RESUMEN
BACKGROUND: Arginase 1 Deficiency (ARG1-D) is a rare, progressive, metabolic disorder that is characterized by devastating manifestations driven by elevated plasma arginine levels. It typically presents in early childhood with spasticity (predominately affecting the lower limbs), mobility impairment, seizures, developmental delay, and intellectual disability. This systematic review aims to identify and describe the published evidence outlining the epidemiology, diagnosis methods, measures of disease progression, clinical management, and outcomes for ARG1-D patients. METHODS: A comprehensive literature search across multiple databases such as MEDLINE, Embase, and a review of clinical studies in ClinicalTrials.gov (with results reported) was carried out per PRISMA guidelines on 20 April 2020 with no date restriction. Pre-defined eligibility criteria were used to identify studies with data specific to patients with ARG1-D. Two independent reviewers screened records and extracted data from included studies. Quality was assessed using the modified Newcastle-Ottawa Scale for non-comparative studies. RESULTS: Overall, 55 records reporting 40 completed studies and 3 ongoing studies were included. Ten studies reported the prevalence of ARG1-D in the general population, with a median of 1 in 1,000,000. Frequently reported diagnostic methods included genetic testing, plasma arginine levels, and red blood cell arginase activity. However, routine newborn screening is not universally available, and lack of disease awareness may prevent early diagnosis or lead to misdiagnosis, as the disease has overlapping symptomology with other diseases, such as cerebral palsy. Common manifestations reported at time of diagnosis and assessed for disease progression included spasticity (predominately affecting the lower limbs), mobility impairment, developmental delay, intellectual disability, and seizures. Severe dietary protein restriction, essential amino acid supplementation, and nitrogen scavenger administration were the most commonly reported treatments among patients with ARG1-D. Only a few studies reported meaningful clinical outcomes of these interventions on intellectual disability, motor function and adaptive behavior assessment, hospitalization, or death. The overall quality of included studies was assessed as good according to the Newcastle-Ottawa Scale. CONCLUSIONS: Although ARG1-D is a rare disease, published evidence demonstrates a high burden of disease for patients. The current standard of care is ineffective at preventing disease progression. There remains a clear need for new treatment options as well as improved access to diagnostics and disease awareness to detect and initiate treatment before the onset of clinical manifestations to potentially enable more normal development, improve symptomatology, or prevent disease progression.
Asunto(s)
Hiperargininemia , Discapacidad Intelectual , Recién Nacido , Humanos , Preescolar , Arginasa/genética , Hiperargininemia/diagnóstico , Hiperargininemia/epidemiología , Hiperargininemia/genética , Convulsiones/diagnóstico , Convulsiones/epidemiología , Convulsiones/etiología , Espasticidad Muscular/diagnóstico , Espasticidad Muscular/epidemiología , Espasticidad Muscular/genética , Arginina/uso terapéutico , Aminoácidos Esenciales , Progresión de la Enfermedad , NitrógenoRESUMEN
OBJECTIVE: To observe the effect of acupuncture at "Yanglingquan" (GB34) and "Baihui" (GV20) on Na+/K+-ATPase, excitatory amino acid transporters (EAATs) and glutamate (Glu) in hippocampus of post-stroke spasticity rats, so as to explore the central mechanism in anti-spasticity. METHODS: In a total of 48 healthy SD rats, 12 rats were randomly selected to be included into sham operation group, and the remaining rats were used to make a middle cerebral artery occlusion (MCAO) model using a suture method. On the 3rd day after modeling, MCAO limb spasticity rats were screened by neurological deficit symptoms and muscle tension scores, and randomly divided into the model, GB34 (Hui-puncture at GB34) and GB34+GV20 (Hui-puncture at GB34 and horizontal insertion at GV20) groups (n=12 rats in each group), and the treatment was lasted for 7 conse-cutive days. The neurological symptoms and muscle tension score were observed with the Zea Longa score and modified Ashworth scale (MAS). The levels of Glu, EAAT1 (GLAST) and EAAT2 (GLT-1) in the ischemic area of cerebral hippocampus were detected by ELISA, the expression of Na+/K+-ATPase α1 (ATP1α1) was detected by Western blot, the expression of ATP1α1 mRNA was detected by real-time PCR, and the expression of GLAST, GLT-1 and ATP1α1 was detected by immunofluorescence. RESULTS: After modeling, Zea Longa score and MAS score were increased (P<0.01), the level of Glu in the ischemic area of cerebral hippocampus was increased (P<0.01), while the expression levels of GLAST, GLT-1, ATP1α1 protein and mRNA were all decreased (P<0.01) in the model group relevant to the sham operation group. After 7 days' treatment, all the increased and decreased levels of the indexes mentioned above were reversed in the two acupuncture groups relevant to the model group (P<0.01, P<0.05), and the effects of acupuncture at GB34+GV20 were obviously superior to that of acupuncture at GB34 (P<0.05, P<0.01). CONCLUSION: Acupuncture can alleviate post-stroke spasticity effectively, which may be related to its effect in up-regulating the expressions of Na+/K+-ATPase and EAATs in hippocampus. The anti-spastic effect of acupuncture at GB34+GV20 is superior to GB34 alone.
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Terapia por Acupuntura , Accidente Cerebrovascular , Puntos de Acupuntura , Terapia por Acupuntura/métodos , Adenosina Trifosfatasas , Animales , Ácido Glutámico , Infarto de la Arteria Cerebral Media , Espasticidad Muscular/genética , Espasticidad Muscular/terapia , ARN Mensajero , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/terapiaRESUMEN
Intake of folate (vitamin B9) is strongly inversely linked with human cancer risk, particularly colon cancer. In general, people with the highest dietary intake of folate or with high blood folate levels are at a reduced risk (approx. 25%) of developing colon cancer. Folate acts in normal cellular metabolism to maintain genomic stability through the provision of nucleotides for DNA replication and DNA repair and by regulating DNA methylation and gene expression. Folate deficiency can accelerate carcinogenesis by inducing misincorporation of uracil into DNA, by increasing DNA strand breakage, by inhibiting DNA base excision repair capacity and by inducing DNA hypomethylation and consequently aberrant gene and protein expression. Conversely, increasing folate intake may improve genomic stability. This review describes key applications of single cell gel electrophoresis (the comet assay) in assessing genomic instability (misincorporated uracil, DNA single strand breakage and DNA repair capacity) in response to folate status (deficient or supplemented) in human cells in vitro, in rodent models and in human case-control and intervention studies. It highlights an adaptation of the SCGE comet assay for measuring genome-wide and gene-specific DNA methylation in human cells and colon tissue.
Asunto(s)
Monitoreo Biológico/métodos , Neoplasias del Colon/genética , Ensayo Cometa/métodos , Ácido Fólico/farmacología , Inestabilidad Genómica , Análisis de la Célula Individual/métodos , Línea Celular , Neoplasias del Colon/epidemiología , Neoplasias del Colon/prevención & control , Roturas del ADN , Metilación de ADN , Reparación del ADN , Replicación del ADN , Ácido Fólico/sangre , Deficiencia de Ácido Fólico/sangre , Deficiencia de Ácido Fólico/genética , Inestabilidad Genómica/efectos de los fármacos , Inestabilidad Genómica/genética , Genotipo , Homocistinuria/sangre , Homocistinuria/genética , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/sangre , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/fisiología , Espasticidad Muscular/sangre , Espasticidad Muscular/genética , Trastornos Psicóticos/sangre , Trastornos Psicóticos/genética , Riesgo , Uracilo/metabolismoRESUMEN
BACKGROUND: Maternal nutrition and genetics are determinants of breast-milk nutrient composition and, as such, are determinants of the nutritional exposure of breastfed infants. OBJECTIVES: The aim of this study was to determine whether common maternal single nucleotide polymorphisms (SNPs) in folate-dependent enzymes are associated with breast-milk folate content in a cohort of mothers enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) study. METHODS: The MIREC study is a Canadian prospective pregnancy cohort study that recruited 2001 participants between 2008 and 2011. Five folate-related SNPs-MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTHFR 1793G>A (rs2274976), MTR 2756A>G (rs1805087), and MTRR 66A>G (rs1801394)-were genotyped. Breast milk was sampled â¼1 mo postpartum, and tetrahydrofolate (THF), 5-methyl-THF, 5-formyl-THF, 5,10-methenyl-THF, and unmetabolized folic acid (UMFA) were measured using liquid chromatography-tandem mass spectrometry in a subset of participants (n = 551). Associations were assessed using Wald's test. Associations were considered significant if P ≤ 0.01 (Bonferroni correction for multiple testing). RESULTS: None of the SNPs were associated with total breast-milk folate. However, the MTHFR 677C>T SNP was associated with breast-milk UMFA (R2 = 0.01; unadjusted P = 0.004), explaining a small portion of total variance; this association remained significant when adjusted for other covariates, including supplemental folic acid consumption. The MTHFR 1793G>A and MTRR 66A>G SNPs tended to be associated with 5-methyl-THF (R2 = 0.008, P = 0.04) and reduced folates (THF + 5-methyl-THF + 5-formyl-THF + 5,10-methenyl-THF; R2 = 0.01, P = 0.02), respectively. CONCLUSIONS: We found that total breast-milk folate content was not associated with any of the folate-related SNPs examined. The association between the MTHFR 677C>T SNP and breast-milk UMFA, albeit modest, highlights the need to better understand the determinants of breast-milk folate and the impact they might have on milk folate bioavailability.
Asunto(s)
Ácido Fólico/metabolismo , Homocistinuria/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Leche Humana/química , Espasticidad Muscular/genética , Polimorfismo de Nucleótido Simple , Adulto , Canadá , Estudios de Cohortes , Femenino , Ácido Fólico/química , Regulación de la Expresión Génica/efectos de los fármacos , Genotipo , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Embarazo , Estudios Prospectivos , Trastornos Psicóticos/genéticaRESUMEN
BACKGROUND: Methylenetetrahydrofolate-reductase (MTHFR) deficiency is a rare autosomal recessive disorder affecting intracellular folate metabolism with affection of different organ systems and clinical manifestation usually in childhood. OBJECTIVE: We report on four adult members of a family with MTHFR deficiency presenting with neurological and thromboembolic complications in adulthood. METHODS: Extensive diagnostic work-up including genetic testing was performed in four adult members. RESULTS: The male siblings aged 42 and 32years presented with various neurological symptoms, and a recent history of deep vein thrombosis. Extensive diagnostic work-up revealed total homocysteine (tHcy) plasma concentrations of 135µmol/L and 231µmol/L. and compound heterozygosity for two novel MTHFR gene mutations in exon 2 (c.202C>G, p.Arg68Gly) and intron 10 (c.1632+2T>G), and the known polymorphic variant MTHFR c.665C>T (p.Ala222Val, MTHFR 677C>T). Their mother was heterozygous for MTHFR c.1632+2T>G and c.665C>T, and a paternal relative was heterozygous for MTHFR c.202.C>G and MTHFR c.665C>T mutation. Both brothers showed partial response to therapy with betaine and multivitamins with clinical improvement. MTHFR activity was determined in fibroblast extracts and was around 4% of the mean control. Cell culture analysis indicated a re-methylation defect due to MTHFR deficiency. CONCLUSION: Severe hyperhomocysteinemia due to two mutations of the MTHFR gene resulted in severe neurological symptoms in adulthood. Vitamin and methionine supplementation stabilize tHcy plasma levels. Severity of clinical manifestation varied greatly between the siblings. Damages to the nervous system may be present for years before becoming clinically manifest.
Asunto(s)
Homocistinuria/complicaciones , Homocistinuria/fisiopatología , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Espasticidad Muscular/complicaciones , Espasticidad Muscular/fisiopatología , Tromboembolia/complicaciones , Tromboembolia/fisiopatología , Adulto , Encéfalo/diagnóstico por imagen , Familia , Femenino , Homocisteína/sangre , Homocistinuria/genética , Homocistinuria/terapia , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Espasticidad Muscular/genética , Espasticidad Muscular/terapia , Mutación , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/genética , Trastornos Psicóticos/fisiopatología , Trastornos Psicóticos/terapia , Tromboembolia/genética , Tromboembolia/terapiaRESUMEN
Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C > T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex. Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid.
Asunto(s)
Ácido Fólico/efectos adversos , Homocistinuria/genética , Memoria a Corto Plazo/efectos de los fármacos , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Espasticidad Muscular/genética , Acetilcolina/genética , Acetilcolina/metabolismo , Animales , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Dieta/efectos adversos , Femenino , Ácido Fólico/administración & dosificación , Homocistinuria/inducido químicamente , Homocistinuria/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/fisiopatología , Metilación , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Ratones , Espasticidad Muscular/inducido químicamente , Espasticidad Muscular/patología , Embarazo , Trastornos Psicóticos/genética , Trastornos Psicóticos/patologíaRESUMEN
To explore the effects of Shaoyao Gancao decoction on contents of amino acids and expressions of receptors in the brains of spastic paralysis rats, the spastic paralysis rat models of stroke convalescence were made by line tethering method. Baclofen was used as the control group, and the experiment group received Shaoyao Gancao decoction at 3â¶1 proportions. After 3 weeks, the neurobehavioral scores, muscular tension and pain threshold were measured and compared. High performance liquid chromatography (HPLC) was used to detect the contents of GABA, Gly, Glu, Asp in cerebral cortex. The protein expressions of GABA receptors Aα1, Bï¼ NMDA receptor NR1, NR2A and NR2B in cerebral cortex were determined by immunohistochemistry assay. The results showed that the Shaoyao Gancao decoction at 3â¶1 proportion could improve the spastic paralysis state after stroke, significantly improve neurological symptoms (P<0.01), decrease muscular tension (P<0.01) and improve pain threshold (P<0.05) as compared with model group. Simultaneously, the contents of inhibitory amino acids GABA and Gly were increased significantly (P<0.01), while with a decrease tendency in excitatory amino acids Glu and Asp (with no statistical significance). In addition, it could significantly increase the protein expressions of neurotransmitter GABA receptors Aα1, and B (P<0.05); reduce the expressions of neurotransmitter NMDA receptors NR1, NR2A and NR2B (P<0.05). These results suggested that the Shaoyao Gancao decoction at 3ï¼1 proportion could effectively relieve spasm and pain. The mechanism might be associated with increasing the contents of inhibitory amino acids and increasing the expressions of their receptors in spastic paralysis rats after stroke, which would consequently enhance the signal transduction of inhibitory amino acids. Meanwhile, there was a decrease tendency in excitatory amino acids, although no significant effect was observed, and it could suppress the expressions of excitatory amino acids receptors, thus weaken the excitatory signal transduction. Thereby the neurotoxicity was relieved eventually. These findings indicated that Shaoyao Gancao decoction could regulate the balance of neurotransmitter system to relieve the spasticity, and eventually achieve tendon tonifying and spasm relieving effect.
Asunto(s)
Aminoácidos/metabolismo , Encéfalo/efectos de los fármacos , Medicamentos Herbarios Chinos/administración & dosificación , Espasticidad Muscular/tratamiento farmacológico , Parálisis/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo , Aminoácidos/química , Animales , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Humanos , Masculino , Espasticidad Muscular/genética , Espasticidad Muscular/metabolismo , Parálisis/genética , Parálisis/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
OBJECTIVE: To investigate the effect of catgut implantation at acupoints on the expressions of γ-amino butyric acid B receptor (GABA(B)) and metabotropic glutamate receptor 1 (mGluR1) in the brain stem of rats with spasticity after stroke. METHODS: In total, 60 male Sprague-Dawley rats were randomly divided into three groups: a sham group (n = 10), a model group (n = 25) and a treatment group (n = 25). The rats in both the model group and the treatment group were subjected to middle cerebral artery occlusion to establish a model of focal cerebral ischemia. Rats with limb-spasm met the inclusion criteria. Only the left carotid artery was isolated in sham group rats. Three days after modeling, the treatment group was subjected to catgut implantation at Dazhui (GV 14), Guanyuan (CV 4), and Zhongwan (CV 12). Neurological deficit symptoms were assessed with the Zea-Longa neurological deficit score. The Modified Ashworth Scale (MAS), and isolated muscle tone were used to evaluate spasticity before and after treatment. Immunohistochemistry was applied to determine the expression of GABA(B) and mGluR1 in the rat brain stem after treatment. RESULTS: After treatment, neural impairment symptoms had significantly improved in the treatment group when compared to the model group (P < 0.05). Both MAS and isolated muscle tone in the treatment group were significantly decreased when compared with the model group (P < 0.05), and were also lower than before treatment. GABA(B) expression was significantly higher and mGluR1 was lower in the treatment group when compared with the model group (P < 0.01 and P < 0.05, respectively). CONCLUSION: Catgut implantation at Dazhui (GV14), Guanyuan (CV 4), and Zhongwan (CV 12), can relieve limb spasticity by increasing the expression of GABA(B) and reducing the expression of mGluR1 in the brain stem of rats after stroke.
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Tronco Encefálico/metabolismo , Espasticidad Muscular/genética , Espasticidad Muscular/terapia , Receptores de Glutamato Metabotrópico/genética , Accidente Cerebrovascular/complicaciones , Ácido gamma-Aminobutírico/metabolismo , Puntos de Acupuntura , Terapia por Acupuntura , Animales , Catgut , Modelos Animales de Enfermedad , Humanos , Masculino , Espasticidad Muscular/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Ácido gamma-Aminobutírico/genéticaRESUMEN
Little is known about the conditions contributing to the stability of DNA methylation patterns in male germ cells. Altered folate pathway enzyme activity and methyl donor supply are two clinically significant factors that can affect the methylation of DNA. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme involved in providing methyl groups from dietary folate for DNA methylation. Mice heterozygous for a targeted mutation in the Mthfr gene (Mthfr(+/-)) are a good model for humans homozygous for the MTHFR 677C>T polymorphism, which is found in 10% of the population and is associated with decreased MTHFR activity and infertility. High-dose folic acid is administered as an empirical treatment for male infertility. Here, we examined MTHFR expression in developing male germ cells and evaluated DNA methylation patterns and effects of a range of methionine concentrations in spermatogonia from Mthfr(+/-) as compared to wild-type, Mthfr(+/+) mice. MTHFR was expressed in prospermatogonia and spermatogonia at times of DNA methylation acquisition in the male germline; its expression was also found in early spermatocytes and Sertoli cells. DNA methylation patterns were similar at imprinted genes and intergenic sites across chromosome 9 in neonatal Mthfr(+/+) and Mthfr(+/-) spermatogonia. Using spermatogonia from Mthfr(+/+) and Mthfr(+/-) mice in the spermatogonial stem cell (SSC) culture system, we examined the stability of DNA methylation patterns and determined effects of low or high methionine concentrations. No differences were detected between early and late passages, suggesting that DNA methylation patterns are generally stable in culture. Twenty-fold normal concentrations of methionine resulted in an overall increase in the levels of DNA methylation across chromosome 9, suggesting that DNA methylation can be perturbed in culture. Mthfr(+/-) cells showed a significantly increased variance of DNA methylation at multiple loci across chromosome 9 compared to Mthfr(+/+) cells when cultured with 0.25- to 2-fold normal methionine concentrations. Taken together, our results indicate that DNA methylation patterns in undifferentiated spermatogonia, including SSCs, are relatively stable in culture over time under conditions of altered methionine and MTHFR levels.
Asunto(s)
Metilación de ADN , Inestabilidad Genómica , Metionina/farmacología , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Espermatogonias/metabolismo , Células Madre Adultas/efectos de los fármacos , Células Madre Adultas/fisiología , Animales , Animales Recién Nacidos , Células Cultivadas , Metilación de ADN/efectos de los fármacos , Suplementos Dietéticos , Femenino , Inestabilidad Genómica/efectos de los fármacos , Homocistinuria/tratamiento farmacológico , Homocistinuria/genética , Masculino , Metionina/uso terapéutico , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Espasticidad Muscular/tratamiento farmacológico , Espasticidad Muscular/genética , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/genética , Espermatogonias/efectos de los fármacosRESUMEN
The methylenetetrahydrofolate reductase (MTHFR) 677 CâT polymorphism may be associated with elevated total homocysteine (tHcy) levels, an independent risk factor for cardiovascular disease. It was the study objective to evaluate in vivo lipid peroxidation and platelet activation in carriers of the MTHFR 677 CâT polymorphism and in non-carriers, in relation to tHcy and folate levels. A cross-sectional comparison of urinary 8-iso-prostaglandin (PG)F(2α) and 11-dehydro-thromboxane (TX)B(2) (markers of in vivo lipid peroxidation and platelet activation, respectively) was performed in 100 carriers and 100 non-carriers of the polymorphism. A methionine-loading test and folic acid supplementation were performed to investigate the causal relationship of the observed associations. Urinary 8-iso-PGF(2α) and 11-dehydro-TXB(2) were higher in carriers with hyperhomocysteinaemia than in those without hyperhomocysteinaemia (p<0.0001). Hyperhomocysteinaemic carriers had lower folate levels (p=0.0006), higher urinary 8-iso-PGF(2α) (p<0.0001) and 11-dehydro-TXB(2) (p<0.0001) than hyperhomocysteinaemic non-carriers. On multiple regression analysis, high tHcy (p<0.0001), low folate (p<0.04) and MTHFR 677 CâT polymorphism (p<0.001) independently predicted high rates of 8-iso-PGF(2α) excretion. Methionine loading increased plasma tHcy (p=0.002), and both urinary prostanoid metabolites (p=0.002). Folic acid supplementation was associated with decreased urinary 8-iso-PGF(2α) and 11-dehydro-TXB2 excretion (p<0.0003) in the hyperhomocysteinaemic group, but not in the control group, with substantial inter-individual variability related to baseline tHcy level and the extent of its reduction. In conclusion, hyperhomocysteinaemia due to the MTHFR 677 CâT polymorphism is associated with enhanced in vivo lipid peroxidation and platelet activation that are reversible, at least in part, following folic acid supplementation. An integrated biomarker approach may help identifying appropriate candidates for effective folate supplementation.
Asunto(s)
Homocistinuria/sangre , Hiperhomocisteinemia/sangre , Metilenotetrahidrofolato Reductasa (NADPH2)/deficiencia , Espasticidad Muscular/sangre , Estrés Oxidativo , Activación Plaquetaria , Polimorfismo de Nucleótido Simple , Biomarcadores , Enfermedades Cardiovasculares/epidemiología , Comorbilidad , Estudios Transversales , Diabetes Mellitus/epidemiología , Dinoprost/análogos & derivados , Dinoprost/orina , Dislipidemias/epidemiología , Ácido Fólico/sangre , Ácido Fólico/uso terapéutico , Homocistinuria/epidemiología , Homocistinuria/genética , Humanos , Hiperhomocisteinemia/tratamiento farmacológico , Hiperhomocisteinemia/epidemiología , Hiperhomocisteinemia/genética , Peroxidación de Lípido , Metionina , Metilenotetrahidrofolato Reductasa (NADPH2)/sangre , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Espasticidad Muscular/epidemiología , Espasticidad Muscular/genética , Trastornos Psicóticos/sangre , Trastornos Psicóticos/epidemiología , Trastornos Psicóticos/genética , Fumar/epidemiología , Tromboxano B2/análogos & derivados , Tromboxano B2/orinaRESUMEN
An exaggerated startle response caused by mutations of the alpha 1 subunit gene of the inhibitory glycine receptor (GLRA1) is the key symptom of human hyperekplexia or startle disease. The recessive mouse mutant spasmodic (spd) carries a missense mutation in the corresponding murine Glra1 gene which reduces the affinity of agonists for the mutant receptor. This mutant has been regarded as an animal model with which to investigate the molecular basis of hyperekplexia and related motor disorders. The recessive mouse mutant spastic (spa) carries an insertional mutation in the glycine receptor beta subunit gene (Glrb) that results in aberrant splicing and, consequently, in a reduced number of functionally intact receptors. The resulting phenotype is similar to that of spasmodic. This study measured the acoustic startle response of spasmodic and spastic mice under different stimulus conditions, in order to test for sensorimotor processing deficits in these animals. Both mutants show increased startle responses to acoustic stimuli of different intensities compared with wild-type animals.