RESUMEN
PURPOSE: To assess the likely pathogenic/pathogenic (LP/P) variants rates in Mendelian dementia genes and the moderate-to-strong risk factors rates in patients with Alzheimer disease (AD). METHODS: We included 700 patients in a prospective study and performed exome sequencing. A panel of 28 Mendelian and 6 risk-factor genes was interpreted and returned to patients. We built a framework for risk variant interpretation and risk gradation and assessed the detection rates among early-onset AD (EOAD, age of onset (AOO) ≤65 years, n = 608) depending on AOO and pedigree structure and late-onset AD (66 < AOO < 75, n = 92). RESULTS: Twenty-one patients carried a LP/P variant in a Mendelian gene (all with EOAD, 3.4%), 20 of 21 affected APP, PSEN1, or PSEN2. LP/P variant detection rates in EOAD ranged from 1.7% to 11.6% based on AOO and pedigree structure. Risk factors were found in 69.5% of the remaining 679 patients, including 83 (12.2%) being heterozygotes for rare risk variants, in decreasing order of frequency, in TREM2, ABCA7, ATP8B4, SORL1, and ABCA1, including 5 heterozygotes for multiple rare risk variants, suggesting non-monogenic inheritance, even in some autosomal-dominant-like pedigrees. CONCLUSION: We suggest that genetic screening should be proposed to all EOAD patients and should no longer be prioritized based on pedigree structure.
Asunto(s)
Enfermedad de Alzheimer , Secuenciación del Exoma , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Glicoproteínas de Membrana , Presenilina-2 , Receptores Inmunológicos , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico , Pruebas Genéticas/métodos , Femenino , Masculino , Anciano , Factores de Riesgo , Estudios Prospectivos , Persona de Mediana Edad , Presenilina-2/genética , Presenilina-1/genética , Linaje , Edad de Inicio , Precursor de Proteína beta-Amiloide/genética , Anciano de 80 o más AñosRESUMEN
PURPOSE: CAG/CAA repeat expansions in TBP>49 are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the existence of SCA48 as a monogenic disease. METHODS: We systematically sequenced TBP repeats in 34 probands of dominant ataxia families with STUB1 variants. In addition, we searched for pathogenic STUB1 variants in probands with expanded alleles of TBP>49 (n = 2) or intermediate alleles of TBP≥40 (n = 47). RESULTS: STUB1 variants were found in half of the TBP40-49 cohort. Mirroring this finding, TBP40-49 alleles were detected in 40% of STUB1 probands. The longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P = .0129) and the faster the disease progression until death (P = .0003). Importantly, 13 STUB1 probands presenting with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode. CONCLUSION: We show that intermediate TBP40-49 alleles act as disease modifiers of SCA48 rather than a STUB1/TBP digenic model. This distinction from what has been proposed before has crucial consequences for genetic counseling in SCA48.
Asunto(s)
Ataxia Cerebelosa , Ataxias Espinocerebelosas , Humanos , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Ataxia Cerebelosa/genética , Fenotipo , Alelos , Expansión de Repetición de Trinucleótido/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Rapid advances were made in the knowledge of amyotrophic lateral sclerosis (ALS) with the recent identification of TARDBP and FUS mutations in familial ALS. More recently, FUS-positive inclusions were found in a subset of TDP-43-negative frontotemporal lobar degeneration (FTLD) prompting us to analyze FUS in FTLD and FTLD-ALS patients. The p.Arg521His mutation was identified in a patient who initially had behavioral disorders and rapidly developed ALS. Although the frequency of mutations is low, our study enlarges the phenotypes associated with FUS mutations and shows that FUS could also play a direct pathogenic role in FTLD spectrum of diseases.
Asunto(s)
Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/genética , Degeneración Lobar Frontotemporal/complicaciones , Degeneración Lobar Frontotemporal/genética , Mutación Missense/genética , Proteína FUS de Unión a ARN/genética , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , FenotipoRESUMEN
Diagnosis of tuberculoma is difficult because of its tumorlike aspects. This report describes the case of a male who displayed a hemiplegia revealing an intracranial mass. Neuroimaging was consistent with a glioblastoma; however, the definite diagnosis was a tuberculoma. Clinical features of tuberculomas are nonspecific. Even though the neuroimaging features are sensitive, they are much less specific, with variability related to the tuberculoma course. Investigations leading to the diagnosis are histologic analysis showing a granuloma with or without caseating necrosis, and the microbiologic identification of Mycobacterium tuberculosis. Every intracranial tumor with malignant radiologic and clinical appearance must evoke a suspicion for tuberculoma.
Asunto(s)
Seudotumor Cerebral/diagnóstico , Tuberculoma Intracraneal/diagnóstico , Neoplasias Encefálicas/diagnóstico , Diagnóstico Diferencial , Glioblastoma/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Seudotumor Cerebral/etiologíaRESUMEN
Radicular involvement in Horton's disease is rare. In all but one of the eight documented cases, C5 nerve roots were affected. We report a new case with C5 involvement. Cervical radiculopathy could be due to arteritis of radicular vessels. Preferential involvement of C5 nerve roots may depend on the vascularization of cervical roots but could be due to the inability to diagnose upper cervical involvement (C1-C3). Outcome is favourable in all cases with corticosteroids.