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3.
Brain ; 143(1): 112-130, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31794024

RESUMO

The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders. We undertook exome sequencing in three unrelated families of Caucasian, Turkish and French-Canadian ethnicities with seven affected children that showed features of early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy in an effort to determine the genetic aetiology underlying neurodevelopmental disorders. All seven affected subjects shared the same identical rare, homozygous, potentially pathogenic variant in a non-canonical, well-conserved splice site within TRAPPC4 (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G). Single nucleotide polymorphism array analysis revealed there was no haplotype shared between the tested Turkish and Caucasian families suggestive of a variant hotspot region rather than a founder effect. In silico analysis predicted the variant to cause aberrant splicing. Consistent with this, experimental evidence showed both a reduction in full-length transcript levels and an increase in levels of a shorter transcript missing exon 3, suggestive of an incompletely penetrant splice defect. TRAPPC4 protein levels were significantly reduced whilst levels of other TRAPP complex subunits remained unaffected. Native polyacrylamide gel electrophoresis and size exclusion chromatography demonstrated a defect in TRAPP complex assembly and/or stability. Intracellular trafficking through the Golgi using the marker protein VSVG-GFP-ts045 demonstrated significantly delayed entry into and exit from the Golgi in fibroblasts derived from one of the affected subjects. Lentiviral expression of wild-type TRAPPC4 in these fibroblasts restored trafficking, suggesting that the trafficking defect was due to reduced TRAPPC4 levels. Consistent with the recent association of the TRAPP complex with autophagy, we found that the fibroblasts had a basal autophagy defect and a delay in autophagic flux, possibly due to unsealed autophagosomes. These results were validated using a yeast trs23 temperature sensitive variant that exhibits constitutive and stress-induced autophagic defects at permissive temperature and a secretory defect at restrictive temperature. In summary we provide strong evidence for pathogenicity of this variant in a member of the core TRAPP subunit, TRAPPC4 that associates with vesicular trafficking and autophagy defects. This is the first report of a TRAPPC4 variant, and our findings add to the growing number of TRAPP-associated neurological disorders.


Assuntos
Autofagia/genética , Anormalidades Craniofaciais/genética , Fibroblastos/metabolismo , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas de Transporte Vesicular/genética , Atrofia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico por imagem , Surdez/genética , Surdez/fisiopatologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Microcefalia/genética , Microcefalia/fisiopatologia , Microscopia de Fluorescência , Espasticidade Muscular/genética , Espasticidade Muscular/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Quadriplegia/genética , Quadriplegia/fisiopatologia , Sítios de Splice de RNA/genética , Síndrome
4.
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
5.
J Neurol ; 267(2): 324-330, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31637490

RESUMO

Adolescent-onset spastic ataxia is a proposed novel phenotype in compound heterozygous carriers of an intronic mutation (c.1909 + 22G > A) in the POLR3A gene. Here, we present ten new cases of POLR3A-related spastic ataxia and discuss the genetic, clinical and imaging findings. Patients belonged to six pedigrees with hereditary spastic paraplegia or cerebellar ataxia of unknown origin. All affected subjects presented with compound heterozygous variants, comprising c.1909 + 22G > A in combination in each pedigree with one of the following novel mutations (Thr596Met, Tyr665LeufsTer11, Glu198Ter, c.646-687_1185 + 844del). The new mutations segregated with the phenotype in all families. The phenotype combined variable cerebellar ataxia, gait and lower limb spasticity, involvement of central sensory tracts and in some cases also intention tremor. The reportedly characteristic hyperintensity along the superior cerebellar peduncle on MRI was observed in ~ 80% of the cases. Our study extends the clinical and molecular phenotype further supporting the pathogenic role of the c.1909 + 22G4A intronic mutation and identifying four novel causative mutations in POLR3A-related spastic ataxia. Certain characteristic MRI features may be useful to guide genetic diagnosis.


Assuntos
Deficiência Intelectual , Espasticidade Muscular , Atrofia Óptica , RNA Polimerase III/genética , Paraplegia Espástica Hereditária , Ataxias Espinocerebelares , Adulto , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pedúnculo Cerebelar Médio/patologia , Espasticidade Muscular/genética , Espasticidade Muscular/patologia , Espasticidade Muscular/fisiopatologia , Mutação , Atrofia Óptica/genética , Atrofia Óptica/patologia , Atrofia Óptica/fisiopatologia , Linhagem , Fenótipo , Espanha , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/patologia , Paraplegia Espástica Hereditária/fisiopatologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/fisiopatologia
10.
Rev Neurol ; 69(7): 289-292, 2019 Oct 01.
Artigo em Espanhol | MEDLINE | ID: mdl-31559627

RESUMO

INTRODUCTION: Intracranial calcifications can have a number of different causes, and the distribution and characteristics they present in neuroimaging can orient the specialist towards one or another. It is important to rule out the most frequent entities that are accompanied by intracranial calcifications, but other more remote genetic causes, such as Coats plus syndrome, should not be overlooked. CASE REPORT: Ex-premature female Infant with a gestational age of 34 weeks, diagnosed with retinopathy at 9 months after presenting strabismus. At 2 years of age, an MRI scan was performed for right hemiparesis, in which an image suggestive of a neoplasm was initially observed. Upon completion of the study with a cranial computed tomography scan, extensive calcifications were observed predominantly in the basal ganglia along with cystic lesions. After ruling out the most frequent causations of intracranial calcifications, the association between the retinopathy and the neurological features was established, and Coats plus syndrome was confirmed by a genetic study that revealed the presence of two hitherto unreported variants in heterozygosis in the CTC1 gene. CONCLUSION: Coats plus syndrome is an extraordinarily rare autosomal recessive disease, caused by mutations in the CTC1 gene, which involves the appearance of retinal telangiectasias, brain cysts, calcifications in deep nuclei and leukoencephalopathy, as well as other bone and gastrointestinal conditions. Treatment is symptomatic and the disease has a poor prognosis.


Assuntos
Ataxia/genética , Neoplasias Encefálicas/genética , Calcinose/genética , Cistos do Sistema Nervoso Central/genética , Leucoencefalopatias/genética , Espasticidade Muscular/genética , Doenças Retinianas/genética , Convulsões/genética , Ataxia/diagnóstico por imagem , Gânglios da Base/diagnóstico por imagem , Gânglios da Base/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Calcinose/patologia , Cistos do Sistema Nervoso Central/diagnóstico por imagem , Cistos do Sistema Nervoso Central/patologia , Pré-Escolar , Diagnóstico Diferencial , Feminino , Heterozigoto , Humanos , Leucoencefalopatias/diagnóstico por imagem , Imagem por Ressonância Magnética , Espasticidade Muscular/diagnóstico por imagem , Mutação de Sentido Incorreto , Paresia/etiologia , Doenças Retinianas/diagnóstico por imagem , Vasos Retinianos/patologia , Convulsões/diagnóstico por imagem , Proteínas de Ligação a Telômeros/genética , Tomografia Computadorizada por Raios X , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
11.
Mutat Res ; 843: 73-80, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31421742

RESUMO

Intake of folate (vitamin B9) is strongly inversely linked with human cancer risk, particularly colon cancer. In general, people with the highest dietary intake of folate or with high blood folate levels are at a reduced risk (approx. 25%) of developing colon cancer. Folate acts in normal cellular metabolism to maintain genomic stability through the provision of nucleotides for DNA replication and DNA repair and by regulating DNA methylation and gene expression. Folate deficiency can accelerate carcinogenesis by inducing misincorporation of uracil into DNA, by increasing DNA strand breakage, by inhibiting DNA base excision repair capacity and by inducing DNA hypomethylation and consequently aberrant gene and protein expression. Conversely, increasing folate intake may improve genomic stability. This review describes key applications of single cell gel electrophoresis (the comet assay) in assessing genomic instability (misincorporated uracil, DNA single strand breakage and DNA repair capacity) in response to folate status (deficient or supplemented) in human cells in vitro, in rodent models and in human case-control and intervention studies. It highlights an adaptation of the SCGE comet assay for measuring genome-wide and gene-specific DNA methylation in human cells and colon tissue.


Assuntos
Monitoramento Biológico/métodos , Neoplasias do Colo/genética , Ensaio Cometa/métodos , Ácido Fólico/farmacologia , Instabilidade Genômica , Análise de Célula Única/métodos , Linhagem Celular , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/prevenção & controle , Quebras de DNA , Metilação de DNA , Reparo do DNA , Replicação do DNA , Ácido Fólico/sangue , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/genética , Instabilidade Genômica/efeitos dos fármacos , Instabilidade Genômica/genética , Genótipo , Homocistinúria/sangue , Homocistinúria/genética , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Espasticidade Muscular/sangue , Espasticidade Muscular/genética , Transtornos Psicóticos/sangue , Transtornos Psicóticos/genética , Risco , Uracila/metabolismo
12.
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
13.
Bipolar Disord ; 21(7): 650-659, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31343802

RESUMO

The evidence for efficacy of many currently available treatments for bipolar disorder is based on studies of nonrefractory patients with bipolar disorder. Therefore, not surprisingly, most treatment recommendations and guidelines for the treatment of bipolar disorder and its many comorbidities depend heavily on data from placebo controlled randomized clinical trials (RCTs), but these RCTs provide little direction for the clinician as to what next steps might be optimal in non- or partial-responders and in those with ongoing medical and psychiatric comorbidities. Given this and the paucity of RCTs at later treatment junctures, we thought it appropriate to begin a discussion of the quality of the data that some experts in the field might consider using in choosing and sequencing drugs and their combination. We acknowledge that many other clinical investigators may prefer very different sequences, but thought the suggestions offered here might be useful to some clinicians in the field, might start discussions of other options in the literature, and, at the same time, provide a preliminary outline for a new round of much-needed clinical trials to better inform clinical practice. Given the very wide range of the quality of the data and clinical principles on which the current suggestions are based, only minimal references are included and a comprehensive review of the literature supporting each option would be outside the scope of this manuscript.


Assuntos
Anticonvulsivantes/uso terapêutico , Antimaníacos/uso terapêutico , Antipsicóticos/uso terapêutico , Transtorno Bipolar/terapia , Psicoterapia , Anquirinas/genética , Transtornos de Ansiedade/terapia , Canais de Cálcio Tipo L/genética , Doenças Cardiovasculares , Tomada de Decisão Clínica , Comorbidade , Monitoramento de Medicamentos , Quimioterapia Combinada , Eletroconvulsoterapia , Medicina Baseada em Evidências , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Testes Genéticos , Homocistinúria/genética , Humanos , Ketamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Espasticidade Muscular/genética , Guias de Prática Clínica como Assunto , Transtornos Psicóticos/genética , Prevenção Secundária , Abandono do Hábito de Fumar , Transtornos Relacionados ao Uso de Substâncias/terapia , Estimulação Magnética Transcraniana
15.
Clin Genet ; 96(4): 366-370, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31309540

RESUMO

The canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling pathways involving CTNNB1 and TBX4, respectively, are crucial for the regulation of human development. Perturbations of these pathways and disruptions from biological homeostasis have been associated with abnormal morphogenesis of multiple organs, including the lung. The aim of this study was to identify the underlying genetic cause of abnormal lung growth, pulmonary hypertension (PAH), severe microcephaly, and muscle spasticity in a full-term newborn, who died at 4 months of age due to progressively worsening PAH and respiratory failure. Family trio exome sequencing showed a de novo heterozygous nonsense c.1603C>T (p.Arg535*) variant in CTNNB1 and a paternally inherited heterozygous missense c.1198G>A (p.Glu400Lys) variant in TBX4, both predicted to be likely deleterious. We expand the phenotypic spectrum associated with CTNNB1 and TBX4 variants and indicate that they could act synergistically to produce a distinct more severe phenotype. Our findings further support a recently proposed complex compound inheritance model in lethal lung developmental diseases and the contention that dual molecular diagnoses can parsimoniously explain blended phenotypes.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Heterozigoto , Fenótipo , Proteínas com Domínio T/genética , beta Catenina/genética , Alelos , Análise Mutacional de DNA , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/genética , Imuno-Histoquímica , Microcefalia/diagnóstico , Microcefalia/genética , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/genética , Mutação , Sequenciamento Completo do Exoma
17.
Intern Med ; 58(19): 2865-2869, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31178521

RESUMO

Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia caused by mutations of FXN. Hypotonus and hyporeflexia of the lower extremities are observed in most FRDA patients. Patients with hyperreflexia, called Friedreich ataxia with retained reflexes (FARR), have also been identified. We herein report the case of a 16-year-old Nepalese boy presenting with early-onset ataxia with prominent spasticity and hyperreflexia of the legs. Mutational analyses established the diagnosis of FRDA presenting as FARR. A haplotype analysis revealed that expanded alleles of the patient shared a common haplotype with Indian and European FRDA patients, suggesting that the mutation descended from a common founder.


Assuntos
Ataxia de Friedreich/complicações , Espasticidade Muscular/etiologia , Reflexo Anormal/fisiologia , Adolescente , Alelos , Análise Mutacional de DNA , Ataxia de Friedreich/genética , Ataxia de Friedreich/fisiopatologia , Haplótipos , Humanos , Proteínas de Ligação ao Ferro/genética , Proteínas de Ligação ao Ferro/metabolismo , Masculino , Espasticidade Muscular/genética , Espasticidade Muscular/fisiopatologia , Mutação , Nepal , Expansão das Repetições de Trinucleotídeos
18.
Pathobiology ; 86(4): 190-200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31238314

RESUMO

OBJECTIVE: This study aims to investigate the association of 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms with neural tube defects (NTDs) in a Tunisian population. METHODS: Genotyping was performed by polymerase chain reaction with restriction fragment length polymorphisms (PCR-RFLPs) using the restriction enzymes. Allele and genotype frequencies were compared between mothers and fathers of fetuses with NTDs with matched controls based on an association analysis using SPSS software. RESULTS: MTHFR (C677T, A1298C) and MTRR A66G polymorphisms were found to be protector factors for NTD fetuses in the mother group. In addition, a combination of the three wild-type alleles C677/A1298/A66 has increased four-fold the incidence of NTDs (p = 0.004, OR = 3.96, 95% CI: 1.53-10.23). In the father group, MTHFR C677T was a risk factor for NTDs. However, no association was found between MTHFR A1298C, MTRR A66G, and the occurrence of this anomaly. The analysis of MTHFR C677T and MTRR A66G polymorphisms has demonstrated a significant difference in vitamin B12 levels between recessive and dominant genotypes in case mothers (p < 0.05). CONCLUSION: Additional studies are required to better understand the roles of parental gene polymorphisms related to folate-homocysteine metabolism in the pathogenesis of NTD.


Assuntos
Ferredoxina-NADP Redutase/genética , Predisposição Genética para Doença , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Defeitos do Tubo Neural/genética , Polimorfismo de Nucleotídeo Único , Alelos , Pai , Feminino , Ácido Fólico/metabolismo , Genótipo , Homocisteína/metabolismo , Homocistinúria/genética , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Mães , Espasticidade Muscular/genética , Defeitos do Tubo Neural/fisiopatologia , Polimorfismo de Fragmento de Restrição , Gravidez , Transtornos Psicóticos/genética , Tunísia
19.
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
20.
Neural Plast ; 2019: 3017678, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984254

RESUMO

Limb spasms are phenomena of hyperreflexia that occur after spinal cord injury. Currently, the clinical treatment is less than ideal. Our goal is to develop a combination therapy based on individualized medicine to reduce spasticity after spinal cord injury. In this study, rats received a severe contusive injury at the T9 segment of the spinal cord, followed by gene therapy with adenoassociated virus encoding human neurotrophic factor 3 (AAV-NT3) and a 2-week exercise program starting at 4 weeks after injury. We quantified the frequency of spasms during a swimming test at 4 and 6 weeks after injury and confirmed the results of the swimming test by measuring the H-reflex of the plantar muscle. We obtained weekly hind limb exercise scores to assess the effect of the interventions in hind limb motor function improvement. Then, we used immunofluorescence to observe the immunoreactivity of spinal motor neurons, synaptophysin, cholinergic interneurons, and GABAergic interneurons. We also measured the expression of KCC2 in the spinal cord by western blot. We found that AAV-NT3 gene therapy, exercise, and combination therapy all attenuated the frequency of spasms in the swimming test conducted at 6 weeks after spinal cord injury and increased rate-dependent depression of H-reflex. Combination therapy was significantly superior to AAV-NT3 alone in protecting motor neurons. Recovery of KCC2 expression was significantly greater in rats treated with combination therapy than in the exercise group. Combination therapy was also significantly superior to individual therapies in remodeling spinal cord neurons. Our study shows that the combination of AAV-NT3 gene therapy and exercise can alleviate muscle spasm after spinal cord injury by altering the excitability of spinal interneurons and motor neurons. However, combination therapy did not show a significant additive effect, which needs to be improved by adjusting the combined strategy.


Assuntos
Terapia por Exercício/métodos , Terapia Genética/métodos , Espasticidade Muscular/terapia , Fatores de Crescimento Neural/genética , Traumatismos da Medula Espinal/complicações , Adenoviridae/fisiologia , Animais , Terapia Combinada , Feminino , Gânglios Espinais/metabolismo , Vetores Genéticos/administração & dosagem , Reflexo H , Injeções Intramusculares , Interneurônios/fisiologia , Neurônios Motores/fisiologia , Espasticidade Muscular/etiologia , Espasticidade Muscular/genética , Músculo Esquelético/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurotrofina 3 , Ratos Wistar
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