Founder effect and ancestral origin of the spinocerebellar ataxia type 7 (SCA7) mutation in Mexican families.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disease characterized by progressive cerebellar ataxia and macular degeneration causing progressive blindness. It accounts for 1 to 11.6 % of spinocerebellar ataxias (SCAs) cases worldwide and for 7.4 % of SCA7 cases in Mexico. We identified a cluster of SCA7 families who resided in a circumscribed area of Veracruz and investigated whether the high incidence of the disease in this region was due to a founder effect. A total of 181 individuals from 20 families were studied. Four microsatellite markers and one SNP flanking the ATNX7 gene were genotyped and the ancestral origin and local ancestry analysis of the SCA7 mutation were evaluated. Ninety individuals from 19 families had the SCA7 mutation; all were found to share a common haplotype, suggesting that the mutation in these families originated from a common ancestor. Ancestral origin and local ancestry analysis of SCA7 showed that the chromosomal segment containing the mutation was of European origin. We here present evidence strongly suggesting that the high frequency of SCA7 in Veracruz is due to a founder effect and that the mutation is most likely of European origin with greatest resemblance to the Finnish population.

Espectroscopia cuantitativa de hidrógeno por resonancia magnética de 3 T en pacientes sintomáticos y asintomáticos con enfermedad de Huntington / Hydrogen magnetic resonance quantitative spectroscopy at 3 T in symptomatic and asymptomatic Huntington’s disease patients

Introducción. La enfermedad de Huntington es un trastorno neurodegenerativo hereditario autosómico dominante, caracterizado por síntomas motores, cognitivos y psiquiátricos. Objetivo. Determinar si existen diferencias en las concentraciones de N-acetilaspartato, creatina y compuestos que contienen colina (glucerilfosforilcolina y fosfocolina) en el núcleo caudado, el putamen y la corteza occipital de pacientes con enfermedad de Huntington, sintomáticos y asintomáticos. Sujetos y métodos. Se realizaron estudios de espectroscopia de hidrógeno por resonancia magnética en un equipo de 3 T a 10 individuos con prueba genética para enfermedad de Huntington, incluidos en tres grupos: negativos (control), positivos sintomáticos y positivos asintomáticos. Los estudios se cuantificaron con LCModel y se analizaron mediante análisis de varianza y prueba de Fisher. Resultados. Los pacientes sintomáticos mostraron disminución de creatina y N-acetilaspartato en las regiones estudiadas, y disminución de colina en el putamen (p < 0,05). En el núcleo caudado se encontró diferencia de colina entre sintomáticos y asintomáticos (p < 0,05). Conclusiones. Los resultados reflejan disfunción en el metabolismo neuronal y sugieren que la creatina y la colina, al ser marcadores de membrana, pueden comportarse en forma indirecta como marcadores de la evolución en la enfermedad de Huntington (AU)

Introduction. Huntington’s disease is an hereditary autosomic-dominant neurodegenerative disorder, characterized by motor, cognitive and psychiatric symptoms. Aim. To quantify differences in N-acetylaspartate, creatine and choline in caudate nucleus, putamen and occipital cortex of patients with Huntington’s disease, symptomatics and asymptomatics. Subjects and methods. Hydrogen magnetic resonance spectroscopy was performed with a 3 T scanner in 10 Huntington’s disease gene-tested subjects, included in three groups: negative (control), positive sympomatics and positive asymptomatics. Data was quantified with LCModel and analyzed with ANOVA and Fisher tests. Results. Symptomatic patients showed decreased creatine and N-acetylaspartate in the three regions, and decreasedcholine only in putamen (p < 0.05). Choline difference was found between symptomatics and asymptomatics in the caudate nucleus (p < 0.05). Conclusions. Results may reflect neuronal dysfunction and suggest that creatine and choline may serve as markers for Huntington’s disease progression (AU)

[Hydrogen magnetic resonance quantitative spectroscopy at 3 T in symptomatic and asymptomatic Huntington's disease patients]. / Espectroscopia cuantitativa de hidrógeno por resonancia magnética de 3 T en pacientes sintomáticos y asintomáticoscon enfermedad de Huntington.

INTRODUCTION: Huntington's disease is an hereditary autosomic-dominant neurodegenerative disorder, characterized by motor, cognitive and psychiatric symptoms. AIM: To quantify differences in N-acetylaspartate, creatine and choline in caudate nucleus, putamen and occipital cortex of patients with Huntington's disease, symptomatics and asymptomatics. SUBJECTS AND METHODS: Hydrogen magnetic resonance spectroscopy was performed with a 3 T scanner in 10 Huntington's disease gene-tested subjects, included in three groups: negative (control), positive symptomatics and positive asymptomatics. Data was quantified with LCModel and analyzed with ANOVA and Fisher tests. RESULTS: Symptomatic patients showed decreased creatine and N-acetylaspartate in the three regions, and decreased choline only in putamen (p < 0.05). Choline difference was found between symptomatics and asymptomatics in the caudate nucleus (p < 0.05). CONCLUSIONS: Results may reflect neuronal dysfunction and suggest that creatine and choline may serve as markers for Huntington's disease progression.

[The absence of a relation between apolipoprotein E genotypes and the severity of multiple sclerosis in Mexican patients]. / Ausencia de relación entre los genotipos de apolipoproteína E y la gravedad de la esclerosis múltiple en pacientes mexicanos.

INTRODUCTION: The clinical course of multiple sclerosis (MS) varies widely. The natural history of the disease has shown that approximately 50% of patients that begin with a relapsing-remitting clinical course will have a progressive course about 10 years after disease onset and will need some kind of aid to walk. The expression of apolipoprotein E (ApoE) increases in nerve tissue undergoing regeneration and the ApoE epsilon-4 allele is associated with abnormal neural repair. Several different reports indicate that the ApoE epsilon-4 allele is associated with a greater progression of disability in patients with MS, although this is still a matter of debate. PATIENTS AND METHODS: We analyse the clinical characteristics of 99 patients diagnosed with MS, we describe the correlation between the presence or absence of the ApoE epsilon-4 allele and the age of onset, clinical subtype, progression of the disease, score on the Expanded Disability Status Scale and the relapse rate. We explore the impact of the presence of the epsilon-2 allele on the progress of the disease. RESULTS: In patients under 21 years of age, we observed a higher frequency of the presence of the epsilon-4 allele (p = 0.057). Nevertheless, no association was found between any of the ApoE alleles and the indices of disease progression. CONCLUSIONS: Our results do not suggest any association between the presence of the ApoE epsilon-4 allele and the progression of disability in patients with MS in our sample.

Ausencia de relación entre los genotipos de apolipoproteína E y la gravedad de la esclerosis múltiple en pacientes mexicanos / The absence of a relation between apolipoprotein E genotypes and the severity of multiple sclerosis

Introducción. El curso clínico de la esclerosis múltiple (EM) es muy variable. La historia natural de la enfermedad ha enseñado que aproximadamente el 50% de los pacientes que inician con un curso clínico brote-remisión tendrá un curso progresivo después de unos 10 años de evolución de la enfermedad y necesitará alguna ayuda para deambular. La expresión de la apolipoproteína E (ApoE) aumenta en el tejido nervioso en regeneración, y el alelo ApoE épsilon-4 está asociado con reparación neural anómala. Diversas comunicaciones indican que el alelo ApoE épsilon4 se asocia a una mayor progresión de la discapacidad en pacientes con EM, aunque es controvertido. Pacientes y métodos. Analizamos las características clínicas de 99 pacientes con diagnóstico de EM, describimos la correlación de la presencia o ausencia del alelo épsilon-4 de la ApoE con la edad de inicio, subtipo clínico, progresión de la enfermedad, puntuación de la Expanded Disability Status Scale y tasa de recaídas. Exploramos el impacto de la presencia del alelo épsilon-2 con la evolución de la enfermedad. Resultados. En pacientes menores de 21 años observamos una mayor frecuencia de la presencia del alelo épsilon-4 (p = 0,057), pero no encontramos ninguna asociación entre algún alelo de ApoE y los índices de progresión de la enfermedad. Conclusiones. Nuestros resultados no indican alguna asociación entre la presencia del alelo ApoE épsilon-4 en la progresión de discapacidad en pacientes con EM en nuestra muestra (AU)

Introduction. The clinical course of multiple sclerosis (MS) varies widely. The natural history of the disease has shown that approximately 50% of patients that begin with a relapsing-remitting clinical course will have a progressive course about 10 years after disease onset and will need some kind of aid to walk. The expression of apolipoprotein E (ApoE) increases in nerve tissue undergoing regeneration and the ApoE epsilon-4 allele is associated with abnormal neural repair. Several different reports indicate that the ApoE epsilon-4 allele is associated with a greater progression of disability in patients with MS, although this is still a matter of debate. Patients and methods. We analyse the clinical characteristics of 99 patients diagnosed with MS, we describe the correlation between the presence or absence of the ApoE epsilon-4 allele and the age of onset, clinical subtype, progression of the disease, score on the Expanded Disability Status Scale and the relapse rate. We explore the impact of the presence of the epsilon-2 allele on the progress of the disease. Results. In patients under 21 years of age, we observed a higher frequency of the presence of the epsilon-4 allele (p = 0.057). Nevertheless, no association was found between any of the ApoE alleles and the indices of disease progression. Conclusions. Our results do not suggest any association between the presence of the ApoE epsilon-4 allele and the progression of disability in patients with MS in our sample (AU)

[Increased risk of neoplasia among relatives of glioma patients]. / Incremento en el riesgo de neoplasia entre familiares de pacientes con glioma.

INTRODUCTION: Some previous studies have suggested familial aggregation of gliomas, although the results have not always been replicated. SUBJECTS AND METHODS: In the present study of a Mexican population, we compared 100 cases of glioma with 124 healthy unrelated controls, as well as their 1st, 2nd and 3rd degree relatives (n = 3,575 and 4,520 respectively). RESULTS: The relatives of the cases had a significantly higher risk of developing brain tumors than the relatives of controls (OR = 5.3; p < 0.05; 95% CI = 1.1-25.7), and their risk of developing any cancer was also increased (OR = 2; p < 0.05; 95% CI = 1.16-3.51), this risk was twofold for men when compared to females (OR = 2; p < 0.05; 95% CI = 1.15-3.37). CONCLUSION: The present study supports familial aggregation of brain tumors and warrants further research into their genetic etiology.

Incremento en el riesgo de neoplasia entre familiares de pacientes con glioma / Increased risk of neoplasia among relatives of gliomapatients

Introducción. Estudios previos han sugerido que existe agregación familiar de gliomas; sin embargo, los resultados no siempre han sido replicables. Sujetos y métodos. En el presente estudio de una población mexicana, comparamos 100 casos de glioma con 124 controles sanos no emparentados, así como sus familiares de primer, segundo y tercer grado (n = 3.575 y 4.520, respectivamente). Resultados. Los familiares de los casos tuvieron un riesgo significativamente mayor de desarrollar tumores cerebrales que los familiares de los controles (odds ratio, OR = 5,3; p < 0,05; intervalo de confianza al 95%, IC 95% = 1,1-25,7), su riesgo de desarrollar cualquier tipo de cáncer también fue mayor (OR = 2; p < 0,05; IC 95% = 1,16-3,51), y este riesgo fue el doble para varones que para mujeres (OR = 2; p < 0,05; IC 95% = 1,15-3,37). Conclusión. El presente estudio apoya la existencia de agregación familiar de neoplasias cerebrales y obliga a profundizar en el estudio de su etiología genética

Introduction. Some previous studies have suggested familial aggregation of gliomas, although the results have not always been replicated. Subjects and methods. In the present study of a Mexican population, we compared 100 cases of gliomawith 124 healthy unrelated controls, as well as their 1st, 2nd and 3rd degree relatives (n = 3,575 and 4,520 respectively).Results. The relatives of the cases had a significantly higher risk of developing brain tumors than the relatives of controls (OR = 5.3; p < 0.05; 95% CI = 1.1-25.7), and their risk of developing any cancer was also increased (OR = 2; p < 0.05; 95% CI = 1.16-3.51), this risk was twofold for men when compared to females (OR = 2; p < 0.05; 95% CI = 1.15-3.37). Conclusion. The present study supports familial aggregation of brain tumors and warrants further research into their genetic etiology

[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.

Predictive and prenatal diagnosis of Huntington's disease: attitudes of Mexican neurologists, psychiatrists, and psychologists.

BACKGROUND: Huntington's disease (HD) is a hereditary disease of the central nervous system. Its molecular diagnosis has allowed predictive and prenatal diagnosis to be done, and it is now a model for the study of the ethical, legal, and social problems arising from the diagnosis of such diseases. METHODS: This study explores the knowledge and attitudes of a group of Mexican specialists regarding the disease and its diagnosis. A self-administered, 30-item multiple-choice questionnaire was completed anonymously by neurologists, psychiatrists, and psychologists. RESULTS: Fifty-five percent of the professionals had experience with HD patients, 59% claimed to know the hereditary risks, and 20% answered incorrectly concerning the risks. Neurologists had the most exposure to HD; 74% acknowledged the existence of predictive diagnosis, although only 10% knew the international guidelines for testing. Eighty-six percent of the participants recommended predictive diagnosis, the reasons being: 55%, if the patients considered having offspring; 41%, for the patient's professional reasons; 6%, if a treatment was available, and 12% did not answer. In cases in which the patient wanted to have offspring, 38% thought that this should be avoided. Thirty-six percent of the subjects considered prenatal diagnosis justified in a couple with a carrier, and 51% justified abortion for affected fetuses. CONCLUSIONS: Genetic counseling and predictive diagnosis in Mexico must be the responsibility of genetics units and specialists who are aware of inheritance risks and of guidelines for HD programs. The number of patients requiring such attention is increasing rapidly.

[The genetics of Alzheimer's disease]. / Genética de la enfermedad de Alzheimer.

Alzheimer's disease is a degenerative disorder of the central nervous system which causes progressive memory and cognitive decline during mid to late adult life and is accompanied by a wide range of neuropathologic features including extracellular amyloid plaques and intra-neuronal neurofibrillary tangles. Four genetic loci for Alzheimer's disease have been identified. They are the amyloid precursor protein gene on chromosome 21, a gene for early onset autosomal dominant form on chromosome 14, another gene on chromosome 1, and the risk-modifying gene apolipoprotein E on Chromosome 19. The etiology is heterogeneous and complex, and additional Alzheimer's disease genes remain to be found. The genes identified in the inherited forms are now being used to understand the pathogenesis of the disease.

Molecular diagnosis of Huntington's disease in Mexican patients by polymerase chain reaction.

Three highly informative markers genetically linked to Huntington's Disease (HD) were used for diagnosis of HD in Mexican patients, two polymorphic HindIII sites located at D4S10 locus and one VNTR marker at D4S111 locus (VNTR-111). Forty chromosomes from healthy subjects were tested in order to evaluate the informativeness of the probes. The RFLP HindIII 1 and 2 and the VNTR-111 probes showed a heterozygosity of 0%, 45%, and 60%, respectively. Five families were analyzed, of these, only in two the markers used were informative. In one of them, six members showed a decreased risk of inheritance of the mutant gene for Huntington's Disease with 95% accuracy (1).

Familial migraine in a Mexican population.

We investigated the frequency of migraine in first-degree relatives of a group of migraine patients in two Mexican populations, one urban and one rural, and in control groups from the same populations. In the urban population, familial aggregation of migraine was found in 52.7% of patients and in the rural in 38.7%. The differences between controls and subjects were statistically significant in both populations. Our findings support the importance of a hereditary factor in migraine but not an autosomal dominant inheritance pattern.

The HLA system and T-cell subsets in Bell's palsy.

The etiology of Bell's palsy (BP) is still unknown, but infectious, immunological and genetic factors have been suggested to play a role in the pathogenesis of the disease. We analyzed blood samples of 92 Mexican Mestizo patients diagnosed as having BP according to established international criteria, and the results were compared to a group of apparently healthy controls of the same ethnic origin. HLA class I (A, B, C) and Class II (DR, DQ) products of the major histocompatibility complex (MHC), and the percentages of CD3, CD4 and CD8 T-cell subsets were investigated. The number of family antecedents was surprisingly high (46%), supporting a genetic basis. There was a slight increase of DRw13, suggesting a possible susceptibility class II-linked gene. A significant decrease of DR4 (pc = 0.001) was detected, which may indicate the existence of a resistance DR-linked gene. Thus, a non DR4 carrier may be in high risk of expressing BP. In the acute phase of the disease, the T-cell subsets showed a decrease in CD3 and CD4 cells when compared to controls. CD8 cells were increased in the same stage. A transient T-cell imbalance was thus observed which recovered in the convalescent phase. None of the patients with CD4 lower than 40% were DR4, suggesting that the DR-linked resistance gene may predispose to the T-cell defect.

Family aggregation in Bell's palsy.

Some authors have reported a familial aggregation in Bell's paralysis. However, the information so far forthcoming is unsatisfactory and even contradictory. Our survey consisted of 115 patients, 30.5% of whom had an affected first-degree relative, which, compared with the control group figure of 3.6%, is highly significant. The frequency of 30.5% of families with an affected first-degree relative is the highest reported in literature.