Single-cell multimodal analysis in a case with reduced penetrance of Progranulin-Frontotemporal Dementia.

We identified an autosomal dominant progranulin mutation carrier without symptoms of dementia in her lifetime (Reduced Penetrance Mutation Carrier, RedPenMC). This resistance to develop expected pathology presents a unique opportunity to interrogate neurodegenerative mechanisms. We performed multimodal single-nuclei analyses of post-mortem frontal cortex from RedPenMC, including transcriptomics and global levels of chromatin marks.

Plasma metabolomics of presymptomatic PSEN1-H163Y mutation carriers: a pilot study.

Background And Objective: PSEN1-H163Y carriers, at the presymptomatic stage, have reduced FDG-PET binding in the cerebrum of the brain (Scholl et al., Neurobiol Aging 32:1388-1399, 2011). This could imply dysfunctional energy metabolism in the brain.

A Novel Duplication in ATXN2 as Modifier for Spinocerebellar Ataxia 3 (SCA3) and C9ORF72-ALS.

Background: The ataxin-2 (ATXN2) gene contains a cytosine-adenine-guanine repeat sequence ranging from 13 to 31 repeats, but when surpassing certain thresholds causes neurodegeneration. Genetic alterations in ATXN2 other than pathological cytosine adenine guanine (CAG) repeats are unknown.

Methods/results: We have identified a 9-base pair duplication in the 2-gene ATXN2 sense/antisense region.

Buccal Cell Micronucleus Frequency Is Significantly Elevated in Patients with Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is part of a group of at least nine dominantly inherited disorders characterized by progressive degeneration of specific neuronal populations and a shared mutational mechanism involving the expansion of a CAG repeat tract in coding regions of novel genes. Efforts have been made to identify biomarkers of disease progression, which would allow timely preventive therapeutic interventions. In the present study was assessed the influence of several genome instability biomarkers on SCA2 clinical severity.

Correlations Between Methionine Cycle Metabolism, COMT Genotype, and Polyneuropathy in L-Dopa Treated Parkinson's Disease: A Preliminary Cross-Sectional Study.

Background: Polyneuropathy (pnp) is recognized as a clinical feature of Parkinson's disease (PD). Whether pnp is a result of the alpha-synucleinopathy or related to treatment is debated. Previous studies support underlying disturbances in the methionine cycle mediated by L-dopa.

Prodromal spinocerebellar ataxia type 2: Prospects for early interventions and ethical challenges.

The characterization of prodromal stages in neurodegenerative disorders is becoming increasingly important because of the need for early neuroprotective therapies. Research during the past 3 decades in spinocerebellar ataxia type 2 has revealed a large body of evidence suggesting that many disease features precede the manifest cerebellar syndrome, which delineates the prodromal stage of this disorder. This stage is defined by clinical, imaging, and functional criteria, which are supported by early molecular events demonstrated in animal models.

SCA2 predictive testing in Cuba: challenging concepts and protocol evolution.

Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN2 gene. Cuba has the highest prevalence (6.57 cases/10(5) inhabitants) of SCA2 in the world.

Executive deficit in spinocerebellar ataxia type 2 is related to expanded CAG repeats: evidence from antisaccadic eye movements.

Although antisaccadic task is a sensitive research tool in psychopathology, it has not been systematically studied in patients with spinocerebellar ataxia type 2 (SCA2). To identify putative biomarkers of executive dysfunction in SCA2 we assessed the antisaccade performance in 41 SCA2 patients and their sex-and-age matched controls using an electronystagmography device. We studied the relationship between findings in the antisaccade task and CAG repeat length and motor function as assessed using the Scale for the Assessment and Rating of Ataxia (SARA), Nine-Hole Pegboard Test and a validated battery for executive dysfunctions.

Comprehensive study of early features in spinocerebellar ataxia 2: delineating the prodromal stage of the disease.

The prodromal phase of spinocerebellar ataxias (SCAs) has not been systematically studied. Main findings come from a homogeneous SCA type 2 (SCA2) population living in Cuba. The aim of this study was to characterize extensively the prodromal phase of SCA2 by several approaches.

Progression of early features of spinocerebellar ataxia type 2 in individuals at risk: a longitudinal study.

Background: The effects of ATXN2 expansion on the nervous system arise before the cerebellar syndrome can be diagnosed; however, progression of the underlying early clinical manifestations is unknown. We aimed to assess progression of the main clinical features in early stages of the spinocerebellar ataxia type 2 (SCA2).

Methods: We did this longitudinal study between Aug 12, 1986, and Sept 3, 2013, in carriers and non-carriers of the SCA2 mutation.

[Epigenetic heredity (deoxyribonucleic acid methylation): Clinical context in neurodegenerative disorders and ATXN2 gene].

Epigenetics is the group of changes in the phenotype which are related with the process independently of the primary DNA sequence. These changes are intimately related with changes in the gene expression level and its profile across the body. These are mediated by histone tail modifications, DNA methylation, micro-RNAs, with chromatin remodeling remaining as the foundation of epigenetic changes.

Genetic features of Huntington disease in Cuban population: implications for phenotype, epidemiology and predictive testing.

Huntington disease is the most frequent polyglutamine disorder with variable worldwide prevalence. Although some Latin American populations have been studied, HD prevalence in Cuban population remains unknown. In order to characterize the disease in Cuba, the relative frequency of HD was determined by studying 130 patients with chorea and 63 unrelated healthy controls, emphasizing in the molecular epidemiology of the disease.

De novo mutations in ataxin-2 gene and ALS risk.

Pathogenic CAG repeat expansion in the ataxin-2 gene (ATXN2) is the genetic cause of spinocerebellar ataxia type 2 (SCA2). Recently, it has been associated with Parkinsonism and increased genetic risk for amyotrophic lateral sclerosis (ALS). Here we report the association of de novo mutations in ATXN2 with autosomal dominant ALS.

Large normal and intermediate alleles in the context of SCA2 prenatal diagnosis.

In 2001 a program for predictive testing of Spinocerebellar Ataxia type 2 was developed in Cuba, based on the detection of an abnormal CAG trinucleotide repeat expansion in the ATXN2 gene. A descriptive study was designed to assess the implications of ATXN2 large normal and intermediate alleles in the context of the SCA2 Prenatal Diagnosis Program. Four clinical scenarios were selected based upon the behaviour of large normal and intermediate alleles when passing from one generation to the next, showing expansions, contractions, or stability in the CAG repeat size.

Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications.

Pathogenic CAG (cytosine-adenine-guanine) expansions beyond certain thresholds in the ataxin-2 (ATXN2) gene cause spinocerebellar ataxia type 2 (SCA2) and were shown to contribute to Parkinson disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Regulation of ATXN2 gene expression and the function of the protein product are not known. SCA2 exhibits an inverse correlation between the size of the CAG repeat and the age at disease onset.

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles.

The role of short, large or intermediate normal alleles (ANs) of the ataxin-2 gene in generating expanded alleles (EAs) causing spinocerebellar ataxia type 2 (SCA2) is poorly understood. It has been postulated that SCA2 prevalence is related to the frequency of large ANs. SCA2 shows the highest worldwide prevalence in Cuban population, which is therefore a unique source for studying the relationship between the frequency of large and intermediate alleles and the frequency of SCA2 mutation.

A comprehensive review of spinocerebellar ataxia type 2 in Cuba.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia characterized by a progressive cerebellar syndrome associated to saccadic slowing, peripheral neuropathy, cognitive disorders, and other multisystem features. SCA2 is caused by the abnormal expansion of cytosine-adenine-guanine triplet repeats in the encoding region of the ATXN2 gene and therefore the expression of toxic polyglutamine expansions in the ataxin 2 protein, which cause progressive neuronal death of Purkinje cells in the cerebellum and several pontine, mesencephalic, and thalamic neurons among other cells. Worldwide, SCA2 is the second most frequent type of spinocerebellar ataxia, only surpassed by SCA3.