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Introduction: There are reports of different clinical statuses in carriers of intermediate alleles (IAs) of CAG trinucleotide repeats in the HTT gene, from individuals affected by a clinical picture indistinguishable from Huntington’s disease (HD) to those without manifestations. Therefore, the possible clinical significance of these alleles has been widely debated. Objectives: The aim of this study was to describe general and clinical features and discard HD phenocopies by molecular assessment in a case series of IA carriers on the HTT gene of a laboratory sample from a neurological center in Mexico. Methods: We selected individuals who had previously been tested for the HTT gene expansion, which resulted in IAs. Clinical information was obtained from medical records, and molecular analysis of the JPH3, PRNP, and TBP genes was performed only in IA carriers with clinical manifestations. In addition, two patients with IA and acanthocytes were evaluated by whole-exome sequencing. The scientific and ethical committees of the National Institute of Neurology and Neurosurgery Manuel Velasco Suárez (NINNMVS) approved this study. Results: From 1994 to 2019, the Genetics Department of the NINNMVS confirmed 34 individuals with IAs, 15 of whom belonged to 11 families with HD (IA-HD) and 19 of whom had no family history of HD (IA-non-HD). We found a high proportion of manifestations of the HD phenotypic spectrum in the IA-non-HD subgroup. In addition, among the 20 samples of IA carriers with manifestations molecularly evaluated, we identified two unrelated subjects with CAG/CTG repeat expansions on the JPH3 gene, confirming HD-like 2 (HDL2), and one patient with the homozygous pathogenic c.3232G>T variant (p.Glu1078Ter) in the VPS13A gene, demonstrating choreoacanthocytosis. Discussion/Conclusion: Our results show the most extensive series of subjects with IAs and clinical manifestations. In addition, we identify three HD phenocopies, two HDL2 cases, and one choreoacanthocytosis case. Therefore, we emphasize evaluating other HD phenocopies in IA carriers with clinical manifestations whose family background is not associated with HD.

Background: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called “prion”, which corresponds to a pathological form (PrPSc) of a normal cellular protein (PrPC) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC, and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer’s disease (AD). In AD, tau aggregates and amyloid-β protein plaques are associated with memory loss and cognitive impairment in patients. Objective: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. Methods: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. Results: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers in the cerebellum. Conclusion: We conclude that phosphorylation of tau may be a response to a toxic and inflammatory environment generated by the pathological form of prion.

Here we studied HLA blocks and haplotypes in a group of 218 Lacandon Maya Native American using a high-resolution next generation sequencing (NGS) method. We assessed the genetic diversity of HLA class I and class II in this population, and determined the most probable ancestry of Lacandon Maya HLA class I and class II haplotypes. Importantly, this Native American group showed a high degree of both HLA homozygosity and linkage disequilibrium across the HLA region and also lower class II HLA allelic diversity than most previously reported populations (including other Native American groups). Distinctive alleles present in the Lacandon population include HLA-A*24:14 and HLA-B*40:08. Furthermore, in Lacandons we observed a high frequency of haplotypes containing the allele HLA-DRB1*04:11, a relatively frequent allele in comparison with other neighboring indigenous groups. The specific demographic history of the Lacandon population including inbreeding, as well as pathogen selection, may have elevated the frequencies of a small number of HLA class II alleles and DNA blocks. To assess the possible role of different selective pressures in determining Native American HLA diversity, we evaluated the relationship between genetic diversity at HLA-A, HLA-B and HLA-DRB1 and pathogen richness for a global dataset and for Native American populations alone. In keeping with previous studies of such relationships we included distance from Africa as a covariate. After correction for multiple comparisons we did not find any significant relationship between pathogen diversity and HLA genetic diversity (as measured by polymorphism information content) in either our global dataset or the Native American subset of the dataset. We found the expected negative relationship between genetic diversity and distance from Africa in the global dataset, but no relationship between HLA genetic diversity and distance from Africa when Native American populations were considered alone.

Epilepsy is a neurological disorder of the central nervous system characterized by hypersynchronized neuronal activity and has been associated with oxidative stress. Oxidative stress interferes with the expression of genes as well as transcriptional factors such as nuclear factor-erythroid 2-related factor 2 (Nrf2). We evaluated the expression of Nrf2 in the rat brain in treated with kainic acid (KA) and pentylenetetrazole (PTZ). Nrf2 immunoreactivity was observed in astrocytes of the hippocampal region in rats exposed at KA. Nrf2 expression was increased significantly in rats with KA and PTZ. These results provide evidence that the increased expression of Nrf2 is part of the mechanism against KA and PTZ toxicity.

La epilepsia es un desorden neurológico caracterizado por una predisposición duradera para generar ataques epilépticos que afecta a millones de personas alrededor del mundo. La liga internacional contra la epilepsia (ILAE por sus siglas en inglés) ha presentado una clasificación operativa de los tipos de ataques dependiendo de la etiología de la enfermedad. Un común denominador de los diferentes tipos de epilepsia es la existencia de desequilibrio de excitación e inhibición como el mecanismo principal de la transición de la función cerebral normal a la convulsión. Un desequilibrio entre los sistemas de neurotransmisores del glutamato y del ácido gamma-aminobutírico puede provocar hiperexcitabilidad, excitotoxicidad, proliferación de especies reactivas del oxígeno y especies reactivas del nitrógeno, estrés oxidante, daño mitocondrial y posteriormente, muerte celular. El estrés oxidante tiene un papel fundamental en los mecanismos de acción en la enfermedad ya que la hiperexcitabilidad neuronal desempeña un papel fundamental en el inicio y progresión de la epilepsia. Para evitar el daño generado por el estrés oxidante, las células están equipadas con una variedad de antioxidantes que sirven para contrarrestar el efecto de los oxidantes en el cual se encuentran involucrados componentes enzimáticos y no enzimáticos. Los compuestos enzimáticos están regulados por el factor nuclear eritroide 2, que en condiciones de estrés oxidante se unen a los elementos de respuesta antioxidante y de esta manera se incrementa la inducción de enzimas citoprotectoras mediadas por este factor, en astrocitos y neuronas. Para el estudio del papel que juega estrés oxidante en la epilepsia, se recurre a modelos animales que emulen estas condiciones de la enfermedad. La presente revisión resume la evidencia sobre el papel que juega el Nrf2 en la epilepsia mediando la activación de sistemas antioxidantes como protectores celulares contra el estrés oxidativo.

Background Cognitive functions represent useful endophenotypes to identify the association between genetic variants and schizophrenia. In this sense, the NR4A2 gene has been implicated in schizophrenia and cognition in different animal models and clinical trials. We hypothesized that the NR4A2 gene is associated with working memory performance in schizophrenia. This study aimed to analyze two variants and the expression levels of the NR4A2 gene with susceptibility to schizophrenia, as well as to evaluate whether possession of NR4A2 variants influence the possible correlation between gene expression and working memory performance in schizophrenia. Methods The current study included 187 schizophrenia patients and 227 controls genotyped for two of the most studied NR4A2 genetic variants in neurological and neuropsychiatric diseases. Genotyping was performed using High Resolution Melt and sequencing techniques. In addition, mRNA expression of NR4A2 was performed in peripheral mononuclear cells of 112 patients and 118 controls. A group of these participants, 54 patients and 87 controls, performed the working memory index of the WAIS III test. Results Both genotypic frequencies of the two variants and expression levels of the NR4A2 gene showed no significant difference when in patients versus controls. However, patients homozygous for the rs34884856 promoter variant showed a positive correlation between expression levels and auditory working memory. Conclusions Our finding suggested that changes in expression levels of the NR4A2 gene could be associated with working memory in schizophrenia depending on patients’ genotype in a sample from a Mexican population.

Epilepsy is characterized by spontaneous recurrent seizures and temporal lobe epilepsy (TLE) is the most common serious neurological example of acquired and frequent epilepsy. Oxidative stress is recognized as playing a contributing role in several neurological disorders, and most recently have been implicated in acquired epilepsies. The MTs occur in several brain regions and may serve as neuroprotective proteins against reactive oxygen species causing oxidative damage and stress. The main aim of this work was to describe the immunohistochemical localization of MT in the specimens derived from the patients affected by TLE. Histopathological examination showed NeuN, GFAP and MT immunopositive cells that were analyzed for determinate in hippocampal and parietal cortex samples. An increase in the reactive gliosis associated with increased MT expression was observed in patients with TLE.

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 ~ 140 kb 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.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons that results in progressive paralysis and muscular atrophy. There are many molecules and genes involved in neuromuscular degeneration in ALS; among these, matrix metalloproteinases (MMPs). MMPs play an important role in the pathology of ALS, and MMP-1, 2, 3, and 9 might serve as disease progression markers. Tissue inhibitors of metalloproteinases (TIMPS) might also function as progression markers in ALS because they participate in regulating the proteolytic activity of MMPs. Moreover, a diversity of genes also plays a role in the pathogenesis of ALS; most MMPs-coding genes present variants related to the pathological proteolytic activity. This short review, however, will focus on the role of matrix metalloproteinases in ALS.

The serum paraoxonase-1 (PON1) associated to HDL presents two common polymorphisms in the positions 192 and 55. These polymorphisms are considered determinant of the capacity of HDL to protect LDL from their oxidative modification. In this context, the PON1 genotype has been associated with cardiovascular diseases, including stroke.To determine the allelic and genotypic frequencies of PON1 L55M and Q192R as well as the enzymatic activities of PON1 in subjects with and without atherothrombotic stroke.There were included 28 people with atherothrombotic stroke and 29 without stroke. The genotyping was carried out by PCR-RFLP and the phenotyping by measurement of the activities of paraoxonase and arylesterase in serum.For the polymorphism Q192R, the allelic frequencies (Q/R) were 0.46/0.54 and 0.48/0.52 (The polymorphisms Q192R and L55M, and the paraoxonase activity of PON1 are not risk factors for atherothrombotic stroke according to the results of this study.La paraoxonasa-1 (PON1) sérica asociada a las HDL presenta dos polimorfismos comunes en las posiciones 192 y 55. Estos polimorfismos se consideran determinantes para la capacidad de las HDL de proteger a las LDL de su modificación oxidativa. En este contexto, el genotipo de PON1 se ha asociado con enfermedades cerebrovasculares, que incluyen el infarto cerebral.Determinar las frecuencias alélicas y genotípicas de PON1-L55M y PON1- Q192R, así como las actividades enzimáticas de PON1 en sujetos con y sin infarto cerebral aterotrombótico.Se incluyeron 28 personas con infarto cerebral aterotrombótico y 29 sin infarto. Las genotipificaciones se realizaron mediante PCR-RFLP y las fenotipificaciones mediante la medición de las actividades paraoxonasa y arilesterasa en suero.Para el polimorfismo Q192R, las frecuencias alélicas (Q/R) fueron 0.46/0.54 y 0.48/0.52 (Los polimorfismos Q192R y L55M, y la actividad paraoxonasa de la PON1 no son factores de riesgo para el infarto cerebral aterotrombótico en este estudio.

Epilepsy is a neurological disorder characterized by recurrent spontaneous seizures due to an imbalance between cerebral excitability and inhibition, with a tendency towards uncontrolled excitability. Epilepsy has been associated with oxidative and nitrosative stress due to prolonged neuronal hyperexcitation and loss neurons during seizures. The experimental animal models report level of ATP diminished and increase in lipid peroxidation, catalase, and glutathione altered activity in the brain. We studied the immunohistochemical expression and localization of antioxidant enzymes GPx, SOD, and CAT in the rat brains treated with KA and PTZ. A significant decrease was observed in the number of immunoreactive cells to GPx, without significant changes for SOD and CAT in KA-treated rats, and decrease in the number of immunoreactive cells to SOD, without significant changes for GPx and only CAT in PTZ-treated rats. Evident immunoreactivity of GPx, SOD, and CAT was observed mainly in astrocytes and neurons of the hippocampal brain region in rats exposed at KA; similar results were observed in rats treated with PTZ at the first hours. These results provide evidence supporting the role of activation of the Nrf2 antioxidant system pathway against oxidative stress effects in the experimental models of epileptic seizures.

Background Several neuropathological studies in spinocerebellar ataxia type 2 (SCA2) have revealed significant atrophy of the cerebellum, brainstem, sensorimotor cortex, and several regions in the frontal lobe. However, the impact of the neurodegeneration on the functional integration of the remaining tissue is unknown. To analyze the clinical impact of these functional changes, we correlated the abnormal functional connectivity found in SCA2 patients with their scores in clinical scales. To obtain the functional connectivity changes, we followed two approaches. In one we used areas with significant cerebellar gray matter atrophy as anchor seeds, and in the other we performed a whole-brain data-driven analysis. Methods Fourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Voxel-based morphometry and resting-state functional magnetic resonance imaging (fMRI) were done to analyze structural and functional brain changes. Independent component analysis and dual regression were used for intrinsic network comparison. Significant functional connectivity differences were correlated with the behavioral scores. Results Seed-based analysis found reduced functional connectivity within the cerebellum and between the cerebellum and frontal/parietal cortices. Cerebellar functional connectivity increases were found with parietal, frontal, and temporal areas. Intrinsic network analysis found a functional decrease in the cerebellar network, and increase in the default-mode and fronto-parietal networks. Further analysis showed significant correlations between clinical scores and the abnormal functional connectivity strength. Conclusion Our findings show significant correlations between functional connectivity changes in key areas affected in SCA2 and these patients' motor and neuropsychological impairments, adding an important insight to our understanding of the pathophysiology of SCA2. © 2015 International Parkinson and Movement Disorder Society

Aim: In previous CYP2D6 genotyping studies in Mexican–Amerindians a very low frequency of poor metabolizers (PMs) has been reported. Moreover, ultrarapid metabolizers (UMs) status has only been analyzed in some groups from Northern Mexico. Materials & methods: In the present study we evaluated the hypothesis of low frequency of PMs in Mexican–Amerindians in Southern Mexican populations from Chiapas (Lacandones [ML] vs Mestizos [MM]). The frequency of UMs is also reported. CYP2D6 alleles *2, *3, *4, *5, *6, *10, *17, *35 and *41 and copy number variations were analyzed in 154 ML and 100 MM healthy volunteers. Results: The PM frequency was 0% in MLs and 1% in MMs, and for UMs was 2.6% in MLs and 3% in MMs. Conclusion: The present data support previous findings reporting a very low frequency of CYP2D6 PMs in Mexican–Amerindians. Furthermore, the predicted UM phenotype in both MMs and MLs was lower than those reported for most Mexican populations. Original submitted 16 May 2014; Revision submitted 26 September 2014

O-hexyl 2,5-dichlorophenyl phosphoramidate (HDCP) is a racemic organophosphate compound (OP) that induces delayed neuropathy in vivo. The O-hexyl 2,5-dichlorophenyl phosphoramidate R (R-HDCP) isomer inhibits and ages neuropathic target esterase (NTE) in hen brain. Moreover, human serum paraoxonase-1 (PON1) is a Ca(2+)-dependent enzyme capable of hydrolyzing OPs. The enzymatic activity of PON1 against OPs depends on the genetic polymorphisms present at position 192 (glutamine or arginine). The catalytic efficiency of PON1 is an important factor that determines neurotoxic susceptibility to some OPs. In the present study, we characterized the stereospecific hydrolysis of HDCP by alloforms PON1 Q192R human serum by chiral chromatography. Forty-seven human samples were characterized for the PON1 192 polymorphism. The hydrolysis data demonstrate that the three alloforms of PON1 show an exclusive and significant stereospecific Ca(2+)-dependent hydrolysis of O-hexyl 2,5-dichlorophenyl phosphoramidate S isomer (S-HDCP) at 19-127 µM at the concentrations that remain in all the samples. This stereoselective Ca(2+)-dependent hydrolysis of S-HDCP is inhibited by EDTA and is independent of the PON1 Q192R alloform. The present research reinforces the hypothesis that R-HDCP (an isomer that inhibits and causes NTE aging) is the enantiomer that induces delayed neuropathy by this chiral phosphoramidate due to the low hydrolysis level of the R-HDCP observed in this study.

article i nfo Background: Vasovagal syncope is a common clinical condition, consequential to reduced cerebral blood flow resulting from a failure in cardiovascular homeostasis during orthostasis. Blood pressure regulation is the basis for syncope development. In this regulation, the α1a-adrenergic receptor plays a major role. Some studies have found a positive correlation between the Arg347Cys polymorphism of the α1a-adrenergic receptor to hyperten- sion and heart autonomic control. The goal of this study is to evaluate the possible association between the Arg347Cys α1a-adrenergic receptor polymorphism and vasovagal syncope in a Mexican population. Methods/major findings: A sample of 89 vasovagal syncope patients and 40 healthy controls were studied. Arg347Cys α1a-adrenergic receptor polymorphism was determined by the PCR-RFLP method. We found an in- creasedfrequency of genotypeArgArginvasovagalsyncopepatients.Inalogisticregressionmodelsignificantas- sociations were found in two genetic models, in codominant model (OR = 13.21: CI 95% 3.69-54.99, p b 0.001) and in additive model (OR = 12.68: CI 95% 3.5-53.07, p b 0.001) for ArgArg genotype with CysCys as reference. Conclusions: Our data suggests an important participation of Arg347Cys polymorphism as susceptibility factor in patients with vasovagal syncope. ArgArg genotype could be a marker for vasovagal syncope susceptibility in the Mexican population.

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.

Epilepsy is considered one of the most common neurological disorders worldwide. Oxidative stress produced by free radicals may play a role in the initiation and progression of epilepsy; the changes in the mitochondrial and the oxidative stress state can lead mechanism associated with neuronal death pathway. Bioenergetics state failure and impaired mitochondrial function include excessive free radical production with impaired synthesis of antioxidants. This review summarizes evidence that suggest what is the role of oxidative stress on induction of apoptosis in experimental models of epilepsy.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder characterized by progressive ataxia and retinal dystrophy. It is caused by a CAG trinucleotide expansion in the ataxin7 gene. Anatomical studies have shown severe cerebellar degeneration and region-specific neocortical atrophy in SCA7 patients. However, the impact of the neurodegeneration on the functional integration of the remaining tissue is still unknown. The aim of this study was to examine functional connectivity abnormalities in areas with significant gray matter atrophy in SCA7 patients and their relationship with number of CAG repeats. Using a combination of voxel-based morphometry and resting-state fMRI, we studied 26 genetically confirmed SCA7 patients and aged-matched healthy controls. In SCA7 patients we found reduced functional interaction between the cerebellum and the middle and superior frontal gyri, disrupted functional connectivity between the visual and motor cortices, and increased functional coordination between atrophied areas of the cerebellum and a range of visual cortical areas compared with healthy controls. The degree of mutation expansion showed a negative effect on both the functional interaction between the right anterior cerebellum and the left superior frontal gyrus and the connectivity between the right anterior cerebellum and left parahippocampal gyrus. We found abnormal functional connectivity patterns, including both hypo- and hyperconnectivity, compared with controls. These abnormal patterns show reasonable association with the severity of gene mutation. Our findings suggest that aberrant changes are prevalent in both motor and visual systems, adding significantly to our understanding of the pathophysiology of SCA7. © 2013 International Parkinson and Movement Disorder Society

Introduction The NR4A2 transcription factor is important in the development, survival and phenotype of dopaminergic neurons and it is postulated as a possible biomarker for Parkinson's disease (PD). Therefore, our aim was to analyze in a sample of a Mexican population with idiopathic PD, mutations (in two hotspot mutation regions) and two polymorphisms (rs34884856 in promotor and rs35479735 intronic regions) of the NR4A2 gene. We also evaluate the levels of NR4A2 gene expression in peripheral blood for a Mexican population, and identify whether they are associated with NR4A2 gene polymorphisms. Methods We conducted a case-control study, which included 227 idiopathic PD cases and 454 unrelated controls. Genetic variants of the NR4A2 gene were genotyped by high-resolution melting (HRM) and validated by an automated sequencing method. The gene expression was performed in peripheral blood using a real-time polymerase chain reaction. Results The rs35479735 polymorphism was associated with a higher risk of developing PD. In addition, NR4A2 gene expression was significantly decreased in patients with PD. Linkage disequilibrium analysis showed a haplotype H4 (3C-3G) that showed lower levels of expression, and contained the risk alleles for both polymorphisms. Conclusions In summary, this is the first study in a Mexican population that considers the analysis of NR4A2 in patients with PD. An association was identified between genotype and mRNA expression levels of NR4A2 in patients with PD. These results suggest that polymorphisms and expression of the NR4A2 gene could play an important role in the risk of developing PD in Mexican populations.

The SPATAX Network; International audience; ObjectiveThe 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.MethodsWe 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.ResultsIn 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.InterpretationWe 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

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. © 2012 Movement Disorder Society

Increased area of the substantia nigra (SN) associated to iron deposition has been proposed as a specific marker for Parkinson’s disease (PD). Echogenicity, assessed by transcranial sonography (TCS), has been used to measure such an iron deposition. On the other hand, ferroxidase activity is known to play a role in brain iron metabolism and thus could be involved in increased SN echogenicity of PD patients. The present study was conducted to search for a possible correlation between both markers: TCS of SN and plasma ferroxidase activity. Twenty-one PD patients and 13 healthy volunteers (HV) were included. Mean SN sonographic areas were 0.31 cm2 for PD patients and 0.12 cm2 for HV (P < 0.001), while plasma ferroxidase activity was reduced in PD patients (P < 0.001). Interestingly, plasma ferroxidase activity was inversely correlated with the SN size by TCS (R2 = 0.31), suggesting a relationship between the two markers.

Mutations in leucine-rich repeat kinase 2 gene (LRRK2) account for as much as 5–6% of familial Parkinson's disease (PD) and 1–2% of sporadic PD. These mutations represent the most frequent cause of autosomal dominant PD, particularly in certain ethnic groups. In this first report concerning LRRK2 mutations in Mexican-mestizos, we screened 319 consecutive PD patients (186 males; 133 females; mean age at onset: 52.4 years) for LRRK2 mutations in exons 31 and 41 and for the mutation in exon 35, which produces the Y1699C substitution. Three (0.94%) patients, two with sporadic PD and one with familial PD (disease mean age at onset, 53.3 years), were heterozygous for LRRK2 mutations. Of these three, two patients had one of two different mutations in exon 31 (R1441G and R1441H, respectively); the other patient carried the G2019S mutation in exon 41. The Y1699C mutation was absent from this PD sample. Four additional subjects, unaffected relatives of one PD patient with a mutation in LRRK2, were subsequently genetically tested. None of the three LRRK2 mutations identified was present in 200 neurologically healthy Mexican control individuals. These findings have important implications for molecular testing of LRRK2 mutations in Mexican PD patients.

Huntington's disease (HD) is an autosomal dominant progressive, disabling neurodegenerative disorder, for which there is no effective treatment. Predictive testing (PT) for this illness began in 1986 and by 1993 it became more precise after cloning of the gene and the discovery of a CAG repeat expansion as the underlying cause. The objective of this paper is to illustrate the implementation and results of a PT program in a group of at-risk Mexican individuals with 12 years of follow-up. Our PT program conforms to the guidelines proposed by the International Huntington Association and the HD Working group of the World Federation of Neurology. Seventy-five individuals requested the testing, four of them did not fulfill the inclusion criteria, and five abandoned the program voluntarily before receiving the test results. Therefore, 66 results were delivered to 41 noncarriers and 25 mutation carriers. We did not have any catastrophic event, but 4 individuals with normal results and 11 mutation carriers were depressed. Even if this is a small sample, it is the first report of PT in a Latin-American population in which we have been faced with the same problems referred to in larger series.

We report the characteristics of 691 Mexican patients with Huntington's disease (HD). These patients, representing 401 families, constitute the largest series of Mexican HD cases as yet described in the literature. We found the clinical characteristics of these patients to be similar to those of other populations, but we observed a higher frequency of infantile cases, a shorter disease duration and a lower suicide rate. In 626 cases, for which molecular analyses were available, CAG-trinucleotide expansion size ranged from 37-106 repeats. The large number of CAG repeats (19.04 +/- 3.02) in normal alleles and the presence of new mutations suggest that the overall prevalence of HD in the Mexican population could be expected to be within range of, or higher than, that reported for Europeans.

Although ATP-binding cassette transporter A1 (ABCA1) is well known for its role in cholesterol efflux and HDL formation, it is expressed in various tissues, where it may have different functions. Because hypoalphalipoproteinemia is highly prevalent in Mexico, we screened the ABCA1 coding sequence in Mexican individuals with low and high HDL cholesterol levels to seek functional variants. A highly frequent nonsynonymous variant (R230C) was identified in low–HDL cholesterol but not in high–HDL cholesterol individuals (P = 0.00006). We thus assessed its frequency in the Mexican-Mestizo general population, seeking possible associations with several metabolic traits. R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. The variant was significantly associated not only with decreased HDL cholesterol and apolipoprotein A-I levels but also with obesity (odds ratio 2.527, P = 0.005), the metabolic syndrome (1.893, P = 0.0007), and type 2 diabetes (4.527, P = 0.003). All of these associations remained significant after adjusting for admixture (P = 0.011, P = 0.001, and P = 0.006, respectively). This is the first study reporting the association of an ABCA1 variant with obesity and obesity-related comorbidities as being epidemiologically relevant in the Mexican population.

Spinocerebellar ataxia type 17 (SCA17) is caused by expansion of a CAG/CAA repeat in the TBP gene. Most pathogenic alleles are interrupted and are stably transmitted from parent to offspring without anticipation. We identified three SCA17 families with expansion of uninterrupted alleles, thus greatly increasing the number of known intergenerational transmissions of such alleles. We found that uninterrupted SCA17 alleles are unstable, associated with anticipation, and show a paternal expansion bias that increases with age. Even small increments in repeat length resulted in inordinate increases in anticipation. Anticipation was also associated with childhood presentation. Sequencing of all SCA17 alleles is required for effective genetic counseling.

Dominant ataxias show wide geographic variation. We analyzed 108 dominant families and 123 sporadic ataxia patients from Mexico for mutations causing SCA1-3, 6-8, 10, 12, 17 and DRPLA. Only 18.5% of dominant families remained undiagnosed; SCA2 accounted for half (45.4%), followed by SCA10 (13.9%), SCA3 (12%), SCA7 (7.4%), and SCA17 (2.8%). None had SCA1, 6, 8, 12 or DRPLA. Among sporadic cases, 6 had SCA2 (4.9%), and 2 had SCA17 (1.6%). In the SCA2 patients we identified 6 individuals with the rare (CAG)(33) allele, 2 of whom showed early onset ataxia. The distribution of dominant ataxia mutations in Mexicans is distinct from other populations.

We investigated the association between apolipoprotein E (APOE) alleles and genotypes and Parkinson disease (PD) in 229 unrelated Mexican Mestizo PD patients and 229 controls. Results showed that both APOE-e4 allele and APOE e4/e3 genotype are associated with PD (OR = 1.736, P = 0.011; OR = 1.688, P = 0.019, respectively). Mean age at onset of PD was not associated to any APOE allele or genotype, but was significantly earlier in familial PD when compared to sporadic cases (P = 0.025). © 2006 Movement Disorder Society

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Dementia is a frequent complication of idiopathic Parkinsonism or PD, usually occurring later in the protracted course of the illness. Some risk factors to develop dementia in PD are aging, severe Parkinson´s symptoms, rigid-akinetic form, hallucinations, and mild cognitive impairment documented at the first examinations. It is not yet clear if some genetic factors are either risk or protector for progression to dementia. In a review of the literature, we found that mutations in the alpha-synuclein gene are the most responsible for developing dementia, either from PARK1 or 4 mutations. GBA (glucocerebrosidase) is another accountable factor. However, the vast majority of patients suffer from non-Mendelian or complex forms of PD, which are likely caused by the combined effects of genetic and environmental factors. There is not until now a clear relation between some polymorphisms in candidate genes and cognitive deterioration, as many studies have not clearly identified this phenotype.

The etiology of Alzheimer's disease (AD) is complex. To date, molecular genetic studies in several families affected with AD have identified three genes associated with highly penetrant early-onset AD: Presenilin 1 (PSEN1), Presenilin 2 (PSEN2) and beta-amyloid precursor protein (APP); and one gene (apolipoprotein E) associated with late-onset AD. Molecular analysis of the PSEN1 gene was performed by direct sequencing of genomic DNA. The possible founder effect was investigated analyzing two highly polymorphic microsatellite markers flanking the PSEN1 gene. Twelve unrelated Mexican families with early-onset AD were analyzed. The Ala431Glu mutation in exon 12 of PSEN1 was found in nine (75%) of these families, which segregated showing autosomal dominant inheritance. Because all families bearing the mutation are from the State of Jalisco (located in Western Mexico), a founder effect was hypothesized. Microsatellite haplotype analysis suggested a common ancestor in these nine kindreds. In conclusion, the Ala431Glu mutation is a prevalent cause of early-onset familial Alzheimer's disease in families from the State of Jalisco, Mexico. Genetic evidence supports that it is a founder mutation descending from a single common ancestor. These findings have important implications for prompt diagnosis and genetic counseling for Mexican patients with familial AD from Jalisco.

Huntington's disease (HD) is a degenerative disorder of the central nervous system with autosomal dominant inheritance. Genetic counseling has always been difficult in this disorder with anguish, depression and denial being very common in both the patient and family members. The discovery of the causal gene has led to precise diagnostic procedures allowing homozygotes for the disease to be identified. Contrary to what occurs in some other autosomal dominant diseases, the course of the disease is not more severe in the homozygote than in the heterozygote. The present authors describe a family comparing two affected siblings: one is heterozygotic and the other homozygous for the HD mutation. They confirm that the age and symptoms of onset did not differ significantly between the subjects; however, the disease seemed to have a more severe progression in the heterozygote than in the homozygote. The authors discuss the ethical dilemma derived from the genetic counseling of a homozygotic patient, given the fact that all his offspring will be affected. Letting the offspring know about their 100% probability of inheriting the disorder is equivalent to delivering a non-requested predictive test, while not informing them constitutes withholding crucial information from the individual.

The expression of apolipoprotein E (apoE) polymorphisms has been proposed as a risk factor for early development of psychotic symptoms in patients with Parkinson's disease. The association between apoE polymorphisms and motor complications is controversial. The aim was to determine the association between apoE polymorphisms and its allele frequency with the development of complications secondary to dopaminergic replacement therapy.We evaluated 231 patients with the diagnosis of Parkinson's disease. The presence of motor complications secondary to treatment was determined by a neurologist, and the genotypification of apoE polymorphisms was performed. Descriptive statistics and chi-squared test were used.Genotype ?3/?3 was expressed in 80.5 % of the sample; there was no association between genotype or allele frequency of apoE polymorphisms and the development of psychosis or dyskinesia. Patients who expressed the ?2 allele showed a tendency to develop motor fluctuations, but without reaching statistical significance (p = 0.08).ApoE polymorphisms are not associated with the development of complications from dopaminergic replacement therapy.INTRODUCCIÓN: se ha propuesto que la expresión de los polimorfismos de la apolipoproteína E (apoE) es un factor predisponente para el desarrollo temprano de psicosis en los pacientes con enfermedad de Parkinson. La relación entre el genotipo de la apoE y el desarrollo de complicaciones motoras es controvertida. El objetivo de esta investigación fue determinar la relación entre los polimorfismos de la apoE y su frecuencia alélica y el desarrollo de complicaciones secundarias al reemplazo dopaminérgico. MÉTODOS: se evaluaron 231 pacientes con diagnóstico de enfermedad de Parkinson. La presencia de complicaciones fue determinada por un neurólogo y se realizó la genotipificación de los polimorfismos de la apoE. Se utilizó la chi cuadrada para determinar la relación entre la presencia o ausencia de las complicaciones estudiadas y el genotipo de la apoE.se identificó el genotipe ?3/?3 en 80.5 % de la muestra. No existió relación entre el genotipo o la frecuencia alélica de los polimorfismos de la apoE y el desarrollo de psicosis o discinesias. Los pacientes que expresaron el alelo ?2 mostraron una tendencia al desarrollo de fluctuaciones, pero sin significación estadística (p = 0.08).los polimorfismos de la apoE no se relacionaron con el desarrollo de complicaciones derivadas del reemplazo dopaminérgico. El tratamiento de la enfermedad de Parkinson se basa principalmente en la administración de precursores de la dopamina (como la levodopa) o de agonistas dopaminérgicos.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder caused by expansion of an unstable ATTCT repeat. SCA10 has been described as a pure cerebellar syndrome accompanied by seizures and has been recognized only in families of Mexican origin. We describe clinical and molecular findings of 18 patients in four Mexican families with SCA10. Affected individuals had an average age at onset of 26.7 years (range 14-44 years) and ATTCT repeats ranging from 920 to 4,140 repeats. We could not detect significant anticipation or correlation between repeat size and age at onset, probably due to the small sample size. In addition to pure cerebellar ataxia and seizures, patients often showed soft pyramidal signs, ocular dyskinesia, cognitive impairment, and/or behavioral disturbances. Brain magnetic resonance imaging showed predominant cerebellar atrophy, and nerve conduction studies indicated polyneuropathy in 66% of patients. One family showed hepatic, cardiac, and hematological abnormalities in affected members. These findings suggest that a wide range of tissues may be affected in SCA10, including those outside of the cerebellum and cerebral cortex.

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.

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.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder characterized by progressive ataxia and retinal dystrophy. It is caused by a CAG trinucleotide expansion in the ataxin7 gene. Anatomical studies have shown severe cerebellar degeneration and region-specific neocortical atrophy in SCA7 patients. However, the impact of the neurodegeneration on the functional integration of the remaining tissue is still unknown. The aim of this study was to examine functional connectivity abnormalities in areas with significant gray matter atrophy in SCA7 patients and their relationship with number of CAG repeats. Using a combination of voxel-based morphometry and resting-state fMRI, we studied 26 genetically confirmed SCA7 patients and aged-matched healthy controls. In SCA7 patients we found reduced functional interaction between the cerebellum and the middle and superior frontal gyri, disrupted functional connectivity between the visual and motor cortices, and increased functional coordination between atrophied areas of the cerebellum and a range of visual cortical areas compared with healthy controls. The degree of mutation expansion showed a negative effect on both the functional interaction between the right anterior cerebellum and the left superior frontal gyrus and the connectivity between the right anterior cerebellum and left parahippocampal gyrus. We found abnormal functional connectivity patterns, including both hypo- and hyperconnectivity, compared with controls. These abnormal patterns show reasonable association with the severity of gene mutation. Our findings suggest that aberrant changes are prevalent in both motor and visual systems, adding significantly to our understanding of the pathophysiology of SCA7.

Background Over 30 human diseases are caused by expansion of unstable microsatellite sequences. Nine of these are caused by expanded CAG tracts encoding polyglutamines in different genes. This subgroup of diseases, usually referred to as the polyglutamine diseases which include Huntington’s disease (HD), several spinocerebellar ataxias (SCAs), and spinal and bulbar muscular atrophy, are amongst the commonest hereditary neurodegenerative diseases. Longer CAG repeat tracts are associated with earlier ages at onset (AAO), but this does not account for all the variance, suggesting the existence of additional modifying factors. DNA repair pathways have been recently associated with the HD motor AAO in a recent HD GWAS. We therefore aimed to confirm the association between HD motor AAO and DNA repair pathways; and to investigate whether these modifying effects of variants in DNA repair genes can be extended to other polyglutamine diseases. Methods We collected an independent cohort of 1462 subjects with HD and polyglutamine SCAs, and genotyped SNPs selected from the most significant hits in the HD study. Results In an overall analysis of DNA repair pathway, we found the most significant association with AAO when grouping all polyglutamine diseases (HD+SCAs, p = 1.43 × 10−5). Significant associations were also found for HD (p = 0.00194), all SCAs (p = 0.00107), SCA2 (p = 0.0035), and SCA6 (p = 0.00162). Testing individual SNPs, 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 these associations follow the same direction as in the HD GWAS. Conclusions We show that DNA repair genes significantly modify the AAO not only in HD, but also in polyglutamine SCAs. This suggests a common pathogenic mechanism for these diseases, which could operate through the observed somatic expansion of repeats. Manipulation of DNA repair pathways may offer novel therapeutic opportunities in multiple diseases.

BACKGROUND. Levodopa-induced dyskinesia is one of the main complications and limitations of the treatment of patients with Parkinson's disease.To determine the incidence and risk factors involved in the development of dyskinesias in a retrospective cohort of Mexican patients with Parkinson's disease.We reviewed a total of 601 cases of Parkinson's disease patients treated at the National Institute of Neurology and Neurosurgery in the period between January 1990 and June 2010; 482 of them had history of exposure to levodopa.The follow-up was equivalent to 4,392 person-years. 154 patients had dyskinesias at some point in the evolution of the disease. The person-time incidence was 35 cases per 1,000 person-years. The onset of motor symptoms before 50 years of age and levodopa dosesor = 600 mg of levodopa were the main risk factors for early development of dyskinesia (HR of 1.01 [95% CI 1.0 to 1.01, p = 0.001] and HR 1.10 [95% CI 1.04 to 1.23, p = 0.04], respectively].The main determinants of dyskinesias were present early age of onset of motor symptoms and the dose of levodopa. Knowledge of these factors will improve the management planning.

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.

motor fluctuations induced by dopamine replacement therapy are among the main complications of the treatment of patients with Parkinson's disease. Our objective was to determine the incidence of motor fluctuations in a retrospective cohort of Mexican patients with Parkinson's disease.we reviewed the files of 584 cases of Parkinson's disease patients treated at the National Institute of Neurology and Neurosurgery between 1990 and 2010. We registered the demographic and clinical data to analyze the disease course.the follow-up was of 4736 person-years. 33.9 % of patients (n = 198) had motor fluctuations at some point in the evolution of the disease. The rate of person-time incidence was 43 cases per 1000 person-years. The daily dose of levodopa equivalents greater than 600 mg/d and the use of levodopa were the main risk factors for early development of motor fluctuations (HR 1.40 [95 % CI = 1.07 to 1.83, p0.001] and HR 1.61 [95 % CI = 1.17 to 2.23, p = 0.004], respectively).the main determinants of early development of motor fluctuations are the levodopa equivalent daily dose and the quantity and early use of levodopa.

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.We analyzed the entire sequence-coding region and dosage mutations of parkin in 63 Mexican-mestizo EOPD patients and 120 controls.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.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. .

Multiple Sclerosis (MS) is a highly polymorphic disease characterized by different neurologic signs and symptoms. In MS, racial and genetic factors may play an important role in the geographic distribution of this disease. Studies have reported the presence of several protective alleles against the development of autoimmune disorders. In the case of MS, however, they help define MS as a complex disease, and confirm the importance of environmental agents as an independent variable not associated with ethnicity. We carried out an on-site epidemiological study to confirm the absence of MS or NMO among Lacandonians, a pure Amerindian ethnic group in Mexico. We administered a structured interview to 5,372 Lacandonians to assess by family background any clinical data consistent with the presence of a prior demyelinating event. Every participating subject underwent a comprehensive neurological examination by a group of three members of the research team with experience in the diagnosis and treatment of demyelinating disorders to detect clinical signs compatible with a demyelinating disease. We did not find any clinical signs compatible with multiple sclerosis among study participants.

Background von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. Patients have significant morbidity and mortality secondary to vascular tumors. Disease management is centered on tumor surveillance that allows early detection and treatment. Presymptomatic genetic testing is therefore recommended, including in at-risk children. Methods We tested 17 families (n = 109 individuals) for VHL mutations including 43 children under the age of 18. Personalized genetic counseling was provided pre and post-test and the individuals undergoing presymptomatic testing filled out questionnaires gathering socio-demographic, psychological and psychiatric data. Mutation analysis was performed by direct sequencing of the VHL gene. Mutation-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations. Results Mutations were identified in 36 patients, 17 of whom were asymptomatic. In the initial screening, we identified at least one tumor in five of 17 previously asymptomatic individuals. At the end of five years, only 38.9% of the mutation-carriers continued participating in our tumor surveillance program. During this time, 14 mutation carriers developed a total of 32 new tumors, three of whom died of complications. Gender, education, income, marital status and religiosity were not found to be associated with adherence to the surveillance protocol. Follow-up adherence was also independent of pre-test depression, severity of disease, or number of affected family members. The only statistically significant predictor of adherence was being symptomatic at the time of testing (OR = 5; 95% CI 1.2 - 20.3; p = 0.02). Pre-test anxiety was more commonly observed in patients that discontinued follow-up (64.7% vs. 35.3%; p = 0.01). Conclusions The high initial uptake rate of genetic testing for VHL disease, including in minors, allowed the discontinuation of unnecessary screening procedures in non mutation-carriers. However, mutation-carriers showed poor adherence to long-term tumor surveillance. Therefore, many of them did not obtain the full benefit of early detection and treatment, which is central to the reduction of morbidity and mortality in VHL disease. Studies designed to improve adherence to vigilance protocols will be necessary to improve treatment and quality of life in patients with hereditary cancer syndromes.

The effect of ABCA1 genetic variation on HDL-C levels has been widely documented, although studies in children are scarce. We recently found a frequent non-synonymous ABCA1 variant (R230C) exclusive to populations with Native American ancestry, associated with low HDL-C levels and other metabolic traits in adults.We genotyped R230C variant in 1253 healthy unrelated Mexican school-aged children aged 6-15 years (595 boys and 658 girls) to seek associations with HDL-C levels and other metabolic traits. HDL subclass distribution was analyzed in a subgroup of 81 age, gender and BMI-matched children.Individuals carrying the C230 allele showed a significantly lower HDL-C levels (P=2.9x10(-8)), and higher TC/HDL-C ratio, BMI, BMI z-score and percent fat mass (P=0.001, 0.049, 0.032 and 0.039, respectively). HDL size was smaller in R230C heterozygotes as compared to R230R homozygotes (P0.05). Moreover, the proportion of HDL(2b) was lower, while the proportion of HDL(3a) and HDL(3b) particles was higher in R230C heterozygous and/or C230C homozygous individuals as compared to R230R homozygotes (P0.05).Our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children.