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1.
Hum Mol Genet ; 27(17): 2965-2977, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29790959

RESUMO

Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues-such as dorsal root ganglia, sensory neurons and cerebellum-in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.


Assuntos
Biomarcadores/sangue , Ataxia de Friedreich/sangue , Ataxia de Friedreich/genética , Redes Reguladoras de Genes , Mediadores da Inflamação/sangue , Inflamação/genética , Transcriptoma , Adulto , Estudos de Casos e Controles , Feminino , Ataxia de Friedreich/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade
2.
Alzheimers Dement ; 16(1): 118-130, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914217

RESUMO

INTRODUCTION: The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes. METHODS: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies. RESULTS: Among the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes. DISCUSSION: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.


Assuntos
Demência Frontotemporal/genética , Predisposição Genética para Doença , Testes Genéticos , Proteína C9orf72/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Progranulinas/genética , Proteínas tau/genética
3.
Neurogenetics ; 20(2): 99-102, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30895394

RESUMO

Primary familial brain calcification (PFBC) is a rare disorder mostly characterized by calcium deposits in the basal ganglia and a wide spectrum of neurologic and psychiatric symptoms, typically inherited as an autosomal dominant trait. Recently, MYORG was reported as the first autosomal recessive causal gene in PFBC patients of Chinese and Middle Eastern origin. Herein, we describe the first PFBC patient of European descent found to carry a novel homozygous MYORG mutation (p.N511Tfs*243). Interestingly, the patient's father, a heterozygous carrier of the same mutation, showed diffuse bilateral cerebral calcifications with no symptoms other than very mild postural tremor.


Assuntos
Encefalopatias/genética , Calcinose/genética , Glicosídeo Hidrolases/genética , Homozigoto , Adulto , Encefalopatias/patologia , Calcinose/patologia , Consanguinidade , Disartria/genética , Saúde da Família , Marcha , Testes Genéticos , Heterozigoto , Humanos , Itália , Masculino , Mutação , Malformações do Sistema Nervoso/genética , Linhagem
4.
Acta Neuropathol ; 137(1): 71-88, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30382371

RESUMO

Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case-control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 is associated with FTLD risk. Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies. Using post-mortem tissue from middle frontal gyrus of patients with FTLD and controls, we identified increased MFSD8 protein levels in MFSD8 rare variant carriers relative to non-variant carrier patients with sporadic FTLD and healthy controls. We also observed an increase in lysosomal and autophagy-related proteins in MFSD8 rare variant carrier and sporadic FTLD patients relative to controls. Immunohistochemical analysis revealed that MFSD8 was expressed in neurons and astrocytes across subjects, without clear evidence of abnormal localization in patients. Finally, in vitro studies identified marked disruption of lysosomal function in cells from MFSD8 rare variant carriers, and identified one rare variant that significantly increased the cell surface levels of MFSD8. Considering the growing evidence for altered autophagy in the pathogenesis of neurodegenerative disorders, our findings support a role of NCL genes in FTLD risk and suggest that MFSD8-associated lysosomal dysfunction may contribute to FTLD pathology.


Assuntos
Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Degeneração Lobar Frontotemporal/genética , Proteínas de Membrana Transportadoras/genética , Idoso , Feminino , Demência Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Estudos de Associação Genética/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Lisossomos/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação/genética , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/patologia , Doença de Pick/genética , Fatores de Risco
5.
Alzheimers Dement ; 15(4): 553-560, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30599136

RESUMO

INTRODUCTION: Primary progressive aphasia (PPA) is a neurological syndrome, associated with both frontotemporal dementia and Alzheimer's disease, in which progressive language impairment emerges as the most salient clinical feature during the initial stages of disease. METHODS: We screened the main genes associated with Alzheimer's disease and frontotemporal dementia for pathogenic and risk variants in a cohort of 403 PPA cases. RESULTS: In this case series study, 14 (3.5%) cases carried (likely) pathogenic variants: four C9orf72 expansions, nine GRN, and one TARDBP mutation. Rare risk variants, TREM2 R47H and MAPT A152T, were associated with a three- to seven-fold increase in risk for PPA. DISCUSSION: Our results show that while pathogenic variants within the most common dementia genes were rarely associated with PPA, these were found almost exclusively in GRN and C9orf72, suggesting that PPA is more TDP43- than tau-related in our series. This is consistent with the finding that PPA frequency in dominantly inherited dementias is the highest in kindreds with GRN variants.


Assuntos
Afasia Primária Progressiva/genética , Proteína C9orf72/genética , Demência Frontotemporal/genética , Progranulinas/genética , Idoso , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética
6.
Ann Neurol ; 80(6): 858-870, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27696483

RESUMO

OBJECTIVE: Seizures are more frequent in patients with Alzheimer's disease (AD) and can hasten cognitive decline. However, the incidence of subclinical epileptiform activity in AD and its consequences are unknown. Motivated by results from animal studies, we hypothesized higher than expected rates of subclinical epileptiform activity in AD with deleterious effects on cognition. METHODS: We prospectively enrolled 33 patients (mean age, 62 years) who met criteria for AD, but had no history of seizures, and 19 age-matched, cognitively normal controls. Subclinical epileptiform activity was assessed, blinded to diagnosis, by overnight long-term video-electroencephalography (EEG) and a 1-hour resting magnetoencephalography exam with simultaneous EEG. Patients also had comprehensive clinical and cognitive evaluations, assessed longitudinally over an average period of 3.3 years. RESULTS: Subclinical epileptiform activity was detected in 42.4% of AD patients and 10.5% of controls (p = 0.02). At the time of monitoring, AD patients with epileptiform activity did not differ clinically from those without such activity. However, patients with subclinical epileptiform activity showed faster declines in global cognition, determined by the Mini-Mental State Examination (3.9 points/year in patients with epileptiform activity vs 1.6 points/year in patients without; p = 0.006), and in executive function (p = 0.01). INTERPRETATION: Extended monitoring detects subclinical epileptiform activity in a substantial proportion of patients with AD. Patients with this indicator of network hyperexcitability are at risk for accelerated cognitive decline and might benefit from antiepileptic therapies. These data call for more sensitive and comprehensive neurophysiological assessments in AD patient evaluations and impending clinical trials. Ann Neurol 2016;80:858-870.


Assuntos
Doença de Alzheimer/epidemiologia , Convulsões/epidemiologia , California/epidemiologia , Estudos de Casos e Controles , Comorbidade , Eletroencefalografia , Feminino , Humanos , Incidência , Imageamento por Ressonância Magnética , Magnetoencefalografia , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Sintomas Prodrômicos , Estudos Prospectivos
8.
Neurobiol Aging ; 75: 224.e1-224.e8, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30528349

RESUMO

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative syndromes associated with several causative and susceptibility genes. Herein, we aimed to determine the incidence of the most common causative dementia genes in a cohort of 118 unrelated Greek FTD spectrum patients. We also screened for novel possible disease-associated variants in additional 21 genes associated with FTD or amyotrophic lateral sclerosis. Pathogenic or likely pathogenic variants were identified in 16 cases (13.6%). These included repeat expansions in C9orf72 and loss-of-function GRN variants, and likely pathogenic variants in TARDBP, MAPT, and PSEN1. We also identified 14 variants of unknown significance in other rarer FTD or amyotrophic lateral sclerosis genes that require further segregation and functional analysis. Our genetic screen revealed a high genetic burden in familial Greek FTD cases (30.4%), whereas only two of the sporadic cases (3.5%) carried a likely pathogenic variant. A substantial number of familial cases still remain without an obvious causal variant, suggesting the existence of other FTD genetic causes besides those currently screened in clinical routine.


Assuntos
Demência Frontotemporal/genética , Predisposição Genética para Doença/genética , Mutação/genética , Esclerose Lateral Amiotrófica/genética , Povo Asiático/genética , Proteína C9orf72/genética , Estudos de Coortes , Expansão das Repetições de DNA/genética , Feminino , Estudos de Associação Genética , Testes Genéticos , Grécia , Humanos , Masculino
9.
Neurosci Lett ; 657: 11-15, 2017 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-28764909

RESUMO

We describe clinical and biomarker findings in an index patient with the onset of Alzheimer's disease (AD) symptoms at age 57 and a family history consistent with an autosomal dominant pattern of inheritance. She had the atypical early features of visual agnosia and prosopagnosia followed by hoarding behavior and Parkinsonism. Structural MRI revealed global atrophy that was most severe in the lateral temporal lobes and insular cortex bilaterally. CSF biomarker assessment showed Aß42, p-tau181, and total tau levels consistent with AD. Genetic assessment revealed a novel mutation in the PSEN1 gene (S230N) in the index patient and her affected brother which was absent in her two clinically unaffected and AD-biomarker negative sisters. The serine residue at codon 230 in PSEN1 is highly conserved across species and in PSEN2, providing strong evidence for its pathogenicity in this family.


Assuntos
Doença de Alzheimer/genética , Colecionismo/genética , Transtornos Parkinsonianos/genética , Prosopagnosia/genética , Idade de Início , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Presenilina-1 , Irmãos
10.
J Alzheimers Dis ; 58(4): 1035-1041, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28550247

RESUMO

BACKGROUND: The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-ß (Aß), including Aß42, proteins thought critical in the pathogenesis of Alzheimer's disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. OBJECTIVE: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other. METHODS: Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as PSEN1 sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on γ-secretase cleavage. RESULTS: Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased Aß42 and decreased APP and Notch intracellular domain production in vitro. CONCLUSION: Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the γ-secretase cleavage of Aß.


Assuntos
Doença de Alzheimer/genética , Mutação/genética , Presenilina-1/genética , Idoso , Doença de Alzheimer/diagnóstico por imagem , Precursor de Proteína beta-Amiloide/genética , Autopsia , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
11.
J Neuropathol Exp Neurol ; 75(3): 284-90, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26888304

RESUMO

Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal ß-amyloid protein precursor processing.


Assuntos
Doença de Alzheimer/patologia , Neuropatologia , Presenilina-1/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Apolipoproteínas E/genética , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , National Institute on Aging (U.S.)/estatística & dados numéricos , Presenilina-2/genética , Estados Unidos/epidemiologia
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