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.

Perceived discrimination in patients with multiple sclerosis and depressive symptomatology.

BACKGROUND: Multiple Sclerosis is the central nervous system's most common demyelinating disease and the second leading cause of neurological disability in young adults. Its natural development involves physical and cognitive impairment. Patients commonly perceive discrimination against them, regardless of its occurrence, accepting it as an inherent part of the disease. OBJECTIVE: This study aimed to determine the association between perceived discrimination and the depressive symptoms and physical disability present in patients diagnosed with multiple sclerosis, treated at the Demyelinating Diseases Clinic of the National Institute of Neurology and Neurosurgery, Manuel Velasco Suárez. METHODS: A cross-sectional study was conducted in 98 patients diagnosed with multiple sclerosis. Demographic and clinical variables were obtained through clinical interviews. The severity of the disease was determined using the Extended Disability Status Scale (EDSS), depressive symptoms were assessed with the Beck Depression Inventory (BDI), and perceived discrimination was rated using the King Internalized Stigma Scale. RESULTS: The studied sample's mean age was 36.3 years, schooling 13.6 years, symptoms onset was at 26.2 years (with a delay in diagnosis of 3.2 years), and a disease evolution of 10.9 years. 71.4% were single; 52% had an unpaid work activity and 57.1% were women. The EDSS average was 3.5 points; 24.5% presented moderate to severe depressive symptoms and 53.1% referred perceived discrimination. CONCLUSIONS: Perceived discrimination in patients with multiple sclerosis was associated with earlier disease onset, depressive symptoms, and the lack of caregivers. Medical care and life quality improvement for this vulnerable group require greater education regarding the disease and the establishment of patient support programs.

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.

Quality of life in patients with multiple sclerosis and its association with depressive symptoms and physical disability.

OBJECTIVE: The aim of this work was to evaluate the quality of life of patients with multiple sclerosis and its association with depressive symptoms and physical health. METHOD: A total of 117 patients clinically diagnosed with Multiple Sclerosis (MS) were studied. The MSQOL-54 scale was applied. The depressive symptoms were assessed using the Beck Depression Inventory (BDI), while degree of physical disability was evaluated with the EDSS (Expanded Disability Status Scale). The results of these last two instruments were associated with MSQOL-54 to determine its influence on the perception of quality of life. RESULTS: We evaluated 65 women (56%) and 52 men (44%), with a mean age of 35 years, a mean age of 27 years at the time of diagnosis, and a mean evolution of 8 years. 88% of the patients showed the relapsing-remitting subtype; 42% had paid employment; 29% of the studied patients required help to perform daily activities; 75% took disease-modifying medications. They obtained on average a score of 3.62 ±â€¯2.30 on the EDSS and 11.5 ±â€¯9.21 on the BDI. The general average in MSQOL-54 was 64.67 ±â€¯17.52. CONCLUSIONS: Quality of life, in patients with multiple sclerosis is an issue that worries health personnel, it is essential to implement strategies for reducing the impact of the disease on patients' lives, mainly through the application of programs aimed to decrees depression and improve social support.

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.

Recent developments in the quest for myoclonic epilepsy genes.

Understanding the latest advances in the molecular genetics of the epilepsies is important, as it provides a basis for comprehending the new practice of epileptology. Epilepsies have traditionally been classified and subtyped on the basis of clinical and neurophysiologic concepts. However, the complexity and variability of phenotypes and overlapping clinical features limit the resolution of phenotype-based classification and confound epilepsy nosology. Identification of tightly linked epilepsy DNA markers and discovery of epilepsy-causing mutations provide a basis for refining the classification of epilepsies. Recent discoveries regarding the genetics surrounding certain epilepsy types (including Lafora's progressive myoclonic epilepsy, the severe myoclonic epilepsy of infancy of Dravet, and idiopathic generalized epilepsies) may be the beginning of a better understanding of how rare Mendelian epilepsy genes and their genetic architecture can explain some complexities of the common epilepsies.

[Juvenile myoclonic epilepsy in chromosome 6p12: clinical and genetic advances]. / Epilepsia mioclónica juvenil del cromosoma 6p12: avances clínicos y genéticos.

Amongst idiopathic generalized epilepsies, juvenile myoclonic epilepsy (JME) is the most common, accounting for 12% to 30% of all epilepsies in the Western world. Classic JME consists of awakening myoclonias, grand mal convulsions and EEG 4 to 6 Hz polyspike waves that appear in adolescence. Probands and affected family members do not have pyknoleptic 3Hz spike and wave absences. However, in 10 to 30% of patients, rare or spanioleptic polyspike wave absences appear. In 1988,1995,1996,we mapped classic JME to a 7 cM locus in chromosome 6p12 11, called EJM1, using families from Los Angeles and Belize. In 2001,we studied one large family from Belize and 21 new families from Los Angeles and Mexico Cities, aided by a BAC/PAC based physical map and 6 new dinucleotide repeats, to narrow EJM1 to an interval between D6S272 and D6S1573. In 2002, we found myoclonin, the putative gene for typical JME in 6p12. At the congress, we will reveal the identity of the myoclonin gene, its putative function and discuss the significance of this discovery in the JME population at large.

Epilepsia mioclónica juvenil en el cromosoma 6p12: avances clínicos y genéticos / Juvenile myoclonic epilepsy in chromosome 6p12: clinical and genetic advances

Entre las epilepsias generalizadas idiopáticas, la epilepsia mioclónica juvenil (EMJ) es la más frecuente y representa el 12-30 por ciento de todas las epilepsias del mundo occidental. La EMJ `clásica' consiste de mioclonía al despertar, crisis convulsivas de gran mal y electroencefalogramas (EEG) con polipunta-ondas de 4 a 6 Hz, que se presentan en la adolescencia. Los probandos y los miembros afectados de la familia no presentan ausencias punta-onda picnolépticas de 3 Hz. Sin embargo, el 10-30 por ciento de los pacientes presentan ausencias polipunta-onda escasas o raras. En 1988, 1995 y 1996 realizamos el mapeo genético de la EMJ `clásica' en un locus de 7 cM en el cromosoma 6p12-11, llamado EMJ1, mediante el empleo de familias de Los Ángeles y Belice. En 2001, estudiamos una familia numerosa de Belice y 21 familias nuevas de Los Ángeles y de Ciudad de México, con la ayuda de un mapa físico basado en recursos BAC/PAC y seis repeticiones dinucleotídicas, para reducir el cromosoma EMJ1 a un intervalo entre los marcadores D6S272 y D6S1573. En 2002, hallamos mioclonín, gen putativo de la EMJ típica en el cromosoma 6p12. En el congreso revelaremos la identidad del gen mioclonín, su función putativa y discutiremos la significación de este descubrimiento en la población con EMJ en general (AU)

Prevalence of acute intermittent porphyria in a Mexican psychiatric population.

BACKGROUND: Acute intermittent porphyria is a hereditary error of porphyrin metabolism in which the main metabolic defect is caused by a decrease in porphobilinogen deaminase activity. Previous work has demonstrated a higher prevalence of acute intermittent porphyria in the psychiatric patient population than in the general population. The goal of this study was evaluate 300 psychiatric patients and 150 control subjects to detect acute intermittent porphyria by measurement of porphobilinogen (PBG) deaminase activity in blood. METHODS: Screening for porphobilinogen deaminase activity was carried out by fluorometric measurement of porphyrins synthesized during 1 h in blood and the measurement of delta-aminolevulinic acid and porphobilinogen in urine. RESULTS: We found two psychiatric patients, one male and one female, with decreased porphobilinogen deaminase activity. When the families of these patients were studied, one brother was found to have an abnormality. Among controls, a woman was found to have the abnormality and her father was found to have typical features of the disease. CONCLUSIONS: These results indicate a prevalence of porphyria in Mexican psychiatric patients similar to controls, and that measurement of PBG deaminase activity is a good tool for defining acute intermittent porphyria carriers.