Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
Brain ; 2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38079474

RESUMO

TDP-43-positive inclusions in neurons are a hallmark of several neurodegenerative diseases including familial amyotrophic lateral sclerosis (fALS) caused by pathogenic TARDBP variants as well as more common non-Mendelian sporadic ALS (sALS). Here we report a G376V-TDP-43 missense variant in the C-terminal prion-like domain of the protein in two French families affected by an autosomal dominant myopathy but not fulfilling diagnostic criteria for ALS. Patients from both families presented with progressive weakness and atrophy of distal muscles, starting in their 5th-7th decade. Muscle biopsies revealed a degenerative myopathy characterized by accumulation of rimmed (autophagic) vacuoles, disruption of sarcomere integrity and severe myofibrillar disorganization. The G376 V variant altered a highly conserved amino acid residue and was absent in databases on human genome variation. Variant pathogenicity was supported by in silico analyses and functional studies. The G376 V mutant increased the formation of cytoplasmic TDP-43 condensates in cell culture models, promoted assembly into high molecular weight oligomers and aggregates in vitro, and altered morphology of TDP-43 condensates arising from phase separation. Moreover, the variant led to the formation of cytoplasmic TDP-43 condensates in patient-derived myoblasts and induced abnormal mRNA splicing in patient muscle tissue. The identification of individuals with TDP-43-related myopathy but not ALS implies that TARDBP missense variants may have more pleiotropic effects than previously anticipated and support a primary role for TDP-43 in skeletal muscle pathophysiology. We propose to include TARDBP screening in the genetic work-up of patients with late-onset distal myopathy. Further research is warranted to examine the precise pathogenic mechanisms of TARDBP variants causing either a neurodegenerative or myopathic phenotype.

2.
Brain ; 144(5): 1422-1434, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-33970200

RESUMO

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.


Assuntos
Oxigenases/genética , Paraplegia Espástica Hereditária/genética , Animais , Feminino , Humanos , Masculino , Camundongos , Mutação , Linhagem , Ratos , Peixe-Zebra
3.
Am J Hum Genet ; 100(3): 523-536, 2017 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-28190456

RESUMO

Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.


Assuntos
Catarata/genética , Disfunção Cognitiva/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Anormalidades Musculoesqueléticas/genética , Monoéster Fosfórico Hidrolases/genética , Adolescente , Adulto , Alelos , Animais , Encéfalo/patologia , Criança , Pré-Escolar , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/patologia , Mutação , Linhagem , Adulto Jovem , Peixe-Zebra/embriologia , Peixe-Zebra/genética
4.
Int J Mol Sci ; 21(11)2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32471306

RESUMO

Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia with typical onset in childhood or early adolescence. The disease is associated with mutations in the voltage-gated calcium channel alpha 1A subunit (Cav2.1) that is encoded by the CACNA1A gene. However, previously unrecognized atypical symptoms and the genetic overlap existing between EA2, spinocerebellar ataxia type 6, familial hemiplegic migraine type 1, and other neurological diseases blur the genotype/phenotype correlations, making a differential diagnosis difficult to formulate correctly and delaying early therapeutic intervention. Here we report a new clinical phenotype of a CACNA1A-associated disease characterized by absence epilepsy occurring during childhood. However, much later in life the patient displayed non-episodic, slowly progressive gait ataxia. Gene panel sequencing for hereditary ataxias led to the identification of a novel heterozygous CACNA1A mutation (c.1913 + 2T > G), altering the donor splice site of intron 14. This genetic defect was predicted to result in an in-frame deletion removing 44 amino acids from the voltage-gated calcium channel Cav2.1. An RT-PCR analysis of cDNA derived from patient skin fibroblasts confirmed the skipping of the entire exon 14. Furthermore, two-electrode voltage-clamp recordings performed from Xenopus laevis oocytes expressing a wild-type versus mutant channel showed that the genetic defect caused a complete loss of channel function. This represents the first description of distinct clinical manifestations that remarkably expand the genetic and phenotypic spectrum of CACNA1A-related diseases and should be considered for an early diagnosis and effective therapeutic intervention.


Assuntos
Canais de Cálcio/genética , Ataxia Cerebelar/genética , Epilepsia/genética , Mutação com Perda de Função , Animais , Canais de Cálcio/metabolismo , Células Cultivadas , Ataxia Cerebelar/complicações , Ataxia Cerebelar/patologia , Epilepsia/complicações , Epilepsia/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Splicing de RNA , Xenopus
5.
Hum Genet ; 137(11-12): 911-919, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30460542

RESUMO

Mutations in the SACS gene have been initially reported in a rare autosomal recessive cerebellar ataxia syndrome featuring prominent cerebellar atrophy, spasticity and peripheral neuropathy as well as retinal abnormalities in some cases (autosomal recessive spastic ataxia of Charlevoix-Saguenay, ARSACS). In the past few years, the phenotypic spectrum has broadened, mainly owing to the availability and application of high-throughput genetic testing methods. We identified nine patients (three sib pairs, three singleton cases) with isolated, non-syndromic hereditary motor and sensory neuropathy (HMSN) who carried pathogenic SACS mutations, either in the homozygous or compound heterozygous state. None of the patients displayed spasticity or pyramidal signs. Ataxia, which was noted in only three patients, was consistent with a sensory ataxia. Nerve conduction and nerve biopsy studies showed mixed demyelinating and axonal neuropathy. Brain MRI scans were either normal or revealed isolated upper vermis atrophy of the cerebellum. Our findings confirm the broad clinical spectrum associated with SACS mutations, including pure polyneuropathy without characteristic clinical and brain imaging manifestations of ARSACS.


Assuntos
Ataxia/genética , Genes Recessivos/genética , Proteínas de Choque Térmico/genética , Neuropatia Hereditária Motora e Sensorial/genética , Ataxia/fisiopatologia , Cerebelo/fisiopatologia , Feminino , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Homozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação , Linhagem
7.
Neurology ; 95(24): e3163-e3179, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33144514

RESUMO

OBJECTIVE: To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years. METHODS: We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and MME single-gene sequencing (n = 104). We further queried WES repositories for MME variants and measured blood levels of the MME-encoded protein neprilysin. RESULTS: In the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). MME was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of MME for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of MME variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with MME variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of MME variants was often consistent with an incompletely penetrant autosomal-dominant trait and less frequently with autosomal-recessive inheritance. CONCLUSIONS: A detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, by variants in either CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. MME variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.


Assuntos
Envelhecimento , Neuropatia Hereditária Motora e Sensorial/genética , Neprilisina/genética , Idade de Início , Idoso , Envelhecimento/sangue , Doença de Charcot-Marie-Tooth/sangue , Doença de Charcot-Marie-Tooth/genética , Feminino , Predisposição Genética para Doença/genética , Neuropatia Hereditária Motora e Sensorial/sangue , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/sangue , Sequenciamento do Exoma
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa