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.

[Pharmacogenomics: the quest for individualized therapy]. / Farmacogenómica: busqueda de la terapia personalizada.

AIM: Different patients exhibit wide variability in the way they respond to medications. Individual differences in drug response can result from environmental factors, as well as genetic determinants. In particular, inherited differences in the metabolism and disposition of drugs can have a great influence on the efficacy and toxicity of medications, so herein we focus on the pharmacogenetics of drug metabolism. DEVELOPMENT: Clinical observations of inherited differences in drug effects were first documented in the 1950s, giving rise to the field of pharmacogenetics. These observations were then followed by population studies of drug disposition phenotype, then biochemical, and eventually molecular elucidation of the genetic defect associated with the inherited trait. Genetic polymorphisms have been described for many phase I and phase II drug-metabolizing enzymes including several cytochromes P450, N-acetyltransferases, and thiopurine S-methyltransferase. Rapid advances in human genomics gave birth to pharmacogenomics, an emerging discipline that uses genome-wide approaches to study the entire spectrum of genes involved in drug response. High-through-put genomic technologies will serve as the foundation of personalized therapies. CONCLUSIONS: Knowledge of an individual's genetic variability in drug response may be clinically and economically important and could provide the basis for a rational approach to drug prescription in neuropsychiatric disorders.

Conceptos actuales sobre cerebelo y cognición / Current concepts regarding the cerebellum and cognition

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[Current concepts regarding the cerebellum and cognition]. / Conceptos actuales sobre cerebelo y cognición.

OBJECTIVE: To review the main cognitive processes regulated by the cerebellum and the anatomical circuits involved in their clinical correlation. DEVELOPMENT: The cerebellum is generally regarded as a regulator of motor function with a key role in movement coordination. Clinical evidence of the relation of the cerebellum to neural functions typically considered as cortical, is supplied by several neuropsychological alterations detected in both degenerative disorders and acute insult to the region such as vascular event and surgery. More anatomical circuits between the cerebellum and several cortical areas and limbic system, with the ventral pons region as main afference and efference relay of all these pathways. Cerebellar structures that are phylogenetically older such as the floculonodullar lobe, vermix, fastigial nuclei and globus nuclei have a tight relationship to emotional control and autonomic manifestations. More complex circuits are founded in the regulation of learning, motor planning and language. Functional imaging studies have helped to confirm the relationship between the cerebellum and memory processes, finding a selective activation of lateral regions during to cerebellar damage, such a frontal like syndromes, memory deficits and aphasia and even though dysmetria with incoordination between mental process velocity and its motor execution. CONCLUSIONS: All the data from clinical and functional studies indicate that the cerebellum has a central co-ordinating function not only of movement but also regulating thought. The cerebellum should, therefore, be reconsidered as a complex neurone system at much the same level as the more advanced cortical structures.

[Neuropsychological evaluation in patients with Parkinson's disease]. / Evaluación neuropsicológica de pacientes con enfermedad de Parkinson.

OBJECTIVE: To analyze the neuro-psychological performance of patients with Parkinson's, disease (PD), in comparison with a group of patients with frontal lobe lesions (FLL) and a control group. METHODS: Eighteen patients with PD, 10 patients with FLL and 10 controlls of similar age and scolarity were studied. Neuro-psychological evaluation included tests of the visuospatial, execution, attention and concentration, memory and language areas. The tests were classified in two categories: those requiring motor responses and those that do not. RESULTS: Patients with PD and FLL had lower scores them the controls in the visuospatial, attention and concentration and language areas, with statistical significance in some cases. The differences with the controls persisted in some tests requiring and not requiring motor response. CONCLUSIONS: Frontal lobes have an important role in the neuro-psychological profile of patients with PD. Cognitive deficits in these patients is unrelated to the motor impairment of the disease.

Optic neuritis progressing to multiple sclerosis.

We report a partially retrospective and longitudinal study of patients with optic neuritis (ON) that developed multiple sclerosis (MS). We assessed clinical features or factors that might differentiate these patients from those with ON that did not develop MS. Of the cases followed, 110 (67%) were found to have an idiopathic origin of the disease; whereas 55 (33%) were found to develop it secondary to another disease. Of the 110 idiopathic cases, 13 (12%), developed MS over an average of 2 years. The results of these patients in the laboratory analyses of blood and CSF as well as the results of the MRI and evoked potential studies, were significantly different from the ON patients without MS. We conclude that the percentage of patients with ON in our sample that developed MS is similar to that found in Japan and is relatively low in comparison to other reports.

Frequency of motor neuron diseases in a Mexico City referral center.

OBJECTIVE: To analyze the incidence and clinical characteristics of MND (Motor Neuron Diseases) in a Mexican institution. MATERIAL AND METHODS: It was a retrospective study, of 274 definitive MND patients seen in a neurological reference hospital of Mexico City during the period of 1965-1995 (248 as Amyotrophic Lateral Sclerosis, 15 as Progressive Bulbar Palsy, 8 as Primary Lateral Sclerosis and 3 as Progressive Spinal Atrophy). RESULTS: The frequency of MND increased gradually in our institution in the 31 years revised. The mean age of onset in our series was approximately 48 years in contrast to a higher age found in other series. The clinical features are similar to those found elsewhere. CONCLUSIONS: Our study showed that the frequency of MND is increasing in Mexico in a similar fashion to that observed in the rest of the world. This makes conceivable that the incidence of MND in Mexico may also resemble the figures reported worldwide. Prospective population studies are required to establish the incidence of MND in Mexico.

Changes in cardiac repolarization and ventricular conduction in a case of acute hematomyelia. Report of a case.

A twenty year old man presented an acute hematomyelia at T2-T3 level and had electrocardiographic changes suggesting subendocardial and subepicardial ischemia; he also had precordial pain and elevation of the MB fraction of creatine phosphokinase. Neurons providing heart inervation are located at the T2-T3 spinal level. The electrocardiographic changes observed were considered neurogenic in origin and were transient. Although there are experimental reports showing electrocardiographic changes associated with compression of the upper part of thoracic spinal cord, this is the first report to our knowledge, in which an acute spinal injury is shown to be associated with neurogenic changes in ventricular repolarization simulating acute myocardial ischemia.

[Plasma cells in the cerebrospinal fluid of patients with cerebral cysticercosis]. / Células plasmáticas en el líquido cefalorraquídeo en pacientes con cisticercosis cerebral.

We studied in twenty patients with proven cerebral cysticercosis the presence of plasma cells in the cerebrospinal fluid (CSF). We found plasma cells in 50 per cent of the patients. All of them had subarachnoid cysticercosis or basal arachnoiditis. The presence of plasma cells was significantly associated to higher protein levels, greater number of inflammatory cells, and higher levels of IgG in the CSF. None of the patients had received medical treatment or steroids prior to the test. These findings suggest a role of plasma cells in the pathogenesis of the cysticercotic disease. The presence of plasma cells in the CSF is part of the immune response against the parasite. We also found that plasma cells are more frequently encountered in the CSF (50 per cent) than eosinophils (20 per cent) in patients with cerebral cysticercosis.

[Integrity of the blood-brain barrier and intrathecal synthesis of IgG in parenchymatous and subarachnoid cerebral cysticercosis]. / Integridad de la barrera hematoencefálica y síntesis intratecal de IgG en cisticercosis cerebral parenquimatosa y subaracnoidea.

Patients with cerebral cysticercosis (CC) have specific antibodies of the IgG type in blood and cerebrospinal fluid (CSF). In order to determine if the specific antibodies present in the CSF come from blood or synthetized in the subarachnoid space, we studied the integrity of the blood brain barrier (BBB) and the intrathecal synthesis of specific antibodies. We found a ruptured BBB with more frequency and in a higher intensity in patients with CC and hydrocephalus (malignant CC) than in patients with parenchymal CC (benign CC). The patients with malignant CC have a greater number of inflammatory cells, a higher albumin index (serum albumin/CSF albumin), a higher level of protein and a higher titre of specific antibodies in the CSF than those with benign CC. In 15 patients in both groups we could demonstrate intrathecal synthesis of antibodies. We conclude that in CC the specific antibodies are produced intrathecally, and in a lesser amount come from the blood through a ruptured blood-brain barrier.