Ejecución neuropsicológica y carga de enfermedad en sujetos en riesgo de desarrollar enfermedad de Huntington / Neuropsychological performance and disease burden in individuals at risk of developing Huntington disease

Introducción La enfermedad de Huntington (EH) es un trastorno neurodegenerativo y hereditario. Gracias al diagnóstico predictivo se han descrito características clínicas incipientes en la fase prodrómica. Objetivo Comparar la ejecución en tareas cognitivas de portadores (PEH) del gen de la huntingtina y no portadores (NPEH) y observar la variabilidad en la ejecución, dependiendo de la carga de la enfermedad y cercanía a la etapa manifiesta (edad de inicio de los síntomas). Método Los 146 participantes de un Programa de Diagnóstico Predictivo de EH (PDP-EH) fueron divididos en PEH (41,1%) y NPEH (58,9%). Mediante fórmulas matemáticas se obtuvo la carga de enfermedad y cercanía a la etapa manifiesta en el grupo PEH y se correlacionó con la ejecución neuropsicológica. Resultados Se observaron diferencias significativas entre los grupos con las pruebas Mini-Mental State Examination (MMSE), Stroop-B, SDMT y fluidez fonológica. En el grupo PEH se observaron correlaciones entre la carga de enfermedad con la MMSE, Stroop-B y SDMT. El grupo «Cerca» de la etapa manifiesta es el que obtuvo la puntuación más baja en las pruebas MMSE, Stroop-B, Stroop-C, SDMT y fluidez verbal semántica. De acuerdo al MANCOVA, el efecto MMSE evidencia diferencias estadísticamente significativas entre carga de la enfermedad y la cercanía de inicio de los síntomas. Conclusiones Se observa un nivel menor de desempeño en el grupo PEH con probabilidad de inicio cercano de la fase manifiesta en pruebas que evalúan la velocidad de procesamiento y atención. La disfunción cognitiva prefrontal se altera de manera precoz varios años antes del diagnóstico motor de la EH. (AU)

Introduction Huntington disease (HD) is a hereditary neurodegenerative disorder. Thanks to predictive diagnosis, incipient clinical characteristics have been described in the prodromal phase. Objective To compare performance in cognitive tasks of carriers (HDC) and non-carriers (non-HDC) of the huntingtin gene and to analyse the variability in performance as a function of disease burden and proximity to the manifest stage (age of symptom onset). Method A sample of 146 participants in a predictive diagnosis of HD programme were divided into the HDC (41.1%) and non-HDC groups (58.9%). Mathematical formulae were used to calculate disease burden and proximity to the manifest stage in the HDC group; these parameters were correlated with neuropsychological performance. Results Significant differences were observed between groups in performance on the Mini-Mental State Examination (MMSE), Stroop-B, Symbol-Digit Modalities Test (SDMT), and phonological fluency. In the HDC group, correlations were observed between disease burden and performance on the MMSE, Stroop-B, and SDMT. The group of patients close to the manifest stage scored lowest on the MMSE, Stroop-B, Stroop-C, SDMT, and semantic verbal fluency. According to the multivariate analysis of covariance, the MMSE effect shows statistically significant differences in disease burden and proximity to onset of symptoms. Conclusions Members of the HDC group close to the manifest phase performed more poorly on tests assessing information processing speed and attention. Prefrontal cognitive dysfunction appears early, several years before the motor diagnosis of HD. (AU)

Neuropsychological performance and disease burden in individuals at risk of developing Huntington disease.

INTRODUCTION: Huntington disease (HD) is a hereditary neurodegenerative disorder. Thanks to predictive diagnosis, incipient clinical characteristics have been described in the prodromal phase. OBJECTIVE: To compare performance in cognitive tasks of carriers (HDC) and non-carriers (non-HDC) of the huntingtin gene and to analyse the variability in performance as a function of disease burden and proximity to the manifest stage (age of symptom onset). METHOD: A sample of 146 participants in a predictive diagnosis of HD programme were divided into the HDC (41.1%) and non-HDC groups (58.9%). Mathematical formulae were used to calculate disease burden and proximity to the manifest stage in the HDC group; these parameters were correlated with neuropsychological performance. RESULTS: Significant differences were observed between groups in performance on the Mini-Mental State Examination (MMSE), Stroop-B, Symbol-Digit Modalities Test (SDMT), and phonological fluency. In the HDC group, correlations were observed between disease burden and performance on the MMSE, Stroop-B, and SDMT. The group of patients close to the manifest stage scored lowest on the MMSE, Stroop-B, Stroop-C, SDMT, and semantic verbal fluency. According to the multivariate analysis of covariance, the MMSE effect shows statistically significant differences in disease burden and proximity to onset of symptoms. CONCLUSIONS: Members of the HDC group close to the manifest phase performed more poorly on tests assessing information processing speed and attention. Prefrontal cognitive dysfunction appears early, several years before the motor diagnosis of HD.

Variantes del gen ABCB1 como factores de riesgo y factores moduladores de la edad de inicio en pacientes mexicanos con enfermedad desmielinizante / ABCB1 gene variants as risk factors and modulators of age of onset of demyelinating disease in Mexican patients

Introducción: Las variantes C1236T, G2677T/A y C3435T del gen ABCB1 alteran la función de la glicoproteína P y el transporte de sustancias endógenas y exógenas en la barrera hematoencefálica; además, actúan como factores de susceptibilidad para algunas enfermedades neurodegenerativas.El objetivo del estudio fue determinar la asociación de polimorfismos ABCB1 (C1236T, G2677T/A y C3435T), sus haplotipos y sus combinaciones de genotipos con la enfermedad desmielinizante.MétodoSe genotipificó a 199 pacientes con enfermedad desmielinizante y a 200 controles mestizos mexicanos mediante PCR-RFLP y secuenciación Sanger para comparar las frecuencias de alelos, genotipos, haplotipos y combinaciones de genotipos entre pacientes y controles. El análisis estadístico se realizó con regresión logística y χ2 de Pearson al 95% de confianza; se calculó la OR y se evaluó la asociación con enfermedad desmielinizante.ResultadosLos haplotipos TTT y CGC fueron los más frecuentes en pacientes y controles. El alelo G2677 (OR = 1,79; IC 95%: 1,12-2,86; p = 0,015) muestra asociación con enfermedad desmielinizante, así como los genotipos GG2677 (OR = 2,72; IC 95% = 1,11-6,68; p = 0,025) y CC3435 (OR = 1,82; IC 95%: 1,15-2,90; p = 0,010) y su combinación GG2677/CC3435 (OR = 2,02; IC 95%: 1,17-3,48; p = 0,010) y el haplotipo CAT (OR = 0,21; IC 95%: 0,05-0,66; p = 0,001).Los portadores TTTTTT presentaron la edad de inicio más temprana (23,0 ± 7,7 vs. 31,6 ± 10,7; p = 0,0001).ConclusionesLa combinación de genotipos GG2677/CC3435 está asociada al desarrollo de enfermedad desmielinizante en esta muestra, principalmente en el sexo masculino, en el cual puede darse acumulación tóxica de sustratos de glicoproteína P.En este estudio, la edad de inicio de la enfermedad desmielinizante podría ser modulada diferencialmente entre sexos por el alelo G2677 del gen ABCB1. (AU)

Introduction: The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases.This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes.MethodsPolymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease.ResultsThe TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI: 1.12-2.86; P = .015), as were the genotypes GG2677 (OR: 2.72; 95% CI: 1.11-6.68; P = .025) and CC3435 (OR: 1.82; 95% CI: 1.15-2.90; P = .010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P = .010), and the CAT haplotype (OR: 0.21; 95% CI: 0.05-0.66; P = .001).TTTTTT carriers presented the earliest age of onset (23.0 ± 7.7 years, vs. 31.6 ± 10.7; P = .0001).ConclusionsThe GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates.In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women. (AU)

ABCB1 gene variants as risk factors and modulators of age of onset of demyelinating disease in Mexican patients.

INTRODUCTION: The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes. METHODS: Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease. RESULTS: The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI, 1.12-2.86; P =  .015), as were the genotypes GG2677 (OR: 2.72; 95% CI, 1.11-6.68; P =  .025) and CC3435 (OR: 1.82; 95% CI, 1.15-2.90; P =  .010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P =  .010), and the CAT haplotype (OR: 0.21; 95% CI, 0.05-0.66; P =  .001). TTTTTT carriers presented the earliest age of onset (23.0 ±â€¯7.7 years, vs 31.6 ±â€¯10.7; P =  .0001). CONCLUSIONS: The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.

Psychological discomfort in carriers and non-carriers of the Huntington disease mutation and its relationship with disease burden.

INTRODUCTION: Huntington's disease (HD) is a neurodegenerative and hereditary disorder. Due to the predictive diagnosis, incipient clinical characteristics have been described in the prodromal phase. Several studies have reported an increase in psychiatric symptoms in carriers of the HD gene without motor symptoms. OBJECTIVE: To identify psychological distress in carriers of the mutation that causes HD, without motor symptoms, utilizing the Symptom Checklist 90 (SCL-90), and to correlate with the burden and proximity of the disease. METHOD: A sample of 175 participants in a HD Predictive Diagnostic Program (PDP-HD) was divided into HEP carriers (39.4%) and NPEH non-carriers (61.6%) of the HD-causing mutation. By means of mathematical formulas, the disease burden and proximity to the manifest stage in the PEH group were obtained and it was correlated with the results of the SCL-90-R. RESULTS: Comparing the results obtained in the SCL-90-R of the PEH and NPEH, the difference is observed in the positive somatic male index, where the PEH obtains higher average scores. The correlations between disease burden and psychological distress occur in the domains; obsessions and compulsions, interpersonal sensitivity, hostility, global severity index and positive somatic distress index. A low correlation is observed between the burden of disease and the scores obtained in psychological discomfort. CONCLUSIONS: In general, we found that the PEH group obtained a higher score in the dimensions evaluated with the SCL-90-R, showing a relationship with the burden and differences due to the proximity of the disease. Higher scores on the SCL-90-R dimensions in carriers of the HD gene may suggest an early finding of psychological symptoms in the disease.

Neuropsychological performance and disease burden in individuals at risk of developing Huntington disease. / Ejecución neuropsicológica y carga de enfermedad en sujetos en riesgo de desarrollar enfermedad de Huntington.

INTRODUCTION: Huntington disease (HD) is a hereditary neurodegenerative disorder. Thanks to predictive diagnosis, incipient clinical characteristics have been described in the prodromal phase. OBJECTIVE: To compare performance in cognitive tasks of carriers (HDC) and non-carriers (non-HDC) of the huntingtin gene and to analyse the variability in performance as a function of disease burden and proximity to the manifest stage (age of symptom onset). METHOD: A sample of 146 participants in a predictive diagnosis of HD programme were divided into the HDC (41.1%) and non-HDC groups (58.9%). Mathematical formulae were used to calculate disease burden and proximity to the manifest stage in the HDC group; these parameters were correlated with neuropsychological performance. RESULTS: Significant differences were observed between groups in performance on the Mini-Mental State Examination (MMSE), Stroop-B, Symbol-Digit Modalities Test (SDMT), and phonological fluency. In the HDC group, correlations were observed between disease burden and performance on the MMSE, Stroop-B, and SDMT. The group of patients close to the manifest stage scored lowest on the MMSE, Stroop-B, Stroop-C, SDMT, and semantic verbal fluency. According to the multivariate analysis of covariance, the MMSE effect shows statistically significant differences in disease burden and proximity to onset of symptoms. CONCLUSIONS: Members of the HDC group close to the manifest phase performed more poorly on tests assessing information processing speed and attention. Prefrontal cognitive dysfunction appears early, several years before the motor diagnosis of HD.

ABCB1 gene variants as risk factors and modulators of age of onset of demyelinating disease in Mexican patients. / Variantes del gen ABCB1 como factores de riesgo y factores moduladores de la edad de inicio en pacientes mexicanos con enfermedad desmielinizante.

INTRODUCTION: The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes. METHODS: Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease. RESULTS: The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI: 1.12-2.86; P=.015), as were the genotypes GG2677 (OR: 2.72; 95% CI: 1.11-6.68; P=.025) and CC3435 (OR: 1.82; 95% CI: 1.15-2.90; P=.010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P=.010), and the CAT haplotype (OR: 0.21; 95% CI: 0.05-0.66; P=.001). TTTTTT carriers presented the earliest age of onset (23.0±7.7 years, vs. 31.6±10.7; P=.0001). CONCLUSIONS: The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.

MTHFR C677T, FII G20210A, FV Leiden G1691A, NOS3 intron 4 VNTR, and APOE epsilon4 gene polymorphisms are not associated with spontaneous cervical artery dissection.

AIMS: The pathogenesis of spontaneous cervical artery dissection remains unknown. We examined the association between different polymorphisms frequently found in young patients with cryptogenic stroke [methylenetetrahydrofolate reductase (MTHFR) C677T, factor II (prothrombin) G20210A, factor V G1691A (Leiden), nitric oxide synthase 3 (NOS3) intron 4 VNTR, and apolipoprotein E (APOE) epsilon4 gene] in patients with a cerebral infarct caused by spontaneous cervical artery dissection. METHODS: Forty-eight patients (27 males) and 96 matching control subjects were recruited. Clinical history, including cardiovascular risk factors, was assessed in all subjects. Genotypes were determined by a polymerase chain reaction with and without a restriction fragment length polymorphism. The genotypes and allele frequencies of the five genetic variants studied were compared between spontaneous cervical artery dissection cases and controls. We also incorporated our data into a meta-analysis of the MTHFR/C677T variant. RESULTS: Of 48 patients with spontaneous cervical artery dissection (28 vertebral and 20 carotid), the mean age of the patients was 36.6 +/- SD 9.9 years. There were no significant associations between the alleles of the five genetic polymorphisms studied and spontaneous cervical artery dissection. In the meta-analysis of the MTHFR/C677T variant, a total of 564 individuals (231 cases and 333 controls) were analysed; no significant association was observed. CONCLUSIONS: The results from this exploratory case-control study show the lack of an association between MTHFR, factor II G20210A, factor V G1691A, NOS3, intron 4 VNTR, and APOE epsilon4 gene polymorphisms and the development of spontaneous cervical artery dissection. Our findings contribute towards a better understanding of the genetic risk factors associated with spontaneous cervical artery dissection.