RESUMO
Fragile X syndrome (FXS) is caused by CGG expansions of ≥200 repeats (full mutation: FM). Typically, FM causes abnormal methylation of the FMR1 promoter and silencing of FMR1, leading to reduction of FMRP, a protein essential for normal neurodevelopment. However, if unmethylated, these alleles cause over-expression of FMR1 mRNA which has been associated with Fragile X Tremor and Ataxia Syndrome (FXTAS), a late onset disorder. This report details the molecular and clinical profile of an asymptomatic male (29 years) identified as a result of cascade testing who was found to have a rare unmethylated FM (UFM) allele, as well as premutation (PM: 55-199 CGG) size alleles in multiple tissues. Full-scale IQ was within the normal range and minimal features of autism were observed. Southern blot analysis identified FM smears in blood (220-380 CGG) and saliva (212-378 CGG). A PM of 159 CGG was identified in blood and saliva. FMR1 promoter methylation analysis showed all alleles to be unmethylated. FMR1 mRNA levels were greater than fivefold of median levels in typically developing controls and males with FXS mosaic for PM and FM alleles. Issues raised during genetic counseling related to risk for FXTAS associated with UFM and elevated FMR1 mRNA levels, as well as, reproductive options, with implications for future practice.
Assuntos
Ataxia/genética , Transtorno Autístico/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Tremor/genética , Adulto , Alelos , Ataxia/patologia , Transtorno Autístico/fisiopatologia , Metilação de DNA/genética , Síndrome do Cromossomo X Frágil/patologia , Triagem de Portadores Genéticos , Humanos , Masculino , Mutação/genética , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Tremor/patologia , Expansão das Repetições de Trinucleotídeos/genética , Adulto JovemRESUMO
AIM: To investigate the patterns of inheritance and gene mutation status in early-onset dementia (EOD). METHODS: Data were collected on 202 consecutive patients presenting to an EOD clinic. Early-onset Alzheimer's disease (EOAD, n = 120) and early-onset frontotemporal dementia (EOFTD, n = 82) were studied. RESULTS: The majority of participants, 72.5% with EOAD and 74.4% with EOFTD, did not have a positive family history of dementia. An autosomal dominant pattern of inheritance was observed in 14.2% of patients with EOAD and 13.4% of patients with FTD. Of those with an autosomal dominant pattern of inheritance, 11.8% of EOAD and 45.5% of FTD probands had known pathogenic mutations. Only 1.6% of the total population of EOAD and 7.3% of EOFTD possessed known gene mutations. CONCLUSION: Early-onset dementia does not appear to be a strongly inherited autosomal dominant condition. The majority of patients were sporadic. Known mutations were uncommon and do not explain the total autosomal dominant burden.
Assuntos
Doença de Alzheimer/genética , Demência Frontotemporal/genética , Adulto , Idade de Início , Idoso , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Biomarkers represent a promising adjunct to clinical techniques in the diagnosis of Alzheimer's Disease (AD) and other neurodegenerative diseases. At present, the potential of cerebrospinal fluid (CSF) biomarkers in diagnosing AD has been suggested but the degree of clinical utility is yet to be defined due to variability between studies. In this paper we compare the performance of two cerebrospinal fluid assay methods in predicting clinically diagnosed AD. METHODS: CSF biomarker concentrations for Aß1-42, P-tau181P and T-tau were analysed using INNOTEST (ELISA) and INNO-BIA AlzBio3 (Luminex) assay methods from Innogenetics, Belgium. Patients were clinically diagnosed based on NINCDS-ADRDA criteria supplemented with structural MRI, (18)F-fluorodeoxy-glucose positron emission tomography (FDG-PET) and cognitive profiling. RESULTS: An abnormally low Aß1-42 was the most useful biomarker in predicting clinical AD. Depending on the assay method, the predictive accuracy remained constant or improved slightly when abnormalities in P-tau181P and T-tau were considered in addition to Aß1-42. The Luminex method with our optimised reference concentrations performed best for patients ≤ 65 years with sensitivity = 1 and a specificity = 0.60 for both Aß1-42 and when one or more abnormal biomarkers were considered. CONCLUSION: Given accurate, robust and reproducible CSF analytical methods, of which the Luminex method seems the most useful and practicable, our investigation suggests that measuring CSF Aß1-42, P-tau and T-tau has utility in the diagnosis of probable AD and, when used with clinical diagnostic techniques, seems especially helpful in the diagnosis of AD with onset prior to the age of 65 years.