Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 153
Filtrar
1.
Gene ; 771: 145360, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33333218

RESUMO

Variants in SETX have been implicated in recessively and dominantly inherited disorders, ataxia with oculomotor apraxia type 2 (AOA2 OMIM# 606002) and amyotrophic lateral sclerosis (ALS4, OMIM# 602433) respectively, in humans. We report two novel bi-allelic pathogenic variants in SETX in patients suffering from ataxia with oculomotor apraxia type 2, extending the allelic spectrum of the gene variants. We also discuss the pathogenicity of SETX variants in relation to the evolutionary conservation status of the affected amino acids. Our analyses suggest that variants of some amino acids which are not fully conserved in evolution, may cause a disorder in humans, provided the particular pathogenic variant is absent in other orthologues.


Assuntos
Esclerose Amiotrófica Lateral/genética , DNA Helicases/genética , Enzimas Multifuncionais/genética , Mutação de Sentido Incorreto , RNA Helicases/genética , Ataxias Espinocerebelares/congênito , Adolescente , DNA Helicases/química , Evolução Molecular , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Enzimas Multifuncionais/química , Linhagem , Domínios Proteicos , RNA Helicases/química , Análise de Sequência de DNA , Ataxias Espinocerebelares/genética , Adulto Jovem
4.
BMC Neurol ; 20(1): 215, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32466761

RESUMO

BACKGROUND: Spastic ataxia of Charlevoix-Saguenay is a neurodegenerative condition due to mutations in the SACS gene and without a cure. Attempts to treatments are scarce and limited to symptomatic drugs. CASE PRESENTATION: Two siblings harboring biallelic variants in SACS underwent oral supplementation (600 mg/die) with docosahexaenoic acid (DHA), a well-tolerated dietary supplement currently used in SCA38 patients. We assessed over a 20 month-period clinical progression using disease-specific rating scales. CONCLUSIONS: DHA was safe over a long period and well-tolerated by the two patients; both showed a stabilization of clinical symptoms, rather than the expected deterioration, warranting additional investigations in patients with mutations in SACS.


Assuntos
Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos , Espasticidade Muscular/dietoterapia , Ataxias Espinocerebelares/congênito , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Irmãos , Ataxias Espinocerebelares/dietoterapia
5.
Artigo em Russo | MEDLINE | ID: mdl-32307416

RESUMO

Spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare autosomal recessive neurodegenerative disease related to SACS gene and characterized by cerebellar, pyramidal and some other signs. The disease was delineated in Quebec, where it cumulates due to founder effect and has similar phenotype with very early onset. ARSACS in other populations is more variable. The first Russian case of ARSACS in a 37-year-old woman, an only patient in a Lak (one of Dagestan ethnicities) family, is presented. Along with main typical features, she had atypical late disease onset (in 32 years) and moderate cognitive decline. MPS-panel 'hereditary paraplegias' detected an earlier reported homo- or hemizygous mutation c.72276C>T (p.Arg2426Stop) in SACS exon 10.


Assuntos
Proteínas de Choque Térmico/genética , Ataxias Espinocerebelares , Adulto , Daguestão , Feminino , Humanos , Espasticidade Muscular , Mutação , Federação Russa , Ataxias Espinocerebelares/congênito
6.
J Mol Neurosci ; 70(1): 131-141, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31701440

RESUMO

ARSACS is an autosomal recessive disorder characterized by ataxia, spasticity, and polyneuropathy. A plethora of worldwide distributed mutations have been described so far. Here, we report two brothers, born to non-consanguineous parents, presenting with cerebellar ataxia and peripheral neuropathy. Whole-exome sequencing revealed the presence of a novel homozygous variant in the SACS gene. The variant was confirmed by Sanger sequencing and found at heterozygous state in both parents. This is the first reported mutation in this gene, in Greek population. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide. Additionally, we performed a systematic review of all published cases with SACs mutations. ARSACS seems to be an important cause of ataxia and many different types of mutations have been identified, mainly located in exon 10. We evaluated the mutation pathogenicity in all previously reported cases to investigate possible phenotype-genotype correlations. We managed to find a correlation between the pathogenicity of mutations, severity of the phenotype, and age of onset of ARSACS. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various ARSACS variants.


Assuntos
Proteínas de Choque Térmico/genética , Espasticidade Muscular/genética , Mutação , Fenótipo , Ataxias Espinocerebelares/congênito , Adolescente , Homozigoto , Humanos , Masculino , Espasticidade Muscular/patologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia
7.
Neurology ; 93(16): e1543-e1549, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31534027

RESUMO

OBJECTIVE: To develop a disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) (DSI-ARSACS) that considers the 3 components (pyramidal, cerebellar, neuropathic) of the disease, and to document its content validity, internal consistency, and construct validity. METHODS: The Beta DSI-ARSACS (17 items) was developed based on literature review and expert inputs and then administered to 26 participants. Items reduction was based on Cronbach α and desirable criteria. Performance measures were administered to assess the construct validity of the final version of the DSI-ARSACS. RESULTS: The final DSI-ARSACS have 8 items that can be easily performed during usual medical follow-up. The mean score was 19.6 ± 8.1 (range 6.0-35.5) and the Cronbach α was 0.912. The DSI-ARSACS score increased with disease stage and age (p ≤ 0.001) and was closely correlated with other measures assessing similar construct (9-Hole Peg Test, 10-Meter Walk Test, Scale for the Assessment and Rating of Ataxia, Berg Balance Scale, Barthel Index) (r s = 0.75-0.95, p < 0.01). A moderate but not significant correlation was found with the 6-Minute Walk test (r s = -0.611, p = 0.108). CONCLUSIONS: The DSI-ARSACS is a valid measure of disease severity for the adult ARSACS population that is able to distinguish between patients with different clinical profiles. Further documentation of metrologic properties is necessary, but these first results are promising.


Assuntos
Ataxia/diagnóstico , Ataxia Cerebelar/diagnóstico , Espasticidade Muscular/diagnóstico , Índice de Gravidade de Doença , Ataxias Espinocerebelares/congênito , Adolescente , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/diagnóstico , Teste de Caminhada , Adulto Jovem
8.
Sci Rep ; 9(1): 11878, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31417125

RESUMO

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurological disease caused by mutations in SACS, which encodes sacsin. The complex architecture of sacsin suggests that it could be a key player in cellular protein quality control system. Molecular chaperones that operate in protein folding/unfolding and assembly/disassembly patterns have been described as essential modulators of selectivity during the autophagy process. We performed RNA-sequencing analysis to generate a whole-genome molecular signature profile of sacsin knockout cells. Using data analysis of biological processes significantly disrupted due to loss of sacsin, we confirmed the presence of decreased mitochondrial function associated with increased oxidative stress, and also provided a demonstration of a defective autophagic pathway in sacsin-depleted cells. Western blotting assays revealed decreased expression of LC3 and increased levels of p62 even after treatment with the lysosomal inhibitor bafilomycin A1, indicating impairment of the autophagic flux. Moreover, we found reduced co-immunolocalization of the autophagosome marker LC3 with lysosomal and mitochondrial markers suggesting fusion inhibition of autophagic compartments and subsequent failed cargo degradation, in particular failed degradation of damaged mitochondria. Pharmacological up-regulation of autophagy restored correct autophagic flux in sacsin knockout cells. These results corroborate the hypothesis that sacsin may play a role in autophagy. Chemical manipulation of this pathway might represent a new target to alleviate clinical and pathological symptoms, delaying the processes of neurodegeneration in ARSACS.


Assuntos
Autofagia/genética , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Proteínas de Choque Térmico/genética , Espasticidade Muscular/genética , Ataxias Espinocerebelares/congênito , Transcriptoma , Sistemas CRISPR-Cas , Células Cultivadas , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Técnicas de Inativação de Genes , Ontologia Genética , Estudos de Associação Genética , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/metabolismo , Fosforilação Oxidativa , Complexo de Endopeptidases do Proteassoma/metabolismo , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ubiquitina/metabolismo
9.
Cerebellum ; 18(4): 817-822, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111429

RESUMO

While heterozygous mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia 28 (SCA28), homozygous mutations in the same gene can cause spastic ataxia 5 (SPAX5). AFG3L2 encodes a mitochondrial ATP-dependent metalloprotease. We here report a SCA28 patient with biallelic AFG3L2 variants and his heterozygous mother. The patient and his mother underwent a detailed neurological examination and fibroblast lines were established. The effect of the two missense variants on mitochondria was assessed by form factor analysis and quantification of mitochondrial proteins (TOMM70, complex V). The 39-year-old index patient presented with a slowly progressive cerebellar gait disorder for 19 years, bilateral ptosis, and dysarthria. A cranial MRI showed mild cerebellar atrophy. He carried two compound-heterozygous, rare, missense variants (c.1847A>G [p.Y616C], c.2167G>A [p.V723M]) in AFG3L2, while his mother was heterozygous for the first change that had previously been described in SPAX5. Altered mitochondrial morphology and interconnectivity, together with reduced protein levels of TOMM70 and complex V (ATPase), suggest mitochondrial structural defects in the patient's fibroblasts. No significant abnormalities were found in his mother's fibroblast cultures albeit all measurements were slightly below the control level. We here present a SCA28 patient with compound-heterozygous AFG3L2 variants and demonstrate mitochondrial abnormalities in skin fibroblast cultures from this patient. Thus, AFG3L2 variants should be considered in both slowly progressive ataxias and phenotypes with clinical features reminiscent of mitochondrial disease. Of note, ptosis was present in both mutation carriers and may serve as a red flag in the diagnosis of SCA28.


Assuntos
Proteases Dependentes de ATP/genética , ATPases Associadas a Diversas Atividades Celulares/genética , Ataxias Espinocerebelares/congênito , Adulto , Atrofia , Progressão da Doença , Fibroblastos/patologia , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Mutação/genética , Mutação de Sentido Incorreto/genética , Exame Neurológico , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/fisiopatologia
10.
Cerebellum ; 18(4): 807-812, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30963395

RESUMO

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterized by the triad of early-onset cerebellar ataxia, peripheral sensorimotor neuropathy, and lower limb spasticity. Here, we present a 28-year-old male patient with symptoms of ARSACS and mild intellectual disability from a consanguineous family of tribal J&K, India. Whole exome sequencing unraveled a novel homozygous frameshift SACS mutation (Cys2869ValfsTer15) in the patient. In addition to the well-established ARSACS imaging features, MRI revealed T2 hyperintense rim around the thalami ("bithalamic stripes") demonstrating that this feature might serve as an additional supportive diagnostic imaging marker for ARSACS. Moreover, retinal nerve fiber layer thickening which has recently been proposed as a diagnostic biomarker for ARSACS was present on routine optic coherence tomography (OCT) also in this patient, indicating that it might indeed present a relatively universal diagnostic biomarker for ARSACS. In sum, our findings extend the geographical distribution of ARSACS to even very remote tribal regions in Asia (such as the Rajouri region of J&K, India) and extend the mutational and imaging spectrum of ARSACS. They provide further support that brain imaging and OCT markers might serve as diagnostic biomarkers for ARSACS in patients with novel SACS mutations, applicable even in remote regions of the world to identify and confirm ARSACS disease.


Assuntos
Ataxia Cerebelar/genética , Espasticidade Muscular/genética , Mutação/genética , Ataxias Espinocerebelares/congênito , Adulto , Ataxia Cerebelar/diagnóstico por imagem , Consanguinidade , Exoma , Mutação da Fase de Leitura , Humanos , Índia , Deficiência Intelectual/etiologia , Imagem por Ressonância Magnética , Masculino , Espasticidade Muscular/diagnóstico por imagem , Linhagem , Retina/patologia , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Tomografia de Coerência Óptica
11.
Nucleic Acids Res ; 47(8): 4086-4110, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30986824

RESUMO

Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset progressive spinocerebellar ataxia caused by mutation in aprataxin (APTX). APTX removes 5'-AMP groups from DNA, a product of abortive ligation during DNA repair and replication. APTX deficiency has been suggested to compromise mitochondrial function; however, a detailed characterization of mitochondrial homeostasis in APTX-deficient cells is not available. Here, we show that cells lacking APTX undergo mitochondrial stress and display significant changes in the expression of the mitochondrial inner membrane fusion protein optic atrophy type 1, and components of the oxidative phosphorylation complexes. At the cellular level, APTX deficiency impairs mitochondrial morphology and network formation, and autophagic removal of damaged mitochondria by mitophagy. Thus, our results show that aberrant mitochondrial function is a key component of AOA1 pathology. This work corroborates the emerging evidence that impaired mitochondrial function is a characteristic of an increasing number of genetically diverse neurodegenerative disorders.


Assuntos
Proteínas de Ligação a DNA/genética , GTP Fosfo-Hidrolases/genética , Mitocôndrias/genética , Mitofagia/genética , Proteínas Nucleares/genética , Ataxias Espinocerebelares/congênito , Linhagem Celular Transformada , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/deficiência , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , GTP Fosfo-Hidrolases/deficiência , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Homeostase/genética , Humanos , Linfócitos/metabolismo , Linfócitos/patologia , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Proteínas Nucleares/deficiência , Análise de Sequência com Séries de Oligonucleotídeos , Osteoblastos/metabolismo , Osteoblastos/patologia , Fosforilação Oxidativa , Transdução de Sinais , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/patologia
12.
J Neurol ; 266(5): 1260-1266, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30840144

RESUMO

We aimed to provide proof-of-principle evidence that intensive home-based speech treatment can improve dysarthria in complex multisystemic degenerative ataxias, exemplified by autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS). Feasibility and piloting efficacy of speech training specifically tailored to cerebellar dysarthria was examined through a 4-week program in seven patients with rater-blinded assessment of intelligibility (primary outcome) and naturalness and acoustic measures of speech (secondary outcomes) performed 4 weeks before, immediately prior to, and directly after training (intraindividual control design). Speech intelligibility and naturalness improved post treatment. This provides piloting evidence that ataxia-tailored speech treatment might be effective in degenerative cerebellar disease.


Assuntos
Disartria/etiologia , Disartria/reabilitação , Espasticidade Muscular/complicações , Fonoterapia/métodos , Ataxias Espinocerebelares/congênito , Retroalimentação Sensorial/fisiologia , Feminino , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Projetos Piloto , Ataxias Espinocerebelares/complicações , Estatísticas não Paramétricas
13.
J Neurol Sci ; 400: 39-41, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30901567

RESUMO

BACKGROUND AND PURPOSE: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) diagnosis is based on the presence of three main clinical features: 1) ataxia, 2) pyramidal involvement, and 3) axonal neuropathy. This study aimed to explore, among a cohort of adults with ARSACS, the prevalence of other signs and symptoms than those commonly describe in this disease and compare their prevalence between younger (<40 years) and older (≥40 years) participants. METHODS: A clinical interview based on a standardized questionnaire was conducted. It included the following items: memory and concentration problems, hearing impairment, epilepsy, spasms, choreathetosis, neuropathic pain, cramps and fecal incontinence. RESULTS: A total of 43 participants were interviewed, with a mean age of 38.9 years and 51.2% were men. Spasms (55.8%), cramps (53.5%), and concentration problems (39.5%) were the most frequent manifestations. Except for choreathetosis, which was present in only one participant, all other signs and symptoms were present in 9.3% to 29.3% of participants. CONCLUSIONS: People with ARSACS may experience many other clinical manifestations than the most commonly described. This study is a preliminary step toward the development of a comprehensive evidence-based clinical care guideline for this population.


Assuntos
Espasticidade Muscular/diagnóstico , Espasticidade Muscular/fisiopatologia , Ataxias Espinocerebelares/congênito , Adolescente , Adulto , Incontinência Fecal/diagnóstico , Incontinência Fecal/etiologia , Incontinência Fecal/fisiopatologia , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/complicações , Espasmo/diagnóstico por imagem , Espasmo/etiologia , Espasmo/fisiopatologia , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/fisiopatologia , Adulto Jovem
14.
J Neurosci ; 39(20): 3948-3969, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30862666

RESUMO

Purkinje cells (PCs) are primarily affected in neurodegenerative spinocerebellar ataxias (SCAs). For generating animal models for SCAs, genetic regulatory elements specifically targeting PCs are required, thereby linking pathological molecular effects with impaired function and organismic behavior. Because cerebellar anatomy and function are evolutionary conserved, zebrafish represent an excellent model to study SCAs in vivo We have isolated a 258 bp cross-species PC-specific enhancer element that can be used in a bidirectional manner for bioimaging of transgene-expressing PCs in zebrafish (both sexes) with variable copy numbers for tuning expression strength. Emerging ectopic expression at high copy numbers can be further eliminated by repurposing microRNA-mediated posttranslational mRNA regulation.Subsequently, we generated a transgenic SCA type 13 (SCA13) model, using a zebrafish-variant mimicking a human pathological SCA13R420H mutation, resulting in cell-autonomous progressive PC degeneration linked to cerebellum-driven eye-movement deficits as observed in SCA patients. This underscores that investigating PC-specific cerebellar neuropathologies in zebrafish allows for interconnecting bioimaging of disease mechanisms with behavioral analysis suitable for therapeutic compound testing.SIGNIFICANCE STATEMENT SCA13 patients carrying a KCNC3R420H allele have been shown to display mid-onset progressive cerebellar atrophy, but genetic modeling of SCA13 by expressing this pathogenic mutant in different animal models has not resulted in neuronal degeneration so far; likely because the transgene was expressed in heterologous cell types. We developed a genetic system for tunable PC-specific coexpression of several transgenes to manipulate and simultaneously monitor cerebellar PCs. We modeled a SCA13 zebrafish accessible for bioimaging to investigate disease progression, revealing robust PC degeneration, resulting in impaired eye movement. Our transgenic zebrafish mimicking both neuropathological and behavioral changes manifested in SCA-affected patients will be suitable for investigating causes of cerebellar diseases in vivo from the molecular to the behavioral level.


Assuntos
Cerebelo/metabolismo , Modelos Animais de Doenças , Células de Purkinje/metabolismo , Ataxias Espinocerebelares/congênito , Animais , Animais Geneticamente Modificados , Cerebelo/crescimento & desenvolvimento , Cerebelo/fisiopatologia , Feminino , Regulação da Expressão Gênica , Masculino , RNA Mensageiro/metabolismo , Elementos Reguladores de Transcrição , Canais de Potássio Shaw/genética , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(3): 217-220, 2019 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-30835349

RESUMO

OBJECTIVE: To carry out mutation analysis for a Chinese family affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). METHODS: Whole exome sequencing (WES) was used to screen potential mutations within genomic DNA extracted from the proband. Suspected mutation was validated by combining clinical data and results of Sanger sequencing. RESULTS: A homozygous deletional mutation c.3665_3675delGTGCTGTCTTA (p.S1222fs) was found in the proband, for which her parents were both heterozygous carriers. CONCLUSION: WES is capable of detecting mutation underlying this disorder and facilitating genetic counseling and prenatal diagnosis for the affected family. A novel pathogenic mutation of the SACS gene was discovered.


Assuntos
Proteínas de Choque Térmico/genética , Feminino , Genes Recessivos , Humanos , Espasticidade Muscular , Mutação , Ataxias Espinocerebelares/congênito
16.
Cerebellum ; 18(3): 448-456, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30778901

RESUMO

Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia characterized by onset between 10 and 20 years of age and a range of neurological features that include progressive cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia in a majority of patients, and elevated serum alpha-fetoprotein (AFP). AOA2 is caused by mutation of the SETX gene which encodes senataxin, a DNA/RNA helicase involved in transcription regulation, RNA processing, and DNA maintenance. Disruption of senataxin in rodents led to defective spermatogenesis and sterility in males uncovering a key role for senataxin in male germ cell survival. Here, we report the first clinical and cellular evidence of impaired spermatogenesis in AOA2 patients. We assessed sperm production in three AOA2 patients and testicular pathology in one patient and compared the findings to those of Setx-knockout mice. Sperm production was impaired in all patients assessed (3/3, 100%). Analyses of testicular biopsies from an AOA2 patient recapitulate features of the histology seen in Setx-knockout mice, strongly suggesting an underlying mechanism centering on DNA-damage-mediated germ cell apoptosis. These findings support a role for senataxin in human reproductive function and highlight a novel clinical feature of AOA2 that extends the extra-neurological roles of senataxin. This raises an important reproductive counseling issue for clinicians, and fertility specialists should be aware of SETX mutations as a possible diagnosis in young male patients presenting with oligospermia or azoospermia since infertility may presage the later onset of neurological manifestations in some individuals.


Assuntos
Infertilidade/genética , Espermatogênese/genética , Ataxias Espinocerebelares/congênito , Adolescente , Adulto , Animais , DNA Helicases , Humanos , Infertilidade/patologia , Masculino , Camundongos , Camundongos Knockout , Enzimas Multifuncionais , Mutação , RNA Helicases/genética , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/genética
17.
Neurogenetics ; 20(1): 45-49, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30680480

RESUMO

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodevelopmental disorder characterized by the association of spastic ataxia and sensorimotor neuropathy. Additional features include retinal changes and cognitive impairment. Today, next-generation sequencing (NGS) techniques are allowing the rapid identification of a growing number of missense variants, even in less typical forms of the disease, but the pathogenic significance of these changes is often difficult to establish on the basis of classic bioinformatics criteria and genotype/phenotype correlations. Herein, we describe two novel cases of missense mutations in SACS. The two individuals were identified during the genetic screening of a large cohort of patients with inherited ataxias. We discuss how protein studies and specialized ophthalmological investigations could represent useful pointers for the interpretation of genetic data. Combination of these tools with NGS for rapid genotyping might help to identify new true ARSACS cases.


Assuntos
Encéfalo/patologia , Ataxia Cerebelar/patologia , Mitocôndrias/patologia , Espasticidade Muscular/genética , Ataxias Espinocerebelares/congênito , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Criança , Feminino , Genes Recessivos , Humanos , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/patologia , Mutação/genética , Fenótipo , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia
18.
Eur J Radiol ; 110: 187-192, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30599859

RESUMO

PURPOSE: Evaluate the specificity and sensitivity of disappearance of susceptibility weighted imaging (SWI) dentate nuclei (DN) hypointensity in oculomotor apraxia patients (AOA). METHOD: In this prospective study, 27 patients with autosomal genetic ataxia (AOA (n = 11), Friedreich ataxia and ataxia with vitamin E deficit (n = 4), and dominant genetic ataxia (n = 12)) were included along with fifteen healthy controls. MRIs were qualitatively classified for the presence or absence of DN hypointensity on FLAIR and SWI sequences. The MRIs were then quantitatively studied, with measurement of a ratio of DN over brainstem white matter signal intensity through manual delineation. The institutional review board approved this study, and written informed consent was obtained. In the cross-sectional analysis, the Mann-Whitney test was applied. RESULTS: Qualitatively, the eleven AOA patients presented absence of both DN SWI and FLAIR hyposignals; three dominant genetic ataxia patients had moderate SWI DN hyposignal and absent FLAIR hyposignal; the thirteen remaining subjects presented normal SWI and FLAIR DN hyposignal. Absence of DN SWI hypointensity was 100% sensitive and specific to AOA. Quantitative signal intensity ratio (mean ± standard deviation) of the AOA group (98·96 ± 5·37%) was significantly higher than in control subjects group (76.40 ± 8.34%; p < 0.001), dominant genetic ataxia group (81·15 ± 9·94%; p < 0·001), and Friedreich ataxia and ataxia with vitamin E deficit group (87·56 ± 2·78%; p < 0·02). CONCLUSION: This small study shows that loss of the normal hypointensity in the dentate nucleus on both SWI and FLAIR imaging at 3 T is a highly sensitive and specific biomarker for AOA.


Assuntos
Apraxias/congênito , Síndrome de Cogan/complicações , Síndrome de Cogan/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Ataxias Espinocerebelares/congênito , Adulto , Apraxias/complicações , Apraxias/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico por imagem
19.
Parkinsonism Relat Disord ; 62: 148-155, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30638817

RESUMO

BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an important form of inherited ataxia with a varied clinical spectrum. Detailed studies of phenotype and genotype are necessary to improve diagnosis and elucidate this disorder pathogenesis. OBJECTIVE AND METHODS: To investigate the clinical phenotype, retinal architecture, neuroimaging features and genetic profile of Brazilian patients with ARSACS, we performed neurological and ophthalmological evaluation in thirteen Brazilian patients with molecularly confirmed ARSACS, and examined their mutation profiles. Optical coherence tomography protocol (OCT) consisted in peripapillary retinal nerve fiber layer (RNFL) measurement and qualitative analysis of perifoveal scans. Neuroimaging protocol accessed the frequency of atrophy in cerebellum, corpus callosum and parietal lobe, brainstem signal abnormalities, and posterior fossa arachnoid cysts. We reviewed the literature to delineate the ARSACS phenotype in the largest series worldwide. RESULTS: All patients had ataxia and spasticity, and 11/13 had peripheral neuropathy. Macular microcysts were present in two patients. Peripapillary striations, dentate appearance of inner retina and papillomacular fold were found in eleven cases. All individuals exhibited thickening of RNFL in OCT. The most frequent radiological signs were cerebellar atrophy (13/13), biparietal atrophy (12/13), and linear pontine hypointensities (13/13). Genetic analysis revealed 14 different SACS variants, of which two are novel. CONCLUSION: Macular microcysts, inner retina dentate appearance and papillomacular fold are novel retinal imaging signs of ARSACS. Ophthalmological and neuroimaging changes are common findings in Brazilian patients. The core clinical features of ARSACS are ataxia, spasticity and peripheral neuropathy with onset predominantly in the first decade of life.


Assuntos
Imagem por Ressonância Magnética/métodos , Espasticidade Muscular/diagnóstico por imagem , Espasticidade Muscular/genética , Neurônios Retinianos/patologia , Análise de Sequência de DNA/métodos , Ataxias Espinocerebelares/congênito , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Brasil/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/epidemiologia , Neuroimagem/métodos , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética
20.
Neuropathol Appl Neurobiol ; 45(6): 531-537, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30636067

RESUMO

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the SACS gene, which encodes for SACSIN. Although animal models are still necessary to investigate the role of SACSIN in the pathology of this disease, more reliable human cellular models need to be generated to better understand the cerebellar pathophysiology of ARSACS. The discovery of human induced pluripotent stem cells (hiPSC) has permitted the derivation of patient-specific cells. These cells have an unlimited self-renewing capacity and the ability to differentiate into different neural cell types, allowing studies of disease mechanism, drug discovery and cell replacement therapies. In this study, we discuss how the hiPSC-derived cerebellar organoid culture offers novel strategies for targeting the pathogenic mutations related to ARSACS. We also highlight the advantages and challenges of this 3D cellular model, as well as the questions that still remain unanswered.


Assuntos
Doenças Cerebelares/patologia , Cerebelo/patologia , Espasticidade Muscular/patologia , Ataxias Espinocerebelares/congênito , Animais , Doenças Cerebelares/terapia , Humanos , Células-Tronco Pluripotentes Induzidas , Modelos Teóricos , Espasticidade Muscular/terapia , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/terapia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA