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1.
Brain ; 144(9): 2798-2811, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34687211

RESUMO

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.


Assuntos
Proteína C9orf72/genética , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/genética , Genes Ligados ao Cromossomo X/genética , Estudo de Associação Genômica Ampla/métodos , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Degeneração Lobar Frontotemporal/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
2.
J Neurol Neurosurg Psychiatry ; 92(5): 485-493, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33239440

RESUMO

OBJECTIVE: To identify potential biomarkers of preclinical and clinical progression in chromosome 9 open reading frame 72 gene (C9orf72)-associated disease by assessing the expression levels of plasma microRNAs (miRNAs) in C9orf72 patients and presymptomatic carriers. METHODS: The PREV-DEMALS study is a prospective study including 22 C9orf72 patients, 45 presymptomatic C9orf72 mutation carriers and 43 controls. We assessed the expression levels of 2576 miRNAs, among which 589 were above noise level, in plasma samples of all participants using RNA sequencing. The expression levels of the differentially expressed miRNAs between patients, presymptomatic carriers and controls were further used to build logistic regression classifiers. RESULTS: Four miRNAs were differentially expressed between patients and controls: miR-34a-5p and miR-345-5p were overexpressed, while miR-200c-3p and miR-10a-3p were underexpressed in patients. MiR-34a-5p was also overexpressed in presymptomatic carriers compared with healthy controls, suggesting that miR-34a-5p expression is deregulated in cases with C9orf72 mutation. Moreover, miR-345-5p was also overexpressed in patients compared with presymptomatic carriers, which supports the correlation of miR-345-5p expression with the progression of C9orf72-associated disease. Together, miR-200c-3p and miR-10a-3p underexpression might be associated with full-blown disease. Four presymptomatic subjects in transitional/prodromal stage, close to the disease conversion, exhibited a stronger similarity with the expression levels of patients. CONCLUSIONS: We identified a signature of four miRNAs differentially expressed in plasma between clinical conditions that have potential to represent progression biomarkers for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. This study suggests that dysregulation of miRNAs is dynamically altered throughout neurodegenerative diseases progression, and can be detectable even long before clinical onset. TRIAL REGISTRATION NUMBER: NCT02590276.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Proteína C9orf72/genética , Demência Frontotemporal/metabolismo , MicroRNAs/sangue , Adulto , Idoso , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/genética , Biomarcadores/sangue , Progressão da Doença , Feminino , Demência Frontotemporal/sangue , Demência Frontotemporal/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Sequenciamento do Exoma
3.
J Neurol Neurosurg Psychiatry ; 92(12): 1278-1288, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34349004

RESUMO

OBJECTIVE: Neurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages. METHODS: We analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical-genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index. RESULTS: pNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades. CONCLUSIONS: This study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression. TRIAL REGISTRATION NUMBERS: NCT02590276 and NCT04014673.


Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Proteína C9orf72/genética , Demência Frontotemporal/diagnóstico , Proteínas de Neurofilamentos/sangue , Progranulinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/genética , Progressão da Doença , Feminino , Demência Frontotemporal/sangue , Demência Frontotemporal/genética , Humanos , Masculino , Pessoa de Meia-Idade
4.
Brain ; 143(1): 303-319, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31855245

RESUMO

Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.


Assuntos
Demência Frontotemporal/genética , Lipofuscinoses Ceroides Neuronais/genética , Transtornos Parkinsonianos/genética , Progranulinas/genética , Adolescente , Adulto , Idade de Início , Ataxia Cerebelar/genética , Criança , Disfunção Cognitiva/genética , Epilepsia/genética , Feminino , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Lipofuscinoses Ceroides Neuronais/diagnóstico por imagem , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/fisiopatologia , Progranulinas/metabolismo , Splicing de RNA/genética , Doenças Raras , Retinose Pigmentar/genética , Proteinopatias TDP-43/diagnóstico por imagem , Proteinopatias TDP-43/genética , Proteinopatias TDP-43/fisiopatologia , Adulto Jovem
5.
Ann Neurol ; 86(2): 158-167, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177556

RESUMO

OBJECTIVE: C9orf72 hexanucleotide repeats expansions account for almost half of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Recent imaging studies in asymptomatic C9orf72 carriers have demonstrated cerebral white (WM) and gray matter (GM) degeneration before the age of 40 years. The objective of this study was to characterize cervical spinal cord (SC) changes in asymptomatic C9orf72 hexanucleotide carriers. METHODS: Seventy-two asymptomatic individuals were enrolled in a prospective study of first-degree relatives of ALS and FTD patients carrying the c9orf72 hexanucleotide expansion. Forty of them carried the pathogenic mutation (C9+ ). Each subject underwent quantitative cervical cord imaging. Structural GM and WM metrics and diffusivity parameters were evaluated at baseline and 18 months later. Data were analyzed in C9+ and C9- subgroups, and C9+ subjects were further stratified by age. RESULTS: At baseline, significant WM atrophy was detected at each cervical vertebral level in C9+ subjects older than 40 years without associated changes in GM and diffusion tensor imaging parameters. At 18-month follow-up, WM atrophy was accompanied by significant corticospinal tract (CST) fractional anisotropy (FA) reductions. Intriguingly, asymptomatic C9+ subjects older than 40 years with family history of ALS (as opposed to FTD) also exhibited significant CST FA reduction at baseline. INTERPRETATION: Cervical SC imaging detects WM atrophy exclusively in C9+ subjects older than 40 years, and progressive CST FA reductions can be identified on 18-month follow-up. Cervical SC magnetic resonance imaging readily captures presymptomatic pathological changes and disease propagation in c9orf72-associated conditions. ANN NEUROL 2019;86:158-167.


Assuntos
Doenças Assintomáticas , Proteína C9orf72/genética , Heterozigoto , Mutação/genética , Neuroimagem/tendências , Medula Espinal/diagnóstico por imagem , Adulto , Idoso , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/genética , Seguimentos , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
6.
J Neurol Neurosurg Psychiatry ; 91(4): 366-372, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32054668

RESUMO

OBJECTIVE: To investigate cognitive inhibition in presymptomatic C9orf72 mutation carriers (C9+) and its associated neuroanatomical correlates. METHODS: Thirty-eight presymptomatic C9orf72 mutation carriers (C9+, mean age 38.2±8.0 years) and 22 C9- controls from the PREV-DEMALS cohort were included in this study. They underwent a cognitive inhibition assessment with the Hayling Sentence Completion Test (HSCT; time to completion (part B-part A); error score in part B) as well as a 3D MRI. RESULTS: C9+ individuals younger than 40 years had higher error scores (part B) but equivalent HSCT time to completion (part B-part A) compared to C9- individuals. C9+ individuals older than 40 years had both higher error scores and longer time to completion. HSCT time to completion significantly predicted the proximity to estimated clinical conversion from presymptomatic to symptomatic phase in C9+ individuals (based on the average age at onset of affected relatives in the family). Anatomically, we found that HSCT time to completion was associated with the integrity of the cerebellum. CONCLUSION: The HSCT represents a good marker of cognitive inhibition impairments in C9+ and of proximity to clinical conversion. This study also highlights the key role of the cerebellum in cognitive inhibition.


Assuntos
Encéfalo/diagnóstico por imagem , Proteína C9orf72/genética , Disfunção Cognitiva/genética , Adulto , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Heterozigoto , Humanos , Inibição Psicológica , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos
7.
Brain ; 137(Pt 9): 2444-55, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24972706

RESUMO

Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.


Assuntos
Povo Asiático/genética , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos/genética , População Branca/genética , Adolescente , Adulto , Idade de Início , Idoso , Povo Asiático/etnologia , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/etnologia , População Branca/etnologia , Adulto Jovem
8.
Neurogenetics ; 15(2): 95-100, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24469240

RESUMO

Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD). Most known GRN mutations are null mutations, such as nonsense and frameshift mutations, which create a premature stop codon resulting in loss of function of the progranulin protein. Complete or near-complete genomic GRN deletions have also been found in three families, but heterozygous partial deletions that remove only one or two exons have not been reported to date. In this study, we analysed three unrelated FTLD patients with low plasma progranulin levels but no point GRN mutations by multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF). We detected two heterozygous partial GRN deletions in two patients. One deletion removed exon 1 and part of intron 1. The second deletion was complex: it removed 1,410 bp extending from the part of intron 1 to the part of exon 3, with a small 5-bp insertion at the breakpoint junction (c.-7-1121_159delinsGATCA). Our findings illustrate the usefulness of a quantitative analysis in addition to GRN gene sequencing for a comprehensive genetic diagnosis of FTLD, particularly in patients with low plasma progranulin levels.


Assuntos
Degeneração Lobar Frontotemporal/genética , Deleção de Genes , Peptídeos e Proteínas de Sinalização Intercelular/genética , Perda de Heterozigosidade , Humanos , Pessoa de Meia-Idade , Linhagem , Progranulinas
9.
J Alzheimers Dis ; 94(4): 1351-1360, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37393503

RESUMO

GRN mutations, causing frontotemporal dementia, can be associated with atypical white matter hyperintensities (WMH). We hypothesized that the presence of WMH may impact neurofilament light chain (NfL) levels, markers of neuroaxonal damage. We analyzed plasma NfL in 20 GRN patients and studied their association to visually-scored WMH burden. The 12 patients displaying atypical WMH had significantly higher NfL levels (98.4±34.9 pg/mL) than those without WMH (47.2±29.4 pg/mL, p = 0.003), independently from age, disease duration and Fazekas-Schmidt grade. NfL correlated with WMH burden (rho = 0.55, p = 0.01). This study prompts considering WMH burden as a variability factor when evaluating NfL levels in GRN patients.


Assuntos
Demência Frontotemporal , Substância Branca , Humanos , Biomarcadores , Demência Frontotemporal/genética , Filamentos Intermediários , Mutação , Proteínas de Neurofilamentos , Progranulinas/genética , Substância Branca/diagnóstico por imagem
10.
Front Cell Neurosci ; 17: 1155929, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37138765

RESUMO

The GGGGCC intronic repeat expansion within C9ORF72 is the most common genetic cause of ALS and FTD. This mutation results in toxic gain of function through accumulation of expanded RNA foci and aggregation of abnormally translated dipeptide repeat proteins, as well as loss of function due to impaired transcription of C9ORF72. A number of in vivo and in vitro models of gain and loss of function effects have suggested that both mechanisms synergize to cause the disease. However, the contribution of the loss of function mechanism remains poorly understood. We have generated C9ORF72 knockdown mice to mimic C9-FTD/ALS patients haploinsufficiency and investigate the role of this loss of function in the pathogenesis. We found that decreasing C9ORF72 leads to anomalies of the autophagy/lysosomal pathway, cytoplasmic accumulation of TDP-43 and decreased synaptic density in the cortex. Knockdown mice also developed FTD-like behavioral deficits and mild motor phenotypes at a later stage. These findings show that C9ORF72 partial loss of function contributes to the damaging events leading to C9-FTD/ALS.

11.
Nat Commun ; 14(1): 342, 2023 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-36670122

RESUMO

Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10-03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.


Assuntos
Esclerose Lateral Amiotrófica , Demência Frontotemporal , Animais , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Demência Frontotemporal/genética , Peixe-Zebra/metabolismo , Neurônios/metabolismo , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Mutação
12.
J Neurol Neurosurg Psychiatry ; 83(10): 956-62, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22832740

RESUMO

BACKGROUND: Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterised by childhood onset that tends to improve in adulthood. The associated gene, NKX2-1 (previously called TITF1), is essential for organogenesis of the basal ganglia, thyroid and lungs. The aim of the study was to refine the movement disorders phenotype. We also studied disease course and response to therapy in a large series of genetically proven patients. METHODS: We analysed clinical, genetic findings and follow-up data in 28 NKX2-1 mutated BHC patients from 13 families. RESULTS: All patients had private mutations, including seven new mutations, three previously reported mutations and three sporadic deletions encompassing the NKX2-1 gene. Hypotonia and chorea were present in early infancy, with delayed walking ability (25/28); dystonia, myoclonus and tics were often associated. Attention deficit hyperactivity disorder (ADHD) was present in seven. Among the 14 patients followed-up until adulthood, nine had persistent mild chorea, two had near total resolution of chorea but persistent disabling prominent myoclonus and three recovered completely. Learning difficulties were observed in 20/28 patients, and three had mental retardation. Various combinations of BHC, thyroid (67%) and lung (46%) features were noted. We found no genotype-phenotype correlation. A rapid and sustained beneficial effect on chorea was obtained in 5/8 patients treated with tetrabenazine. CONCLUSION: Early onset chorea preceded by hypotonia is suggestive of BHC. Associated thyroid or respiratory disorders further support the diagnosis and call for genetic studies. Tetrabenazine may be an interesting option to treat disabling chorea.


Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Coreia , Transtornos Cromossômicos , Mutação , Proteínas Nucleares/genética , Tetrabenazina/uso terapêutico , Fatores de Transcrição/genética , Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Captação Adrenérgica/efeitos adversos , Adulto , Idade de Início , Transtorno do Deficit de Atenção com Hiperatividade/genética , Criança , Pré-Escolar , Coreia/diagnóstico , Coreia/tratamento farmacológico , Coreia/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/tratamento farmacológico , Transtornos Cromossômicos/genética , Transtornos Cognitivos/genética , Hipotireoidismo Congênito/genética , Análise Mutacional de DNA , Feminino , Seguimentos , França , Genes Dominantes , Humanos , Lactente , Masculino , Testes Neuropsicológicos , Fenótipo , Prognóstico , Análise Serial de Proteínas , Doenças Respiratórias/genética , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Fator Nuclear 1 de Tireoide , Resultado do Tratamento
13.
IEEE J Biomed Health Inform ; 26(12): 6024-6035, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36129856

RESUMO

Frontotemporal dementia and amyotrophic lateral sclerosis are rare neurodegenerative diseases with no effective treatment. The development of biomarkers allowing an accurate assessment of disease progression is crucial for evaluating new therapies. Concretely, neuroimaging and transcriptomic (microRNA) data have been shown useful in tracking their progression. However, no single biomarker can accurately measure progression in these complex diseases. Additionally, large samples are not available for such rare disorders. It is thus essential to develop methods that can model disease progression by combining multiple biomarkers from small samples. In this paper, we propose a new framework for computing a disease progression score (DPS) from cross-sectional multimodal data. Specifically, we introduce a supervised multimodal variational autoencoder that can infer a meaningful latent space, where latent representations are placed along a disease trajectory. A score is computed by orthogonal projections onto this path. We evaluate our framework with multiple synthetic datasets and with a real dataset containing 14 patients, 40 presymptomatic genetic mutation carriers and 37 controls from the PREV-DEMALS study. There is no ground truth for the DPS in real-world scenarios, therefore we use the area under the ROC curve (AUC) as a proxy metric. Results with the synthetic datasets support this choice, since the higher the AUC, the more accurate the predicted simulated DPS. Experiments with the real dataset demonstrate better performance in comparison with state-of-the-art approaches. The proposed framework thus leverages cross-sectional multimodal datasets with small sample sizes to objectively measure disease progression, with potential application in clinical trials.


Assuntos
MicroRNAs , Humanos , MicroRNAs/genética , Estudos Transversais , Imagem Multimodal , Biomarcadores , Progressão da Doença
14.
Ann Clin Transl Neurol ; 9(11): 1778-1791, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36264717

RESUMO

OBJECTIVE: MicroRNAs are promising biomarkers of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), but discrepant results between studies have so far hampered their use in clinical trials. We aim to assess all previously identified circulating microRNA signatures as potential biomarkers of genetic FTD and/or ALS, using homogeneous, independent validation cohorts of C9orf72 and GRN mutation carriers. METHODS: 104 individuals carrying a C9orf72 or a GRN mutation, along with 31 controls, were recruited through the French research network on FTD/ALS. All subjects underwent blood sampling, from which circulating microRNAs were extracted. We measured differences in the expression levels of 65 microRNAs, selected from 15 published studies about FTD or ALS, between 31 controls, 17 C9orf72 presymptomatic subjects, and 29 C9orf72 patients. We also assessed differences in the expression levels of 30 microRNAs, selected from five studies about FTD, between 31 controls, 30 GRN presymptomatic subjects, and 28 GRN patients. RESULTS: More than half (35/65) of the selected microRNAs were differentially expressed in the C9orf72 cohort, while only a small proportion (5/30) of microRNAs were differentially expressed in the GRN cohort. In multivariate analyses, only individuals in the C9orf72 cohort could be adequately classified (ROC AUC up to 0.98 for controls versus presymptomatic subjects, 0.94 for controls versus patients, and 0.77 for presymptomatic subjects versus patients) with some of the signatures. INTERPRETATION: Our results suggest that previously identified microRNAs using sporadic or mixed cohorts of FTD and ALS patients could potentially serve as biomarkers of C9orf72-associated disease, but not GRN-associated disease.


Assuntos
Esclerose Lateral Amiotrófica , Demência Frontotemporal , MicroRNAs , Doença de Pick , Humanos , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , MicroRNAs/genética , Biomarcadores
15.
J Med Genet ; 47(8): 554-60, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20577002

RESUMO

BACKGROUND: Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS). METHODS: The relative contributions of the different mutations to ALS were estimated by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations. RESULTS: 31 pathogenic missense mutations were found in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harboured ANG variants. One family of Japanese origin with the P56S VAPB mutation was identified. Seven novel mutations (three in SOD1, two in TARDBP, two in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including five pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease onset than those presenting with a more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration. CONCLUSIONS: This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.


Assuntos
Esclerose Lateral Amiotrófica/genética , Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Proteína FUS de Ligação a RNA/genética , Ribonuclease Pancreático/genética , Superóxido Dismutase/genética , Proteínas de Transporte Vesicular/genética , Adulto , Distribuição por Idade , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/enzimologia , Esclerose Lateral Amiotrófica/epidemiologia , Família , Feminino , Humanos , Longevidade , Masculino , Pessoa de Meia-Idade , Mutação/genética
16.
Cortex ; 145: 145-159, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34717271

RESUMO

C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72-related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.


Assuntos
Afasia Primária Progressiva , Apraxias , Afasia Primária Progressiva/genética , Atrofia , Proteína C9orf72/genética , Humanos , Idioma , Imageamento por Ressonância Magnética , Fala
17.
Neurology ; 97(1): e88-e102, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-33980708

RESUMO

OBJECTIVE: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates. METHODS: Patients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA. RESULTS: Among the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%). CONCLUSIONS: This study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies.


Assuntos
Afasia Primária Progressiva/genética , Progranulinas/genética , Idoso , Afasia Primária Progressiva/diagnóstico por imagem , Atrofia , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Estudos Transversais , Feminino , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Frequência do Gene , Humanos , Testes de Linguagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Testes Neuropsicológicos , Estudos Prospectivos , Fala , Tomografia Computadorizada de Emissão de Fóton Único
18.
Ann Neurol ; 65(4): 470-3, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19350673

RESUMO

TDP-43 (TAR-DNA binding protein) aggregates in neuronal inclusions in motoneuron disease (MND), as well as in frontotemporal lobar degeneration (FTLD) and FTLD associated with MND (FTLD-MND). Mutations in TARDBP gene, coding for TDP-43, were found in patients with pure MND. We now describe TARDBP mutations in two patients with FTLD-MND, presenting with a behavioral variant of FTLD and semantic dementia, suggesting that TDP-43 may also have a direct pathogenic role in FTLD disorders.


Assuntos
Proteínas de Ligação a DNA/genética , Demência/complicações , Demência/genética , Doença dos Neurônios Motores/complicações , Doença dos Neurônios Motores/genética , Mutação/genética , Adulto , Idoso , Análise Mutacional de DNA , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenilalanina/genética
19.
Brain ; 132(Pt 7): 1753-63, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19491146

RESUMO

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.


Assuntos
Biopterinas/análogos & derivados , Dopaminérgicos/uso terapêutico , Dopamina/biossíntese , Distúrbios Distônicos/genética , Levodopa/uso terapêutico , Adolescente , Adulto , Idade de Início , Oxirredutases do Álcool/genética , Biopterinas/biossíntese , Criança , Pré-Escolar , Distúrbios Distônicos/tratamento farmacológico , Distúrbios Distônicos/metabolismo , Feminino , GTP Cicloidrolase/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Tirosina 3-Mono-Oxigenase/genética , Ubiquitina-Proteína Ligases/genética , Adulto Jovem
20.
Neurobiol Aging ; 85: 154.e9-154.e11, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262553

RESUMO

GRN null mutations are among the main genetic causes of frontotemporal dementia through progranulin haploinsufficiency. Most missense mutations are considered not pathogenic. The p.Trp7Arg substitution is localized within the signal peptide domain and no formal evidence for its pathogenicity has yet been provided. We identified the p.Trp7Arg substitution in 3 carriers with low plasma progranulin levels. This evidences that this missense mutation leads to functional haploinsufficiency and should thus be considered pathogenic. Assessing the pathogenicity of variants of unknown significance has significant implications for clinical practice, genetic counseling, and future therapeutic interventions.


Assuntos
Demência Frontotemporal/etiologia , Haploinsuficiência/genética , Mutação de Sentido Incorreto , Progranulinas/genética , Proteína C9orf72/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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