guanosine monophosphate, phosphodiesterase type 5A, and Rho A/Rho-kinase. Because persistently increased homocysteine also downregulates NO, a similar mechanism could be proposed for priapism secondary to homocystinuria. In patients presenting with priapism, specific features of homocystinuria should be sought; in selected patients, screening with plasma total homocysteine might be appropriate. Ischemic priapism secondary to homocystinuria appears to respond well to the standard treatment options of aspiration, intracavernosal injection with phenylephrine, and, if required, a shunting procedure. Johnson M, Murphy E, Raheem A, Ralph D. Poorly Controlled Homocystinuria: A Rare Cause of Ischemic Priapism? Sex Med 2018;X:XXX-XXX.

Concepts: Artery, Nitric oxide, Cyclic guanosine monophosphate, Homocysteine, Downregulation and upregulation, Homocystinuria, Cystathionine, Cystathionine beta synthase


Several studies have reported hyperhomocysteinemia in vitiligo patients, suggesting the potential role of elevated homocysteine levels in precipitating vitiligo.

Concepts: Homocysteine, Methylenetetrahydrofolate reductase, Homocystinuria, Vitiligo, Hyperhomocysteinemia


Deficiency of cystathionine β-synthase (CBS) activity is the most common cause of increased homocysteine (Hcy). However, until now the underlying mechanisms why CBS activity decreased still remain unresolved. The goal of this study was to explore the contribution of nitrative stress to deficiency of CBS activity, and further identify the possible nitration sites of CBS protein. Results showed that in elderly people, there was an increased nitrative stress level, which was relative to elevated Hcy level. In natural aging rats and diet-induced hyperhomocysteinemia (HHcy) rats, the levels of Hcy and nitrative stress were both elevated, and interestingly, pretreatment with peroxynitrite (ONOO(-)) scavenger FeTMPyP ameliorated the elevation of Hcy as well as nitrative stress. Further experiments showed the reduction of CBS bioactivity and elevation of CBS nitration in two rats models were both reversed by FeTMPyP pretreatment. In vitro, replacement of tyrosine (Tyr, Y) residue (Tyr(163), Tyr(223), Tyr(381), Tyr(518)) in CBS with alanine (Ala, A) abolished the Hcy-mediated CBS inactivation. These results highlighted that deficiency of CBS activity was correlated with the nitration of CBS at Tyr(163), Tyr(223), Tyr(381) and Tyr(518), which may play a mutual role in the progression of HHcy. This discovery may shed a novel light on the pathogenesis of HHcy and provide a possible gene therapy target to HHcy.

Concepts: Protein, Amino acid, Middle age, Gerontology, Old age, Homocystinuria, Alanine, Cystathionine


In general, hyperhomocysteinemia is increasingly appreciated as a risk factor for various diseases, including osteoporosis. However, its effects in non-adults remain largely unknown. Our aim was to determine whether dietary-caused increased homocysteine levels have deleterious effects on bone structure during growth.

Concepts: Protein, Bone, Amino acid, Collagen, Investment, Homocysteine, Methionine, Homocystinuria


Protein-depleted states generate allosteric inhibition of liver cystathionine β-synthase (CBS), which governs the first enzymatic step of the transsulfuration cascade, resulting in upstream accretion of homocysteine (Hcy) in body fluids. A similar Hcy increase may arise from normal hepatocytes undergoing experimentally-induced impairment of betaine-homocysteine methyltransferase (BHTM) activity or from components of lean body mass (LBM) submitted to any inflammatory disorder. LBM comprises a composite agglomeration of extrarenal tissues characterized by naturally occurring BHTM inactivity. As a result of cellular injury, LBM releases high concentrations of Hcy into the extracellular space, contrasting with the disruption of normal remethylation pathways. Hyperhomocysteinemia acts as a biomarker, reflecting the severity of insult and operating as an alarm signal. Elevated Hcy levels constitute a precursor pool recognized by a CBS coding region that reacts to meet increased methionine requirements in LBM tissues, using its enhanced production in hepatocytes. Preservation of methionine homeostasis benefits from its high metabolic priority and survival value.

Concepts: Metabolism, Glycogen, Enzyme inhibitor, Cysteine, Homocysteine, Methionine, Homocystinuria, Cystathionine


Homocystinuria due to cystathionine beta synthase (CBS) deficiency presents with a wide clinical spectrum. Treatment by the enteral route aims at reducing homocysteine levels by using vitamin B6, possibly methionine-restricted diet, betaine and/or folate and vitamin B12 supplementation. Currently no nutritional guidelines exist regarding parenteral nutrition (PN) under acute conditions.

Concepts: Nutrition, Vitamin, Folic acid, Vitamin B12, B vitamins, Homocysteine, Homocystinuria, Cystathionine


Hydrogen sulfide (H2S), a cardioprotective gas, is endogenously produced from homocysteine by cystathionine beta synthase (CBS) and cystathionine gamma lyase (CSE) enzymes. However, effect of H2S or homocysteine on CBS and CSE expression, and cross-talk between CBS and CSE are unclear. We hypothesize that homocysteine and H2S regulate CBS and CSE expressions in a dose dependent manner in cardiomyocytes, and CBS deficiency induces cardiac CSE expression. To test the hypothesis, we treated murine atrial HL1 cardiomyocytes with increasing doses of homocysteine or Na2S/GYY4137, a H2S donor, and measured the levels of CBS and CSE. We found that homocysteine upregulates CSE but downregulates CBS whereas Na2S/GYY4137 downregulates CSE but upregulates CBS in a dose-dependent manner. Moreover, the Na2S-treatment downregulates specificity protein-1 (SP1), an inducer for CSE, and upregulates miR-133a that targets SP1 and inhibits cardiomyocytes hypertrophy. Conversely, in the homocysteine-treated cardiomyocytes, CBS and miR-133a were downregulated and hypertrophy was induced. In vivo studies using CBS+/-, a model for hyperhomocysteinemia, and sibling CBS+/+ control mice revealed that deficiency of CBS upregulates cardiac CSE, plausibly by inducing SP1. In conclusion, we revealed a novel mechanism for H2S-mediated regulation of homocysteine metabolism in cardiomyocytes, and a negative feedback regulation between CBS and CSE in the heart.

Concepts: Metabolism, Heart, Hydrogen sulfide, Feedback, Negative feedback, Induced demand, Homocystinuria, Cystathionine