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Habekost C.T.,Federal University of Rio Grande do Sul | Habekost C.T.,Instituto Nacional Of Genetica Medica Populacional Inagemp | Schestatsky P.,Federal University of Rio Grande do Sul | Torres V.F.,Neurology Service | And 14 more authors.
Orphanet Journal of Rare Diseases | Year: 2014

Background: Neurologic impairments in female heterozygotes for X-linked Adrenoleukodystrophy (X-ALD) are poorly understood. Our aims were to describe the neurological and neurophysiological manifestations of a cohort of X-ALD heterozygotes, and to correlate them with age, disease duration, mutations, X-inactivation and serum concentrations of a marker of neuronal damage, neuron-specific enolase (NSE). Methods. All 45 heterozygotes identified in our region, with previous VLCFA and molecular diagnosis, were invited to be evaluated through myelopathy scales JOA and SSPROM, nerve conduction studies and somatosensory evoked responses. X inactivation pattern was tested by HUMARA methylation assay. Serum NSE was measured by eletrochemiluminescense. Results: Thirty three heterozygote women were recruited: 29 (87%) were symptomatic. Symptomatic and asymptomatic women presented different m ± sd ages (43.9 ± 10.2 versus 24.3 ± 4.6), JOA (14.5 ± 1.7 versus 16.6 ± 0.2) and SSPROM (86.6 ± 7.9 versus 98.4 ± 1.1) scores (p < 0.05). Both JOA (r = -0.68) and SSPROM (r = -0.65) correlated with age, irrespectively of the disease status (p = 0.0001, Spearman). Delayed latencies in the central ascending conduction studies on the lower limbs were present in 72% of all heterozygotes, and correlated with SSPROM (r = -0.47, p = 0.018, Spearman). NSE values were higher in heterozygote than in control women (12.9 ± 7 and 7.2 ± 7 ng/ml, p = 0.012, Mann-Whitney U). Mutation severity and inactivation patterns were not associated with neurologic status. Conclusion: Neurologic manifestations, clearly related to age, were quite common in the present cohort. JOA and SSPROM scales were able to discriminate the asymptomatic from the symptomatic heterozygotes. Both scales might be useful tools to follow disease progression, in future studies. © 2014 Habekost et al.; licensee BioMed Central Ltd. Source

Habekost C.T.,Genetics and Molecular Biology | Habekost C.T.,Instituto Nacional Of Genetica Medica Populacional Inagemp | Pereira F.S.,Laboratory of Genetic Identification | Vargas C.R.,Genetics and Biochemistry | And 12 more authors.
Metabolic Brain Disease | Year: 2015

X-linked adrenoleukodystrophy heterozygote women can present adult onset myeloneuropathy and little is known about its natural history. We aimed to describe the progression rate of the neurological impairment in the prospective follow-up of our cohort and to look for prognostic factors. The neurological scales Japanese Orthopaedic Association (JOA) and Severity Score System for Progressive Myelopathy (SSPROM) were applied at baseline in 29 symptomatic carriers and in follow-up visits. Age at onset, disease duration, X inactivation pattern, determination of the allele expressed, plasma levels of the very long chain fatty acids and of the neuron-specific enolase, and somato-sensory evoked potentials, were taken at baseline. The slope of the linear regression of both JOA and SSPROM versus disease duration since the first symptom was estimated using mixed modeling. JOA and SSPROM decreased 0.42 and 1.87 points per year, respectively (p < 0.001). None of the parameters under study influenced these rates. We estimated that the number of carriers per arm needed in a future 12 month trial with 80 % power and a 50 % reduction in disease progression would be 225 women for JOA and 750 for SSPROM. The progression rates of the studied neurological scales were small, did not depend on any modifier factor known, and reflected the characteristically slow worsening of symptoms in X-ALD heterozygotes. Better biomarkers are still necessary for future studies. © 2015, Springer Science+Business Media New York. Source

De Castilhos R.M.,Medical Genetics Service | De Castilhos R.M.,Federal University of Rio Grande do Sul | De Castilhos R.M.,Instituto Nacional Of Genetica Medica Populacional Inagemp | Furtado G.V.,Laboratory of Genetic Identification | And 29 more authors.
Cerebellum | Year: 2014

This study describes the frequency of spinocerebellar ataxias and of CAG repeats range in different geographical regions of Brazil, and explores the hypothetical role of normal CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes on age at onset and on neurological findings. Patients with symptoms and family history compatible with a SCA were recruited in 11 cities of the country; clinical data and DNA samples were collected. Capillary electrophoresis was performed to detect CAG lengths at SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA12, SCA17, and DRPLA associated genes, and a repeat primed PCR was used to detect ATTCT expansions at SCA10 gene. Five hundred forty-four patients (359 families) were included. There were 214 SCA3/MJD families (59.6%), 28 SCA2 (7.8%), 20 SCA7 (5.6%), 15 SCA1 (4.2%), 12 SCA10 (3.3%), 5 SCA6 (1.4%), and 65 families without a molecular diagnosis (18.1%). Divergent rates of SCA3/MJD, SCA2, and SCA7 were seen in regions with different ethnic backgrounds. 64.7% of our SCA10 patients presented seizures. Among SCA2 patients, longer ATXN3 CAG alleles were associated with earlier ages at onset (p<0.036, linear regression). A portrait of SCAs in Brazil was obtained, where variation in frequencies seemed to parallel ethnic differences. New potential interactions between some SCA-related genes were presented. © Springer Science+Business Media 2013. Source

Franca M.C.,University of Campinas | Franca M.C.,Laboratory of Genetic Identification | Emmel V.E.,Laboratory of Genetic Identification | D'Abreu A.,University of Campinas | And 14 more authors.
Frontiers in Neurology | Year: 2012

Background: Age at onset (AO) in Machado-Joseph disease (MJD) is closely associated with the length of the CAG repeat at the mutant ATXN3 allele, but there are other intervening factors. Experimental evidence indicates that the normal ATXN3 allele and the C-terminal heat shock protein 70 (Hsp70)-interacting protein (CHIP) may be genetic modifiers of AO in MJD. Methods:To investigate this hypothesis, we determined the length of normal and expanded CAG repeats at the ATXN3 gene in 210 unrelated patients with MJD. In addition, we genotyped five single nucleotide polymorphisms (SNPs) within the CHIP gene.We first compared the frequencies of the different genotypes in two subgroups of patients who were highly discordant for AO after correction for the length of the expanded CAG allele.The possible modifier effect of each genewas then evaluated in a stepwise multiple linear regression model. Results: AO was associated with the length of the expanded CAG allele (r 2 =0.596, p <0.001). Frequencies of the normal CAG repeats at the ATXN3 gene and of CHIP polymorphisms did not differ significantly between groups with highly discordant ages at onset. However, addition of the normal allele improved the model fit for prediction of AO (r2 =0.604, p =0.014). Indeed, we found that the normal CAG allele at ATXN3 had a positive independent effect on AO. Conclusion: The normal CAG repeat at the ATXN3 gene has a small but significant influence on AO of MJD. © 2012 França, Emmel, D'Abreu, Maurer-Morelli, Secolin, Bonadia, daSilva, Nucci, Jardim, Saraiva-Pereira, Marques, Paulson and Lopes-Cendes. Source

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