Presymptomatic Testing for Huntington's Disease in Mexico: 28 Years of Experience.

INTRODUCTION: Huntington's disease (HD) is a genetic neurodegenerative disorder with dominant inheritance. Our center in Mexico City has offered presymptomatic testing (PT) since 1995. OBJECTIVE: To describe the main clinical and demographic characteristics of at-risk HD individuals who applied to the PT program, the reasons for seeking it, and the molecular results. METHODS: A cross-sectional study was conducted with sociodemographic and clinical data of all PT applicants from 1995-2023. Reasons for seeking PT were assessed using a modified questionnaire. In addition, anxiety, and depressive symptoms before and after PT were evaluated with Beck's instruments; cognitive impairment (CI) was assessed with the Mini-Mental State Examination (MMSE) and molecular results. RESULTS: 214 people applied for PT (2.1% of the at-risk population identified in our center); 63% were women (mean age of 37.11 years). 204 (95.3%) were accepted and 190 received results. 70% indicated that the main reason for applying for PT was to inform their offspring about the risk of inheriting HD. Significant differences were observed in the reasons for seeking PT by age group. Although some subjects received treatment, Beck's instrument scores did not indicate special attention or pharmacological treatment. The MMSE showed probable CI in 20 subjects. Of those who received results, 37% were carriers of a full penetrance allele. CONCLUSION: Our center has the only formal PT program for HD in Mexico. The reasons for seeking PT are varied and age-related. Although PT is offered to all subjects at risk for HD, uptake remains low.

Association of variants in the ABCB1, CYP2C19 and CYP2C9 genes for Juvenile Myoclonic Epilepsy.

Juvenile myoclonic epilepsy (JME) is the most common of the generalized genetic epilepsies, with multiple causal and susceptibility genes; however, its etiopathogenesis is mainly unknown. The toxic effects caused by xenobiotics in cells occur during their metabolic transformation, mainly by enzymes belonging to cytochrome P450. The elimination of these compounds by transporters of the ABC type protects the central nervous system, but their accumulation causes neuronal damage, resulting in neurological diseases. The present study has sought the association between single nucleotide genetic variants of the CYP2C9, CYP2C19, and ABCB1 genes and the development of JME in patients compared to healthy controls. The CC1236 and GG2677 genotypes of ABCB1 in women; allele G 2677, genotypes GG 2677 and CC 3435 in men; the CYP2C19*2A allele, and the CYP2C19*3G/A genotype in both sexes were found to be risk factors for JME. Furthermore, carriers of the TTGGCC genotype combination of the ABCB1 gene (1236/2677/3435) have a 10.5 times higher risk of developing JME than non-carriers. Using the STRING database, we found an interaction between the proteins encoded by these genes and other possible proteins. These findings indicate that the CYP450 system and ABC transporters could interact with other genes in the JME.

Low quality of life, increased number of anti-seizure drugs, and the lack of caregiver support are associated with internalized stigma in adult Mexican patients with epilepsy.

BACKGROUND: People with epilepsy (PWE) have been subject to stigma throughout history, a factor that could compromise their performance in daily life. In Mexico, little is known about the factors that may be affecting internalized stigma. OBJECTIVE: To evaluate the internalized stigma in adult PWE, its relationship with the quality of life, cognitive and depressive symptomatology, and clinical-demographic characteristics. MATERIAL AND METHODS: We conducted a cross-sectional study with a consecutive sampling approach in patients with epilepsy treated at the National Institute of Neurology and Neurosurgery Manuel Velasco Suárez (NINNMVS). Sociodemographic and clinical data, depressive symptomatology (Beck's depression inventory, DBI), cognition (MoCA test), quality of life (QOLIE-31 scale), and internalized stigma (King's internalized stigma scale, ISS) were evaluated. Correlations were made between the continuous variables and the ISS to select those with statistical significance and include them in a multiple linear regression model, along with the dummy variables, to explain internalized stigma. RESULTS: Of 128 patients, 74 (58%) were women; 38% of the patients had more than 20 years of epilepsy evolution. In addition, 39% presented depressive symptoms, and around 60% manifested a possible cognitive impairment. The variables that showed statistical significance concerning the ISS were selected along with dummy variables for multiple linear regression analysis. The resultant model considers the QOLIE-31 total score (ß = -0.489), the number of anti-seizure drugs (ASD, ß = 0.253), and those patients without caregiver support (ß = -0.166) with an adjusted R2 value of 0.316. CONCLUSIONS: A diminishing quality of life, an increased number of ASD, and patients without caregiver support influence a slight to moderate variation of internalized stigma in Mexican PWE. Therefore, it is necessary to continue studying other possible factors that influence internalized stigma to generate effective strategies to reduce its negative effects on PWE.

Native American ancestry significantly contributes to neuromyelitis optica susceptibility in the admixed Mexican population.

Neuromyelitis Optica (NMO) is an autoimmune disease with a higher prevalence in non-European populations. Because the Mexican population resulted from the admixture between mainly Native American and European populations, we used genome-wide microarray, HLA high-resolution typing and AQP4 gene sequencing data to analyze genetic ancestry and to seek genetic variants conferring NMO susceptibility in admixed Mexican patients. A total of 164 Mexican NMO patients and 1,208 controls were included. On average, NMO patients had a higher proportion of Native American ancestry than controls (68.1% vs 58.6%; p = 5 × 10-6). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 × 10-10). Class II HLA alleles HLA-DQB1*03:01, -DRB1*08:02, -DRB1*16:02, -DRB1*14:06 and -DQB1*04:02 showed the most significant associations with NMO risk. Local ancestry estimates suggest that all the NMO-associated alleles within the HLA region are of Native American origin. No novel or missense variants in the AQP4 gene were found in Mexican patients with NMO or multiple sclerosis. To our knowledge, this is the first study supporting the notion that Native American ancestry significantly contributes to NMO susceptibility in an admixed population, and is consistent with differences in NMO epidemiology in Mexico and Latin America.

Genetic mutations in early-onset Parkinson's disease Mexican patients: molecular testing implications.

Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed.

High frequency of Parkin exon rearrangements in Mexican-mestizo patients with early-onset Parkinson's disease.

BACKGROUND: Parkin mutations in patients with early-onset Parkinson's disease (EOPD) are estimated to occur in 49% of familial cases and 18% of sporadic cases. METHODS: We analyzed the entire sequence-coding region and dosage mutations of parkin in 63 Mexican-mestizo EOPD patients and 120 controls. RESULTS: Parkin mutations were present in 34 patients (54.0%). Exon rearrangements, predominantly spanning exons 9 and 12 (31.7% and 19.0%, respectively) were present in 32 patients, with 17.5% carrying simple heterozygous and 25.4% carrying compound heterozygous parkin mutations. CONCLUSIONS: A higher frequency of parkin exon rearrangements than of sequence mutations was observed. Patients with parkin exons 9 and 12 rearrangements showed a later age at onset than did cases with other regions affected (40.3 ± 4.5 vs 30.1 ± 8.8; P = .005), suggesting a mutational hot spot in the etiology of Mexican-mestizo patients with EOPD. To our knowledge, this study represents the largest sampling of Mexican-mestizo patients with EOPD cases for which parkin sequence and dosage alterations were analyzed. .

[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)

[Frequency of apolipoprotein E in a Nahua population]. / Frecuencia de la apolipoproteína E en una población Nahua.

The presence of different ethnic groups in Mexico may give rise to genetic diversity between the native Indian population and the Mestizos. It is therefore of medical and anthropological interest to analyze the genotypes of disease-associated loci, such as polymorphism in the apolipoprotein E gene, whose 4/4 allele increases the risk of Alzheimer's disease and coronary heart disease in other populations. We studied a Nahua Indian-population in the State of Morelos (Santo Domingo Ocotitlan). The ABO blood type of all individuals was determined and compared with the findings of other Nahua group from the State of Puebla. Without statistical significant differences in O, A and AB groups between both populations (p > 0.05). The allelic and genotypic frequency of apolipoprotein E was similar to that observed in other Mexican indian (Mazatecans, Mayans) and Mestizo populations, however there was a statistically significant difference when the results were compared to the allelic frequencies of other Amerinds: The Cayapa (Ecuador) for the epsilon 3 and epsilon 4 alleles (p < 0.002); the Nuuk (Greenland) for epsilon 3 and epsilon 4 alleles (p < 0.0001 and p < 0.002 respectively); and the Ammssalik (Greenland) for both alleles with p < 0.0001 and p = 0.04 respectively. In the case of the genotypes, there was statistically significant difference for the 4/3 genotypes, but a non significant difference for the 4/4 genotype. This is a descriptive study which contributes to the knowledge of the genetic structure of Mexican population.