RESUMEN
Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides "proof of principle" that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH, and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since, in general, Arg to Cys changes comprise about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.
Asunto(s)
Arginina/química , Cisteamina/química , Cisteína/química , Cistinosis/terapia , Mutación , Animales , Apolipoproteína E3/metabolismo , Argininosuccinatoliasa/metabolismo , Cistationina betasintasa/metabolismo , Cistinosis/genética , Cistinosis/metabolismo , Homeostasis , Humanos , Concentración de Iones de Hidrógeno , Conformación Molecular , Mutación Missense , Oxidación-Reducción , Compuestos de Sulfhidrilo/química , Tromboplastina/metabolismoRESUMEN
INTRODUCTION: Adenosine kinase deficiency (ADK deficiency) is a recently described disorder of methionine and adenosine metabolism resulting in a neurological phenotype with developmental delay, muscular hypotonia, and epilepsy as well as variable systemic manifestations. The underlying neuropathology is poorly understood. We have investigated MRI and (1)H-MRS changes in ADK deficiency in order to better understand the in vivo neuropathologic changes of ADK deficiency. METHODS: Systematic evaluation of 21 MRIs from eight patients (age range 9 days-14.6 years, mean 3.9 years, median 2.7 years) including diffusion-weighted imaging in six and (1)H-MRS in five patients. RESULTS: Brain maturation was delayed in the neonatal period and in infancy (6/6), but ultimately complete. White matter changes occurring in five of eight patients were discrete, periventricular, and unspecific (4/5), or diffuse with sparing of optic radiation, corona radiata, and pyramidal tracts (1/5). Choline was low in white matter spectra (3/3), while there was no indication of low creatine in white matter or basal ganglia (5/5), and diffusion was variably decreased or increased. Central tegmental tract hyperintensity was a common finding (6/8), as was supratentorial atrophy (6/8). CONCLUSIONS: MRI changes in ADK deficiency consist of delayed but ultimately completed brain maturation with later onset of mostly unspecific white matter changes and potentially transient central tegmental tract hyperintensity. Immaturity on neonatal MRI is consistent with prenatal onset of disease and reduced choline with lower membrane turnover resulting in delayed myelination and deficient myelin maintenance.
Asunto(s)
Adenosina Quinasa/deficiencia , Encefalopatías Metabólicas/enzimología , Encefalopatías Metabólicas/patología , Encéfalo/metabolismo , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Espectroscopía de Protones por Resonancia Magnética/métodos , Adenosina Quinasa/metabolismo , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Imagen Molecular/métodos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Several studies have observed positive associations between bone disease and cardiovascular disease. A potential common pathway is hyperhomocysteinemia; however, to date, there is a lack of data regarding hyperhomocysteinemic populations. Therefore, we examined both cross-sectionally and longitudinally, whether there is an association between bone parameters and arterial stiffness in a hyperhomocysteinemic population, and investigated the potential common role of homocysteine (hcy) level on these associations. Cross-sectional and longitudinal data of the B-PROOF study were used (n = 519). At both baseline and 2-year follow-up we determined bone measures-incident fractures and history of fractures, bone-mineral density (BMD) and quantitative ultrasound (QUS) measurement. We also measured arterial stiffness parameters at baseline-pulse wave velocity, augmentation index and aortic pulse pressure levels with applanation tonometry. Linear regression analysis was used to examine these associations and we tested for potential interaction of hcy level. The mean age of the study population was 72.3 years and 44.3 % were female. Both cross-sectionally and longitudinally there was no association between arterial stiffness measures and BMD or QUS measurements or with incident fractures (n = 16) within the 2-3 years of follow-up. Hcy level did not modify the associations and adjustment for hcy did not change the results. Arterial stiffness was not associated with bone parameters and fractures, and hcy neither acted as a pleiotropic factor nor as a mediator. The potential association between bone and arterial stiffness is therefore not likely to be driven by hyperhomocysteinemia.
Asunto(s)
Arterias/patología , Hiperhomocisteinemia/fisiopatología , Rigidez Vascular/fisiología , Densidad Ósea , Huesos/metabolismo , Huesos/fisiología , Estudios Transversales , Humanos , Hiperhomocisteinemia/metabolismo , Osteoporosis/metabolismo , Osteoporosis/fisiopatologíaRESUMEN
OBJECTIVES: Whereas evidence exists about the benefits of intensive exercise on cardiovascular outcomes in older adults, data are lacking regarding long-term effects of physical fitness and physical activity on cardiovascular health. Therefore, we aimed to investigate the longitudinal association of physical fitness, physical activity and muscle strength with arterial stiffness measures. DESIGN: a longitudinal follow-up study (2 years) of data from the B-PROOF study. SETTING: a subgroup of the B-PROOF study (n=497). PARTICIPANTS: Four hundred ninety-seven participants with a mean age of 72.1 years (SD 5.4) of which 57% was male. MEASUREMENTS: All performed at baseline and after two-year follow-up. Arterial stiffness was estimated by pulse wave velocity (PWV) measured with applanation tonometry. Furthermore, augmentation index (AIx) and aortic pulse pressure (PP) were assessed. Physical activity was estimated using a validated questionnaire regarding daily activities. Physical fitness was measured with a physical performance score, resulting from a walking, chair-stand and balance test. Muscle strength was assessed with hand-grip strength using a handheld dynamometer. RESULTS: The median performance score was 9.0 [IQR 8.0-11.0], the mean physical activity was 744.4 (SD 539.4) kcal/day and the mean hand-grip strength was 33.1 (SD 10.2) kg. AIx differed between the baseline and follow-up measurement (26.2% (SD 10.1) vs. 28.1% (SD 9.9); p < 0.01), whereas PWV and aortic PP did not. In multivariable linear regression analysis, physical performance, physical activity and hand-grip strength at baseline were not associated with the amount of arterial stiffness after two years of follow-up. CONCLUSION: Physical fitness, activity and muscle strength were not associated with arterial stiffness. More research is warranted to elucidate the long-term effects of daily and intensive physical activity on arterial stiffness in an elderly population.
Asunto(s)
Envejecimiento/fisiología , Ejercicio Físico/fisiología , Fuerza de la Mano/fisiología , Aptitud Física/fisiología , Rigidez Vascular/fisiología , Anciano , Presión Arterial , Femenino , Estudios de Seguimiento , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Equilibrio Postural , Análisis de la Onda del Pulso , Encuestas y Cuestionarios , CaminataRESUMEN
Ibogaine is a naturally occurring psychoactive alkaloid extracted from the roots of the Tabernanthe iboga plant, which in alternative medicine is used to treat drug dependency. However, this upcoming, online advocated therapy can be dangerous due to its potentially lethal adverse effects. We present three cases in which toxic side effects were noted. We used the Naranjo scale to estimate the probability of a causal relationship between these effects and ibogaine. Findings in these three cases are suggestive of a causal relationship between the use of ibogaine and serious respiratory and cardiac problems (including lengthening of the QT interval). In our opinion it is of great importance that clinicians are aware of these potentially serious side effects and realise that widespread online marketing practices will give many more people access to ibogaine.
Asunto(s)
Ibogaína/efectos adversos , Taquicardia Ventricular/inducido químicamente , Taquicardia/inducido químicamente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Torsades de Pointes/inducido químicamenteRESUMEN
Hyperhomocysteinemia (HHcy) is a risk factor for vascular disease, but the underlying mechanisms remain incompletely defined. Reduced bioavailability of nitric oxide (NO) is a principal manifestation of underlying endothelial dysfunction, which is an initial event in vascular disease. Inhibition of cellular methylation reactions by S-adenosylhomocysteine (AdoHcy), which accumulates during HHcy, has been suggested to contribute to vascular dysfunction. However, thus far, the effect of intracellular AdoHcy accumulation on NO bioavailability has not yet been fully substantiated by experimental evidence. The present study was carried out to evaluate whether disturbances in cellular methylation status affect NO production by cultured human endothelial cells. Here, we show that a hypomethylating environment, induced by the accumulation of AdoHcy, impairs NO production. Consistent with this finding, we observed decreased eNOS expression and activity, but, by contrast, enhanced NOS3 transcription. Taken together, our data support the existence of regulatory post-transcriptional mechanisms modulated by cellular methylation potential leading to impaired NO production by cultured human endothelial cells. As such, our conclusions may have implications for the HHcy-mediated reductions in NO bioavailability and endothelial dysfunction.
Asunto(s)
Arginina/análogos & derivados , Células Endoteliales/metabolismo , Metilación , Óxido Nítrico/metabolismo , S-Adenosilhomocisteína/metabolismo , Arginina/metabolismo , Células Cultivadas , Regulación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hiperhomocisteinemia/metabolismo , Óxido Nítrico/deficiencia , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Enfermedades Vasculares/metabolismoRESUMEN
BACKGROUND/OBJECTIVES: This study aimed to investigate whether higher homocysteine and lower vitamin B12 concentrations increase the risk of future nursing home (NH) admission and all-cause mortality in independently living older persons. SUBJECTS/METHODS: In total, 1117 independently living participants (mean age=75.1, s.d.=6.4) were included in this prospective sub-study of the Longitudinal Aging Study Amsterdam. EDTA plasma samples, collected in 1995-1996, were analysed for total homocysteine (µmol/l). Time to NH admission was assessed using a follow-up until 2002-2003. In addition, we studied mortality until 1 June 2007. Cox proportional hazards models were used to examine the association between homocysteine in quartiles and risk of NH admission and mortality. RESULTS: During follow-up, 126 persons (11.3%) were admitted to NHs, and 513 persons (45.9%) deceased. In men, no significant associations were observed. In women, after adjustment for confounding, the highest quartile of homocysteine was associated with a significantly higher risk of NH admission compared with the first quartile (hazard ratio (HR)=2.97, 95% confidence interval (CI)=1.36-6.49). Both women in the third and the fourth quartile of homocysteine had a significantly higher mortality risk (HR=1.70, 95% CI=1.08-2.65 and HR=1.91, 95% CI=1.22-3.00, respectively) compared with the first quartile. Vitamin B12 was not related to an increased risk of NH admission and mortality. CONCLUSIONS: Elevated plasma homocysteine is associated with an increased risk of NH admission and mortality in older women, but not in older men.
Asunto(s)
Homocisteína/sangre , Mortalidad , Casas de Salud , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Estudios Longitudinales , Masculino , Países Bajos/epidemiología , Modelos de Riesgos Proporcionales , Factores SexualesRESUMEN
Cystinosis is an autosomal recessive lysosomal storage disease caused by mutations in CTNS. The most prevalent CTNS mutation is a homozygous 57-kb deletion that also includes an adjacent gene named SHPK (CARKL), encoding sedoheptulokinase. Patients with this deletion have elevated urinary concentrations of sedoheptulose. Using derivatisation with pentafluorobenzyl hydroxylamine and liquid chromatography-tandem mass spectrometry (LC-MS/MS), we developed a new sensitive method for the quantification of sedoheptulose in dried blood spots. This method can be utilized as a quick screening test to detect cystinosis patients homozygous for the 57-kb deletion in CTNS; which is the most common mutation of cystinosis. Sedoheptulose concentrations in the deleted patients were 6 to 23 times above the upper limit for controls. The assessment of sedoheptulose in a bloodspot from a known cystinosis patient homozygous for the 57-kb deletion retrieved from the Dutch neonatal screening program showed that sedoheptulose was already elevated in the neonatal period. There was no overlap in sedoheptulose levels between cystinosis patients homozygous for the 57-kb deletion and cystinosis patients not homozygous for this deletion. Our presented method can be used prior to mutation analysis to detect cystinosis patients homozygous for the 57-kb deletion. We feel that the presented method enables fast (pre)-symptomatic detection of cystinosis patients homozygous for the 57-kb deletion, allowing early treatment.
Asunto(s)
Cistinosis/diagnóstico , Cistinosis/enzimología , Eliminación de Gen , Heptosas/sangre , Tamizaje Neonatal/métodos , Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinosis/sangre , Cistinosis/genética , Humanos , Recién Nacido , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem , Factores de Transcripción/genéticaRESUMEN
OBJECTIVE: The incidence of cerebrovascular accidents (CVA) occurring perinatally is relatively high and aspects of the multifactorial pathophysiology remain unclear. Elevated homocysteine concentrations have been shown to be associated with an increased risk for CVA in children and even in newborns. We studied the possible homocysteine lowering effect of folinic acid in newborns. METHOD: We included 37 newborns in our prospective randomized folinic acid (given as 5-formyltetrahydrofolate) intervention study from patients admitted to our neonatal intensive care unit (18 controls, 19 intervention group). We measured total homocysteine (tHcy) and plasma folate concentrations at three time points (baseline, 1 and 2 weeks after intervention). The intervention group was treated with folinic acid (70 µg/kg/day) for 2 weeks. We calculated median concentrations (25th and 75th percentiles). RESULTS: Median tHcy concentrations at the three time points did not differ from each other in the control group nor in the intervention group. We also could not observe different tHcy concentrations between both groups. Plasma folate concentrations increased in the intervention group (mean increase 167% (95% confidence interval (CI) -291, 625)) compared with control group (mean increase -12% (95% CI -132, 108)), P for treatment effect: 0.03. CONCLUSION: We could not demonstrate a homocysteine lowering effect of folinic acid administration in newborns. This indicates that one carbon metabolism in newborns differs form adults. Cobalamin might be a better strategy to lower tHcy concentrations in newborns.
Asunto(s)
Trastornos Cerebrovasculares/sangre , Suplementos Dietéticos , Ácido Fólico/sangre , Homocisteína/sangre , Enfermedades del Recién Nacido/sangre , Leucovorina/farmacología , Trastornos Cerebrovasculares/prevención & control , Femenino , Humanos , Recién Nacido/sangre , Enfermedades del Recién Nacido/prevención & control , Recien Nacido Prematuro/sangre , Masculino , Estudios Prospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: Axonal degeneration is the likely cause of disease progression in multiple sclerosis (MS). Our previous results indicated that neuron-specific N-acetylaspartate (NAA) is a candidate CSF biomarker for disease progression in MS. The aim of this study was to explore the potential of NAA as an early biomarker of axonal damage in MS. Next, we wanted to know the additional value of measurement of NAA compared to other candidate markers for axonal damage, such as neurofilament subunits and tau protein. METHODS: Levels of NAA, neurofilament light, neurofilament heavy, and tau were determined in CSF of patients with clinically isolated syndrome (CIS, n = 38), relapsing-remitting MS (RRMS, n = 42), secondary progressive MS (SPMS, n = 28), and primary progressive MS (PPMS, n = 6); patients without neurologic disease (ND, n = 28); noninflammatory neurologic controls (n = 18); and inflammatory neurologic controls (n = 39). RESULTS: CSF NAA levels were decreased in patients with SPMS compared to ND controls, patients with CIS, and patients with RRMS. CSF NAA levels in patients with CIS and RRMS were similar to those in ND subjects. All axonal damage proteins showed specific patterns of changes and relations with disease activity measures. The neurofilament light chain levels were already increased in patients with CIS, especially in patients who converted to MS. The neurofilament heavy chain levels were highest in the patients with SPMS. Tau levels were similar in MS and ND. CONCLUSIONS: CSF N-acetylaspartate (NAA) levels were not different from patients without neurologic disease in early stages of multiple sclerosis, though decreased as the disease progressed. Combining CSF NAA and neurofilament levels yields information on different phases of axonal pathology.
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Ácido Aspártico/análogos & derivados , Esclerosis Múltiple/líquido cefalorraquídeo , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Aminoácidos/líquido cefalorraquídeo , Ácido Aspártico/líquido cefalorraquídeo , Axones/patología , Biomarcadores , Estudios de Cohortes , Progresión de la Enfermedad , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple/patología , Esclerosis Múltiple Crónica Progresiva/líquido cefalorraquídeo , Esclerosis Múltiple Crónica Progresiva/patología , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/patología , Degeneración Nerviosa/patología , Proteínas tau/líquido cefalorraquídeoAsunto(s)
Homocistinuria/complicaciones , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Espasticidad Muscular/etiología , Trastornos Psicóticos/etiología , Adulto , Encéfalo/patología , Homocistinuria/patología , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Mutación MissenseRESUMEN
BACKGROUND: Elevated homocysteine levels are associated with various neurodegenerative diseases and have even been identified as a risk factor for some of these. Homocysteine levels may be elevated in patients with multiple sclerosis (MS) but large studies are lacking and the relation with disease progression remains to be determined. AIM: The aim of the study was to investigate homocysteine levels in patients with MS and in controls, and to study the relationship between homocysteine levels and clinical progression in MS. METHODS: Serum homocysteine levels were compared between MS subtypes (n = 219) and controls (n = 152). Homocysteine levels were associated with baseline and follow-up clinical severity scores. RESULTS: The results showed that serum homocysteine values were similar in patients with MS and controls. Baseline scores on the Expanded Disability Status Scale were higher in patients with secondary progressive MS (SPMS) in the top compared with the bottom quartile of homocysteine levels (p = 0.02). The baseline scores on the Multiple Sclerosis Functional Composite (MSFC) and Paced Auditory Serial Addition Test (PASAT), which measures cognitive functioning, were lower in patients with SPMS in the top compared with the bottom quartile of homocysteine levels (MSFC, p = 0.02; PASAT, p = 0.02). High homocysteine levels were associated with a decline in PASAT scores during follow-up in patients with primary progressive MS (p = 0.009). CONCLUSION: Serum total homocysteine levels are associated with several measures of disease progression in MS but are not elevated in patients with MS compared with controls. The association of homocysteine levels with cognition in patients with progressive MS raises the question of whether homocysteine directly impacts on MS or reflects a more general neurodegenerative process.
Asunto(s)
Homocisteína/sangre , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple/sangre , Esclerosis Múltiple/diagnóstico , Enfermedades Neurodegenerativas/sangre , Adulto , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/patología , Neurología/métodos , Factores de RiesgoRESUMEN
OBJECTIVE: To investigate whether secondary impairment of the transmethylation pathway is a mechanism underlying the neurologic involvement in homocystinuria due to remethylation defects. METHODS: Twelve patients with neurologic disease due to remethylation defects were examined by brain magnetic resonance spectroscopic imaging ((1)H MRSI). Brain N-acetylaspartate, choline-containing compounds (Cho), and creatine (Cr) were quantified and compared to with controls. Metabolites of remethylation cycle and creatine biosynthesis pathway were measured in plasma and urine. RESULTS: MRSI revealed isolated Cho deficiency in all regions examined (mean concentration units +/- SD, patients vs controls): frontal white matter (0.051 +/- 0.010 vs 0.064 +/- 0.010; p = 0.001), lenticular nucleus (0.056 +/- 0.011 vs 0.069 +/- 0.009; p < 0.001), and thalamus (0.063 +/- 0.010 vs 0.071 +/- 0.007; p = 0.006). In contrast to controls, the Cho/Cr ratio decreased with age in patients in the three brain regions examined. Low creatine urinary excretion (p < 0.005), normal urine and plasma guanidinoacetate, and a paradoxical increase in plasma S-adenosylmethionine (p < 0.005) concentrations were observed. CONCLUSION: Patients with homocystinuria due to remethylation defects have an isolated brain choline deficiency, probably secondary to depletion of labile methyl groups produced by the transmethylation pathway. Although biochemical studies suggest mild peripheral creatine deficiency, brain creatine is in the reference range, indicating a possible compartmentation phenomenon. Paradoxical increase of S-adenosylmethionine suggests that secondary inhibition of methylases contributes to the transmethylation defect in these conditions.
Asunto(s)
Encéfalo/metabolismo , Deficiencia de Colina/metabolismo , Colina/metabolismo , Homocisteína S-Metiltransferasa/metabolismo , Homocistinuria/sangre , Homocistinuria/orina , Adolescente , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/fisiopatología , Química Encefálica/fisiología , Niño , Preescolar , Deficiencia de Colina/etiología , Deficiencia de Colina/fisiopatología , Creatina/sangre , Creatina/orina , Femenino , Homocistinuria/fisiopatología , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Metilación , S-Adenosilmetionina/metabolismoRESUMEN
Mildly cobalamin-deficient elderly were supplemented with 1000 microg cobalamin (group C, n=34), 1000 microg cobalamin with 400 microg folic acid (group CF, n=31) or a placebo (n=30) for 6 months. Participants provided one single blood sample 3, 5 or 7 months after cessation of supplementation to monitor early changes in plasma concentrations of cobalamin, holotranscobalamin (holoTC) and methylmalonic acid (MMA). At the end of supplementation (groups C+CF), one participant met our criteria for mild cobalamin deficiency, as did 13, 14 and 43% of the participants assessed at respectively 3, 5 and 7 months post-supplementation. Cobalamin and holoTC declined on average with 47 and 56% relative to concentrations at the end of supplementation for the group assessed at 7 months post-supplementation. Essentially similar declines were observed for those participants assessed at 3 and 5 months post-supplementation. Mean MMA concentrations increased by 15% (P=0.07) in those participants assessed at 3 and 5 months post-supplementation, and increased by 50% (P=0.002) in those participants assessed at 7 months post-supplementation. Considering MMA as a sensitive tissue marker for cobalamin status, oral supplementation may afford adequate cobalamin status for a period of up to 5 months after cessation in the majority of participants.
Asunto(s)
Ácido Fólico/sangre , Estado Nutricional , Deficiencia de Vitamina B 12/sangre , Deficiencia de Vitamina B 12/epidemiología , Vitamina B 12/sangre , Complejo Vitamínico B/sangre , Anciano de 80 o más Años , Disponibilidad Biológica , Biomarcadores/sangre , Suplementos Dietéticos , Femenino , Ácido Fólico/farmacología , Estudios de Seguimiento , Humanos , Masculino , Ácido Metilmalónico/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , Resultado del Tratamiento , Vitamina B 12/administración & dosificación , Vitamina B 12/farmacocinética , Deficiencia de Vitamina B 12/tratamiento farmacológico , Complejo Vitamínico B/administración & dosificación , Complejo Vitamínico B/farmacocinéticaRESUMEN
BACKGROUND: Periconceptional folic acid supplementation may protect against congenital heart defects (CHDs). Identification of candidate genes in folate metabolism has suggested that the 677C-->T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene may be particularly associated with the risk of CHDs. AIM: To assess the relationship between MTHFR 677C-->T and CHDs by literature review and meta-analysis. METHODS: Studies were identified by searches of electronic literature for papers focussing on MTHFR 677C-->T and the risk of any type of CHD. Both case-control comparisons and transmission-disequilibrium tests (TDTs) in family-based designs were included. RESULTS: We found 13 eligible studies. Of 10 case-control studies, four focused on the fetal polymorphism, two studied the maternal polymorphism, and a further four investigated both. Three further publications used a family-based association study to assess the effect of the T allele on cardiac development. Overall analysis yielded odds ratios of 1.3 (95%CI 0.97-1.73) and 1.2 (95%CI 0.83-1.74) for fetal and maternal MTHFR TT genotypes, respectively. TDTs revealed no association between fetal 677T allele and CHDs. DISCUSSION: This relatively small meta-analysis found no substantial evidence of increased CHD risk in individuals with MTHFR 677CT and TT genotypes. Heterogeneity regarding population background, study design and type of heart defects complicates the pooling and comparison of the studies. The effect of modification by periconceptional folic acid intake should be taken into account. Further larger studies and well-defined phenotypic subcategory analyses are needed to decide whether the MTHFR 677C-->T polymorphism of the affected child and/or their mother is truly a risk factor for the development of CHDs.
Asunto(s)
Cardiopatías Congénitas/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple/genética , Estudios de Casos y Controles , Preescolar , Femenino , Genotipo , Humanos , Recién Nacido , Factores de RiesgoAsunto(s)
Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Polimorfismo de Nucleótido Simple , Disrafia Espinal/enzimología , Disrafia Espinal/genética , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Variación Genética , Genotipo , Humanos , Masculino , Países Bajos , Factores de RiesgoRESUMEN
Facioscapulohumeral muscular dystrophy (FSHD) is associated with a contraction of the D4Z4 allele on chromosome 4qter. There is also marked DNA hypomethylation of the D4Z4 allele. The DNA hypomethylation may have a central role in the pathogenesis of FSHD. Supplemental folic acid can boost DNA methylation. We evaluated the effect of oral folic acid and methionine supplementation on the methylation level of 4qter D4Z4 alleles in peripheral-blood lymphocytes of nine patients affected with FSHD and six healthy controls. Methylation levels did not change, while recommended serum-folate concentrations were reached.
Asunto(s)
Alelos , Metilación de ADN/efectos de los fármacos , Ácido Fólico/farmacología , Metionina/farmacología , Distrofia Muscular Facioescapulohumeral/genética , Adolescente , Adulto , Estudios de Casos y Controles , ADN/genética , Suplementos Dietéticos , Femenino , Ácido Fólico/administración & dosificación , Ácido Fólico/sangre , Humanos , Masculino , Metionina/administración & dosificación , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Distrofia Muscular Facioescapulohumeral/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Proyectos PilotoRESUMEN
BACKGROUND: An elevated plasma total homocysteine (tHcy) level is a risk factor for many clinical conditions, including vascular disease and venous thrombosis. The tHcy levels are partly determined by genetic factors. Extensive candidate gene studies have identified several genetic variants, including the MTHFR 677C>T, that influence tHcy levels, but so far only part of the genetic variation in tHcy can be explained. OBJECTIVE: In order to identify chromosomal regions that influence tHcy levels, a genome-wide linkage analysis was conducted. PATIENTS/METHODS: Our study population consisted of 13 pedigrees and 469 subjects with data on fasting plasma tHcy levels. A set of 377 markers covering the genome was genotyped in 275 subjects. The variance component linkage method (SOLAR version 2.1.3) was used for the two-point and multipoint linkage analyses. RESULTS: The heritability of the age- and sex-adjusted homocysteine levels was 44%. The multipoint linkage analysis identified one region with suggestive linkage on chromosome 16q (LOD score 1.76; nominal P = 0.0024). Weaker evidence of linkage was found for regions on chromosome 12q (LOD score 1.57; nominal P = 0.0036) and chromosome 13q (LOD score 1.52; nominal P = 0.0041). CONCLUSIONS: In our families the plasma tHcy level was highly heritable. The multipoint linkage analysis identified three regions that showed weak to suggestive linkage to tHcy levels.
Asunto(s)
Ligamiento Genético , Homocisteína/genética , Polimorfismo Genético , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Mapeo Cromosómico , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 16/genética , Femenino , Genoma Humano , Genotipo , Homocisteína/sangre , Humanos , Escala de Lod , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Linaje , Sitios de Carácter CuantitativoRESUMEN
Hyperhomocysteinaemia has been regarded as a new modifiable risk factor for atherosclerosis and vascular disease. Homocysteine is a branch-point intermediate of methionine metabolism, which can be further metabolised via two alternative pathways: degraded irreversibly through the transsulphuration pathway or remethylated to methionine by the remethylation pathway. Both pathways are B-vitamin-dependent. Plasma homocysteine concentrations are determined by nongenetic and genetic factors. The metabolism of homocysteine, the role of B vitamins and the contribution of nongenetic and genetic determinants of homocysteine concentrations are reviewed. The mechanisms whereby homocysteine causes endothelial damage and vascular disease are not fully understood. Recently, a link has been postulated between homocysteine, or its intermediates, and an alterated DNA methylation pattern. The involvement of epigenetic mechanisms in the context of homocysteine and atherosclerosis, due to inhibition of transmethylation reactions, is briefly overviewed.
Asunto(s)
Homocisteína/metabolismo , Hiperhomocisteinemia/diagnóstico , Enfermedades Vasculares/diagnóstico , Animales , Metilación de ADN , Femenino , Humanos , Hiperhomocisteinemia/complicaciones , Hiperhomocisteinemia/genética , Masculino , Modelos Biológicos , Enfermedades Vasculares/complicaciones , Enfermedades Vasculares/genética , Complejo Vitamínico B/metabolismoRESUMEN
BACKGROUND: High circulating levels of homocysteine are a risk factor for arterial and venous thrombosis. This association has been established in numerous case-control studies. In some of these studies, patients were treated with anticoagulants at the time of venapuncture. It is not clear whether homocysteine concentrations are influenced by anticoagulants. If anticoagulation does, indeed, have an effect on homocysteine levels, it might underestimate or overestimate the possible association of homocysteine levels and vascular disease. METHODS: In this study we used two different groups to investigate the effect of coumarin derivatives on homocysteine concentrations. Homocysteine levels were measured in 40 patients who were on the waiting list for orthopedic surgery and who were expected to receive prophylactic anticoagulant therapy after the operation. Measurements were taken before the operation, as well as during and after coumarin therapy. Homocysteine concentrations were also measured in a second study group consisting of 12 healthy volunteers who were treated with oral anticoagulants. RESULTS: Mean homocysteine concentrations increased by 6% (95% CI 2-10%) during the treatment with coumarin derivatives. This corresponds to a 1 mumol/L increase in homocysteine concentration. After the anticoagulant treatment period, the concentrations decreased again. We determined that this slight increase does not influence the interpretation of epidemiological studies. We also observed no significant effect of anticoagulants on homocysteine concentration after 13 weeks of treatment of healthy volunteers (decrease of 3.6%, or approximately 0.6 micromol/L; 95% CI -17.5-8.5%). CONCLUSION: We conclude that anticoagulation does not influence homocysteine concentrations to any significant degree.