Phenotypic Variability in a Mexican Mestizo Family with Retinal Vasculopathy with Cerebral Leukodystrophy and TREX1 Mutation p.V235Gfs*6.

BACKGROUND: Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset, autosomal dominant disease involving microvessels of the brain and eye resulting in central nervous system degeneration with visual disturbances, stroke, motor impairment, and cognitive decline. Frameshift mutations at the C-terminus of TREX1 gene are the molecular cause of this disorder. OBJECTIVES: The objective of this study is to present the different clinical manifestations of RVCL in three-related patients and to investigate the presence of TREX1 mutation in the extended genealogy. METHODS: Multidisciplinary testing was performed in three related patients. Based on their family history, the study was extended to 34 relatives from the same small community. Neurological evaluation, sequencing of TREX1, and presymptomatic diagnosis were offered to all participants. RESULTS: The patients exhibited the heterozygous TREX1 mutation p.V235Gfs*6, but with phenotypic variability. In addition, 15 relatives were identified as pre-manifest mutation carriers. The remaining participants did not carry the mutation. CONCLUSIONS: This is the figrst report of a large Mexican genealogy with RVCL, where the same TREX1 mutation causes a variation in organ involvement and clinical progression. The early identification and follow-up of individuals at risk may help provide insights into the basis for this variability in presentation.

DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases.

OBJECTIVE: The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome-wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. METHODS: We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single-nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. RESULTS: In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10(-5) ). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10(-5) ) and all SCAs (p = 2.22 × 10(-4) ) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10(-5) ), all in the same direction as in the HD GWAS. INTERPRETATION: We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983-990.

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.

Synaptotagmin XI in Parkinson's disease: New evidence from an association study in Spain and Mexico.

INTRODUCTION: The pathophysiology of PD (Parkinson's disease) has been related to the ubiquitin proteasome system and oxidative stress. Parkin acts as ubiquitin ligase on several substrates. Because genetic variants often have different frequencies across populations, population specific analyses are necessary to complement and validate results from genome-wide association studies. METHODS: We carried out an association study with genes coding for parkin substrates and cellular stress components in the Galician population (Northern Spain). SNCA and MAPT SNPs were also analyzed. We studied 75 SNPs in a discovery sample of 268 PD patients and 265 controls from Galicia. A replication sample of 271 patients and 260 controls was recruited from Mexico City. RESULTS: We observed significant association between PD and SNPs in MAPT. Nominal p-values<0.05 were obtained in the Galician cohort for SNPs in SYT11, coding for synaptotagmin XI. These results were replicated in the Mexican sample. DISCUSSION: The associated markers lie within a ~140kb strong linkage disequilibrium segment that harbors several candidate genes, including SYT11. SNPs from the GBA-SYT11-RAB25 region have been previously associated with PD, however the functionally relevant variants remain unknown. Our data support a likely role of genetic factors within 1q22 in PD susceptibility.

HLA-A*02:01:01/-B*35:01:01/-C*04:01:01 haplotype associated with lamotrigine-induced maculopapular exanthema in Mexican Mestizo patients.

AIM: Several HLA alleles have been associated with antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) in different populations; however, this has not been investigated in Mexican Mestizos (MM). Thus, the purpose of this preliminary study was to determine the association of HLA class I alleles with AED-induced cADRs in MM patients. MATERIALS & METHODS: This case-control association study included 21 MM patients with phenytoin (PHT)-, carbamazepine (CBZ)-, or lamotrigine (LTG)-induced maculopapular exanthema (MPE) or Stevens-Johnson syndrome (SJS); 31 MM patients tolerant to the same AEDs; and 225 unrelated, healthy MM volunteers. HLA class I genotyping was performed. Differences in HLA allele frequencies between AED-induced cADR patients and AED-tolerant patients were assessed. Frequencies of alleles possibly associated with AED-induced cADRs in MM patients were compared with those in MM population. RESULTS: The frequency of HLA-C*08:01 allele in PHT-induced MPE was higher than that in the PHT-tolerant group (pc=0.0179) or in the MM population (pc<0.0001). For the first time, HLA-A*02:01:01/-B*35:01:01/-C*04:01:01 haplotype was associated with LTG-induced MPE (pc=0.0048 for LTG-tolerant groups and pc<0.0001 for MM population). CONCLUSION: Our data suggest the HLA-A*02:01:01/-B*35:01:01/-C*04:01:01 haplotype may be a biomarker for LTG-induced MPE and the HLA-C*08:01 allele for PHT-induced MPE. We also identified HLA-A*01:01:01 and -A*31:01:02 as candidates alleles associated with CBZ-induced MPE in MM patients. However, further investigations are necessary to confirm these findings.

Genetics of Alzheimer's disease.

Alzheimer's disease (AD) is the most frequent cause of dementia in the elderly and represents an important and increasing clinical challenge in terms of diagnosis and treatment. This review highlights the role of genetics in understanding the pieces of the complex AD puzzle and summarizes the genes known to be involved in Alzheimer's disease. The amount of risk of Alzheimer's disease that is attributable to genetics is estimated to be ∼70%. Mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are responsible for early-onset autosomal dominant AD. Although mutations in these genes account for ∼1% of AD cases, their identification has been crucial to understand the molecular mechanisms of AD. For the more common complex late-onset AD, the ɛ-4 allele of the gene encoding apolipoprotein E (APOE) has been recognized as a major genetic risk factor. More recently, several potential disease risk genes have been identified with the use of advanced genomic methods like genome-wide association studies (GWAS). In the end, the knowledge of the pathophysiological mechanisms leading to AD will enable the development of more accurate diagnostic tests and new disease-treating strategies.

Dependencia y maltrato en el anciano con demencia / Dependência e maltrato em idosos com demência / Dependence and abuse affecting elderly persons with dementia

La relevancia del problema de salud pública que representan en el mundo las demencias, su asociación con la dependencia y el riesgo de maltrato en los ancianos con demencia por parte de sus cuidadores primarios o sus familiares, hacen necesario el análisis y la reflexión “de las implicaciones éticas, económicas, jurídicas, políticas y no sólo las consideraciones médicas”, de este problema, que reviste un interés particular dentro del campo de la Bioética. Se realizó una encuesta con el objetivo de determinar la dependencia física y detectar el maltrato, así como la asociación entre maltrato y respeto de sus preferencias en el anciano con demencia. Se evaluaron 61 ancianos con demencia de leve a moderada, de los cuales 73,8% fueron mujeres y 26,2% hombres. El porcentaje de pacientes que sufren maltrato fue de 29,2% en mujeres y 18,8% en hombres. No se encontró asociación estadísticamente significativa entre maltrato y dependencia física. Sin embargo, se encontró un riesgo de maltrato de 47,30% en ancianos con demencia a quienes no se les respetan sus preferencias con respecto a quienes sí se le respetan, medida con significancia estadística (IC 95%, 6,73-495,18).

The dependence and risk of abuse facing elderly people with dementia at the hand of their caregivers or relatives poses a public health problem the world over. Accordingly, analysis and reflection on the problem in light of “ethical, legal, political implications and not only medical considerations” is essential and of particular interest in the fi eld of the bioethics. The authors conducted a survey to determine the extent of physical dependence and to detect abuse, as well as the association between abuse and respect for the preferences of elderly persons with dementia. Sixty-one elderly persons with mild to moderate dementia were evaluated: 73.8% were women and 26.2%, men. Abuse was reportedamong 29.2% of the women and 18.8% of the men. No statistically significant association was found between abuse and physical dependence. However, risk of abuse was found among 47.30% of the elderly with dementia whose preferences were not being respected,compared to those whose preferences were. This is statistically significant (IC 95%, 6.73-495.18).

A importância mundial do problema da demência na saúde pública, sua associação com a dependência e o risco de abuso de idosos com demência por seus cuidadores e familiares obrigam a analisar e reflexionar “não apenas sobre considerações médicas, mas também sobre as repercussões éticas, econômicas, jurídicas e políticas” desta questão de particular interesse no campo da bioética. Foi realizada uma pesquisa para determinar a dependência física e detectar o abuso, bem como a associação entre abuso e respeito as suas preferências em idosos com demência. Foram avaliados 61 pacientes idosos com demência leve a moderada, dos quais 73,8% eram do sexo feminino e 26,2% de sexo masculino. A porcentagem de pacientes que sofrem abuso foi 29,2% nas mulheres e 18,8% nos homens. Não houve associação estatisticamente significativa entre abuso e dependência física. No entanto, encontrou-se risco de maus tratos de 47,30% em pacientes idosos com demência aos que não se respeitam as suas preferências com relação aos que se lhes respeitam, medido com significância estatística (95% CI, 6,73-495, 18).

Factores genéticos involucrados en la susceptibilidad para desarrollar enfermedad de Parkinson

resumen está disponible en el texto completo

SUMMARY: Parkinson's disease (PD) is the main cause of parkinsonism (rigidity, resting tremor, bradykinesia and loss of postural reflexes). There is evidence highlighting the importance of the interaction between environmental factors and genetics on the pathogenesis of PD. The research about the role of genetics in Parkinson's disease began with familial aggregation studies, which have shown that approximately 10-15% of patients with PD have a positive firstdegree family history of PD; this proportion is higher than a 1% found in controls. Twins studies have found a larger concordance rate in monozygotic twins with early-onset PD (symptoms onset before 40 years of age). Nevertheless, dopaminergic functional studies in twins using PET (Positron Emission Tomography) with [18F]dopa have also shown a substantial role for inheritance in late-onset, sporadic PD. In one of these studies with clinically discordant twins (monozygotic and dizygotic), the concordance rate at baseline for subclinical striatal dopaminergic dysfunction was higher in monozygotic than dizygotic twin pairs (55% vs 18%, respectively) using functional neuroimaging criteria. Nine loci have been so far identified and six genes inherited as a Mendelian fashion have been cloned. Also, α-synuclein (PARK1) gene mutations were found to be pathogenic and responsible for a rare PD with an autosomal dominant inheritance in a large Greek-Italian family (the Contursi kindred). These findings have not been reproduced in patients with late-onset, sporadic PD. Mutations in the gene encoding for parkin (PARK2) are responsible for PD with an autosomal recessive trait and are relatively common in patients with early-onset PD. Mutations in α-synuclein and parkin genes suggest that the dysfunction of the ubiquitine-proteasome system, that mediates degradation of proteins, plays an important role in the pathogenesis of PD. Ubiquitine is a key component of this system and is attached to the proteins by ubiquitine-ligases in order to mark them to be cleaved by the proteasome. The production of freeubiquitine involves a type of proteins called ubiquitine-hydrolases. Mutations in a gene that encodes for one of these proteins, UCHL1, have been also involved in familial PD. Cellular death models in PD have been centered in oxidative stress and excitoxicity mechanisms. Even though these mechanisms are still considered important, the models that highlight the abnormal aggregation of proteins and the failure of the ubiquitine proteolytic system are more consistent with available experimental data. The product of DJ-1 (PARK7) was recently involved in familial PD. This could protect dopaminergic neurons from damage due to oxidative stress as suggested by its structure similarity with the stress-induced bacterial chaperone (Hsp-31); it also could help in the appropriate folding of proteins. Other studies suggest DJ-1 mutations could contribute to the elevated levels of oxidative stress seen in PD. Theories about the pathogenesis of PD have been developed independently of the findings in the genetics field. One particularly prominent model suggests that various mitochondrial alterations that produce failure in the production of cellular energy or elevated free radicals levels or both have an important role in PD pathogenesis, and some recent genetic findings support this theory. Mutations in the gene encoding for PINK1 (PARK6), a mitochondrial protein-kinase, have been found in some patients with familial PD. Recently, a gene localized in PARK8 (LRRK2/dardarine) has been cloned. It is responsible for familial PD with autosomal dominant inheritance, typical age of onset and clinical findings similar to the ones found in idiopathic PD. Association studies with candidate genes have discovered the influence of some polymorphisms on certain PD clinical features, at least in the populations studied. The relative risk and age of onset of PD, as well as the levodopa induced dyskinesia, are among these characteristics. Candidate genes were chosen because of their alleged role on the pathogenesis of PD. The major candidate genes studied so far are related to dopamine synthesis, transport and metabolism, xenobiotics and other neuronal toxins detoxification, mitochondrial metabolism, and also transcription factors and neurotrophic genes involved in the mesencephalic dopaminergic system development. Of the susceptibility genes so far studied, only the MAO-B >188 bp allele has shown a significant association in a meta-analysis. Additionally, only six genes (DRD2, ND3, BNDF, α-synuclein, UCHL1 and Nurr-1) have shown important associations with PD in several studies and have fulfilled the criteria for their replication and meta-analysis. These mixed results could be related to differences in sample size, ethnical background and methodology as to make it almost impossible to summarize independent studies. Other possible contributions are populations stratification, biologic credibility of the association between the gene and the phenotype and gene to gene interactions. However, these mutations are not found in the great majority of patients with sporadic PD. In these patients, normal gene polymorphisms must confer susceptibility to PD, and certain, not-yetidentified, environmental factors must interact with them in order to produce clinically PD. Normally, each subject receives one maternal and one paternal allele for each gene. During meiosis, the chromosomal recombination is undertaken in such a way the probability of two loci being transmitted together to the next generation is indirectly proportional to the distance in the chromosome between them. The group of alleles inherited as a cluster are known as haplotype and the study and knowledge of haplotypes present in the populations could be associated with clinical phenotypes. If loci are inherited as stable fragments, association studies can be developed for each haplotype and not for each locus, which saves time, money, human and material resources. The HapMap will contribute to a better design of genetic association studies with clinical phenotypes. A better understanding of the genetics involved in the relative risk of PD will be an important step to improve its prevention, diagnosis and treatment. Genetic testing for PD may be premature and is not currently recommended unless the patient has a strong family history, a family member is known to be carrier of a causal mutation, there is parental consanguinity, or the patient exhibits symptoms at an unusually early age (before 40 years of age). Presymptomatic testing for such an incurable neurodegenerative disease must always be accompanied by proper education and counseling and must be carried out at a center with expertise in this area. Currently there are no well-standardized presymptomatic protocols for PD genetic testing; therefore, it is recommended to follow the Huntington's disease protocol. This review summarizes relative risk of genetics in PD.

Ataxia: efectos psicosociales / Psychosocial impact ataxia

Las ataxias hereditarias son un grupo de padecimientos caracterizados por anormalidades en el equilibrio debido a afección del cerebelo o sus vías de conexión. En México no hay estudios de prevalencia de estos padecimientos ni de los efectos psicosociales que provocan, por lo que el objetivo de este trabajo fue estudiar en un grupo de pacientes con ataxia, los efectos psicosociales que tiene el padecimiento en su vida personal, social y familiar, además de evaluar el grado de depresión entre sus cuidadores. Se estudiaron 22 pacientes con diagnóstico clínico de ataxia. De los 22 en 54.5 por ciento había patrón de herencia autosómico dominante. Del total de pacientes, 10 tuvieron depresión moderada y 3 severa. En sus relaciones sociales 21 pacientes perdieron todo contacto con su núcleo social. El 32 por ciento ya no desempeña ninguna actividad remunerativa, lo que hace que dependan en el aspecto económico de otro integrante de la familia, lo cual se ve directamante reflejado en la afección de su situación económica. Debido al carácter progresivo e incapacitante de este grupo de padecmientos es seguro que con la evolución de la enfermedad los pacientes lleguen a depender por completo de otra persona, lo queafecta de manera directa las relaciones interpersonales de cada familia.

Estudios neuropsicológicos y problemas éticos de la enfermedad de Huntington / Neuropsychological studies and ethical problems in Huntington's disease

Se exponen aspectos históricos de la intervención Neuropsicológica en el estudio de los padecimientos de origen subcortical analizando los déficits cognitivos y comportamentales por patología en estas estructuras, haciendo especial énfasis en la Enfermedad de Huntington, caracterizada por: Movimientos Coreícos, Déficit Cognitivo y alteraciones de Conducta. La Evaluación Neuropsicológica muestra decremento en: Atención, Memoria y Lentificación Global del pensamiento. En la conducta destaca: irritabilidad, falta de motivación y depresión. Se analizan aspectos éticos en la atención e investigación de estos pacientes, particularmente en cuanto al consejo genético, debido a la reciente posibilidad de contar con un diagnóstico predictivo y prenatal es esta enfermedad, planteando la necesidad de contar con un programa de consejo genético y terapia de apoyo pre y postprueba, así como de un comité ético que regule el manejo y confidencialidad de los resultados.

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

La enfermedad de Alzheimer es una enfermedad degenerativa del sistema nervioso central que produce deterioro cognitivo y de memoria progresivo en la edad adulta. Las alteraciones neurpatológicas más importantes en la enfermedad son las placas amiloides y las marañas de neurofibrillas. De los cuatro genes relacionados con el padecimiento, el gen precursor de la proteína amiloide en el cromosoma 21, el de la presenilina 1 en el cromosoma 14 y el de la presenilina 2 en el cromosoma 1, son los tres responsables de la enfermedad en familias con patrón hereditario autosómico dominante. El cuarto gen se localiza en el cromosoma 19; su producto es la apolipoproteína E, la cual es un factor de riesgo genético para desarrollar el padecimiento. La enfermedad de Alzheimer tiene una etiología heterogénea y compleja y falta descrubrir otros genes relacionados con ella. Los identificados hasta el momento son de importancia para entender la fisiopatogenia de la enfermedad

Estudio de cromatina X y Y en pacientes epilépticos / X and Y chromatin study in epileptic patients

Algunos autores han informado que las alteraciones en el número de cromosomas sexuales son más frecuentes en pacientes epilépticos. En este trabajo se estudió la cromatina X y Y en una población de pacientes epilépticos con objeto de detectar alteraciones en el número de cromosomas sexuales en ellos. Se estudiaron 608 hombres y 537 mujeres mediante la cromatina X, no encontrándose ninguna alteración en esta prueba. En 279 hombres se determinó la cromatina Y en la cual tampoco se encontraron anormalidades

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 sybjects 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 percent, 45 percent, and 60 percent, respectively. Five families were analyzed, of these, only in two the markers used were informative. In one of them, six membrers showed a decreased risk of inheritance of the mutant gene for Huntington's Didease with 95 percent accuracy

Predictive and prenatal diagnosis of Hunington'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 groups of Mexican specialistis 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 percent claimed to know the hereditary risk, and 20 percent answered incorrectly concerning the risks. Neurologists had the most exposure to HD; 74 percent acknowledged the existence of predictive diagnosis, although only 10 percent knew the international guidelines for testing. Eighty-six percent of the participants recommended predictive diagnosis, the reasons being: 55 percent, if the patients considered having offspring; 41 percent, for the patients's professional reasons; 6 percent, if a treatment was available, and 12 percent did not answer. In cases in which the patient wanted to have offspring, 38 percents thought that this should be avoided. Thirty-six percent of the subto have offspring, 38 percent thought that this should be avoided. Thirty-six percent of the subjects considered prenatal diagnosis justified in a couple with a carrier, and 51 percent justified abortion affected fetuses. Conclusions. Genetic counseling and predictive diagnosis in Mexico must be the responsibility of genetic units and specialists who are of inheritance risks and of guidelines for HD programs. The number of patients requiring such attention is increasing rapidly

El papel del psiquiatra en el diagnóstico predicitivo en la enfermedad de huntington / The part of psychiatra in genetic prediction of Huntington's disease

Acualmente el diagnóstico predictivo de la enfermedad de Huntington (EH) se efectúa por medio de un equipo multidisciplinario. El psiquiatra es importante durante la evaluación de los candidatos que desean que se les realice el diagnóstico predictivo para la EH. Ya que pueden presentarse diversos problemas psiquiátricos por el hecho de saberse en riesgo, y posteriormente al recibir el resultado. La adaptación al resultado sea este positivo o negativo es difícil. Este artículo describe la experiencia psiquiátrica obtenida en nuestra investigación en el Instituto Nacional de Neurología y Neurocirugía de México