Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 452
Filtrar
1.
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
2.
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
3.
Gene ; 704: 68-73, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30986448

RESUMO

AIM: The purpose of the present study is to evaluate and understand the association of global and MTHFR gene specific methylation in preeclampsia and recurrent miscarriages in light of MTHFR C677T polymorphism. METHODS: The subjects comprised of recurrent miscarriage cases, their gestation matched controls, preeclampsia cases and matched controls. A set of women at full term were also recruited. Fasting blood sample (~5 ml) was drawn from all the participants followed by DNA extraction, global DNA methylation and MTHFR gene specific methylation. MTHFR C677T polymorphism was analysed by PCR followed by RFLP. RESULTS HIGHER: Global DNA methylation at maternal front (p = 0.04) and hypomethylation of MTHFR gene at fetal front (p = 0.001) might be a characteristic of preeclampsia. Recurrent miscarriage cases were having significantly (p = 0.002) hyper MTHFR gene specific methylation as compared to controls. Women carrying CT genotype were found to be having significantly (p = 0.001) higher global DNA methylation in PE cases and MTHFR gene specific methylation (p = 0.005) in RM cases. Intergenerational analysis revealed similar patterns of global DNA methylation and MTHFR gene specific methylation among both PE and RM cases at maternal and fetal fronts. CONCLUSION: The study highlights the importance of global DNA methylation in Preeclampsia and MTHFR gene specific methylation in recurrent miscarriages. MTHFR C677T gene polymorphism in association with global and gene specific methylation seem to play a pivotal role in PE and RM respectively.


Assuntos
Aborto Habitual/genética , Metilação de DNA , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pré-Eclâmpsia/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Homocistinúria/complicações , Homocistinúria/genética , Humanos , Índia , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Espasticidade Muscular/complicações , Espasticidade Muscular/genética , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/diagnóstico , Gravidez , Segundo Trimestre da Gravidez/genética , Terceiro Trimestre da Gravidez/genética , Transtornos Psicóticos/complicações , Transtornos Psicóticos/genética
4.
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
5.
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 , Ratos Wistar
6.
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
7.
Mitochondrion ; 45: 18-21, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29408632

RESUMO

Mitochondrial DNA (mtDNA) mutations have been implicated in a wide variety of neurological conditions and are maternally inherited through a complex process which is not fully understood. Genetic counselling for mitochondrial conditions secondary to a mtDNA mutation can be challenging as it is not currently possible to accurately predict the mutational load/heteroplasmy of the mutation which could be passed to the offspring. In general, one expects that the higher the level of heteroplasmy the more likely that the same mtDNA mutation will be seen in the offspring. We report here a family which places a caveat on genetic counselling for mtDNA disorders. The proband is a 63 year old woman with m.14459G>A associated dystonia/spasticity/ataxia. The m.14459G>A mutation was detected at homoplasmic/near homoplasmic levels in her muscle tissue and fibroblasts, but did not appear to have been passed on to any of her offspring. To our knowledge, this is the first report of complete selection against a homoplasmic variant within maternally transmitted mtDNA. It is not clear if this novel phenomenon occurred by random chance or by another method of mitochondrial selection.


Assuntos
Ataxia/genética , DNA Mitocondrial/genética , Distonia/genética , Transmissão Vertical de Doença Infecciosa , Doenças Mitocondriais/genética , Espasticidade Muscular/genética , Mutação Puntual , Feminino , Fibroblastos/patologia , Humanos , Pessoa de Meia-Idade , Músculos/patologia
8.
Brain Dev ; 41(3): 276-279, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30482549

RESUMO

BACKGROUND: The human GATA zinc finger domain containing 2B (GATAD2B) encodes a subunit of the MeCP1-Mi-2/nucleosome remodeling and deacetylase complex, which is involved in chromatin modification and transcription. Recently, patients with severe intellectual disabilities and characteristic features associated with GATAD2B mutations have been identified. CASE REPORT: The patient was a 4-year-old male with dysmorphic features, including frontal bossing, hypertelorism, epicanthal folds, down-slanting palpebral fissures, a flat nasal bridge, a high arched palate, and micrognathia. He spoke no meaningful words and exhibited severe intellectual disability. Hypermetropic astigmatism and mild spasticity of the lower extremities were noted. Whole-exome sequencing revealed a de novo missense mutation in GATAD2B (NM_020699:exon4:c.502C>T; p.(Glu168∗)). CONCLUSION: We report a novel GATAD2B mutation in a boy exhibiting bilateral leg spasticity and white matter abnormalities on brain magnetic resonance imaging.


Assuntos
Deficiências do Desenvolvimento/genética , Fatores de Transcrição GATA/genética , Deficiência Intelectual/genética , Mutação/genética , Encéfalo/diagnóstico por imagem , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico por imagem , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Espasticidade Muscular/complicações , Espasticidade Muscular/genética
9.
IEEE J Biomed Health Inform ; 23(1): 26-37, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30176611

RESUMO

The advancement of scientific and medical research over the past years has generated a wealth of experimental data from multiple technologies, including genomics, transcriptomics, proteomics, and other forms of -omics data, which are available for a number of diseases. The integration of such multisource data is a key component toward the success of precision medicine. In this paper, we are investigating a multisource data integration method developed by our group, regarding its ability to drive to clusters of connected pathways under two different approaches: first, a disease-centric approach, where we integrate data around a disease, and second, a gene-centric approach, where we integrate data around a gene. We have used as a paradigm for the first approach Huntington's disease (HD), a disease with a plethora of available data, whereas for the second approach the GBA2, a gene that is related to spastic ataxia (SA), a phenotype with sparse availability of data. Our paper shows that valuable information at the level of disease-related pathway clusters can be obtained for both HD and SA. New pathways that classical pathway analysis methods were unable to reveal, emerged as necessary "connectors" to build connected pathway stories formed as pathway clusters. The capability to integrate multisource molecular data, concluding to something more than the sum of the existing information, empowers precision and personalized medicine approaches.


Assuntos
Biologia Computacional/métodos , Doença de Huntington , Deficiência Intelectual , Espasticidade Muscular , Atrofia Óptica , Mapas de Interação de Proteínas , Transdução de Sinais , Ataxias Espinocerebelares , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Deficiência Intelectual/fisiopatologia , Informática Médica , Espasticidade Muscular/genética , Espasticidade Muscular/metabolismo , Espasticidade Muscular/fisiopatologia , Atrofia Óptica/genética , Atrofia Óptica/metabolismo , Atrofia Óptica/fisiopatologia , Medicina de Precisão , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/fisiopatologia , beta-Glucosidase/genética , beta-Glucosidase/metabolismo
10.
Clin Neuroradiol ; 29(2): 215-221, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29379980

RESUMO

PURPOSE: Hereditary spastic paraplegia (HSP) and hereditary spastic ataxia (HSA) are a heterogeneous group of genetic disorders characterized by progressive lower limb spasticity resulting from pyramidal tract dysfunction. By identifying critical imaging findings within the clinical context of spasticity, radiologists are uniquely positioned to recommend specific genetic testing, and thus facilitate diagnosis. METHODS: We present two examples of HSP and HSA that had gone clinically unrecognized for years, and in which magnetic resonance imaging played a critical role in the diagnosis. RESULTS: Radiologists' awareness of HSP and HSA, combined with a critical review of the clinical history and characteristic imaging findings led to specific genetic testing and a definitive diagnosis. CONCLUSION: Awareness of HSP and HSA among radiologists will expedite more accurate diagnosis, explanation of patient symptoms, recommendation for syndrome-specific treatment, and family planning considerations.


Assuntos
Deficiência Intelectual/diagnóstico , Espasticidade Muscular/diagnóstico , Atrofia Óptica/diagnóstico , Paraplegia Espástica Hereditária/diagnóstico , Ataxias Espinocerebelares/diagnóstico , Adolescente , Mutação da Fase de Leitura/genética , Proteínas de Choque Térmico/genética , Humanos , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Espasticidade Muscular/genética , Mutação/genética , Atrofia Óptica/genética , Proteínas/genética , Paraplegia Espástica Hereditária/genética , Ataxias Espinocerebelares/genética , Adulto Jovem
11.
Int J Mol Sci ; 19(10)2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30308956

RESUMO

The GBA2 gene encodes the non-lysosomal glucosylceramidase (NLGase), an enzyme that catalyzes the conversion of glucosylceramide (GlcCer) to ceramide and glucose. Mutations in GBA2 have been associated with the development of neurological disorders such as autosomal recessive cerebellar ataxia, hereditary spastic paraplegia, and Marinesco-Sjogren-Like Syndrome. Our group has previously identified the GBA2 c.1780G>C [p.Asp594His] missense mutation, in a Cypriot consanguineous family with spastic ataxia. In this study, we carried out a biochemical characterization of lymphoblastoid cell lines (LCLs) derived from three patients of this family. We found that the mutation strongly reduce NLGase activity both intracellularly and at the plasma membrane level. Additionally, we observed a two-fold increase of GlcCer content in LCLs derived from patients compared to controls, with the C16 lipid being the most abundant GlcCer species. Moreover, we showed that there is an apparent compensatory effect between NLGase and the lysosomal glucosylceramidase (GCase), since we found that the activity of GCase was three-fold higher in LCLs derived from patients compared to controls. We conclude that the c.1780G>C mutation results in NLGase loss of function with abolishment of the enzymatic activity and accumulation of GlcCer accompanied by a compensatory increase in GCase.


Assuntos
Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Linfócitos/metabolismo , Espasticidade Muscular/genética , Espasticidade Muscular/metabolismo , Mutação de Sentido Incorreto , Atrofia Óptica/genética , Atrofia Óptica/metabolismo , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , beta-Glucosidase/genética , Alelos , Biomarcadores , Linhagem Celular , Ativação Enzimática , Glucosilceramidase/metabolismo , Glucosilceramidas/metabolismo , Humanos , beta-Glucosidase/metabolismo
12.
Orphanet J Rare Dis ; 13(1): 165, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30231904

RESUMO

BACKGROUND: Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a recessive neurological disorder with cerebellar, pyramidal and neuropathic features. Natural history data are urgently needed to increase trial readiness. This study aimed to describe the clinical phenotype including dexterity, coordination, strength, mobility, balance, disease severity, participation, and quality of life observed in adults with ARSACS homozygous for the c.8844delT mutation. METHODS: Cross-sectional study with comparisons between disease stages and with reference values. Outcome measures included Standardized Finger-to-Nose Test, Grip/pinch strength, LEMOCOT, Six-Minute Walk Test, 10-Meter Walk Test, Berg Balance Scale, Spastic Paraplegia Rating Scale, Scale for the Assessment and Rating of Ataxia, LIFE-H, and SF-12. RESULTS: Twenty-eight participants were recruited with a mean age of 38.1 years. The majority presented with lower limb coordination and fine dexterity scores below three standard deviations compare to reference values, scored under predicted values for mobility measures and were at increased risk of fall. Participants at an earlier disease stage performed better than the others, but individual variability was observed. CONCLUSIONS: Results showed overall impaired motor performances and, even in a genetically homogeneous ARSACS population, an individual variability within disease stages. This study lays the foundation for a longitudinal study using quantified measurements.


Assuntos
Deficiência Intelectual/fisiopatologia , Espasticidade Muscular/fisiopatologia , Atrofia Óptica/fisiopatologia , Ataxias Espinocerebelares/congênito , Atividades Cotidianas , Adolescente , Adulto , Estudos Transversais , Feminino , Homozigoto , Humanos , Deficiência Intelectual/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/genética , Mutação/genética , Atrofia Óptica/genética , Qualidade de Vida , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/fisiopatologia , Adulto Jovem
13.
PLoS Genet ; 14(8): e1007550, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30067756

RESUMO

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous human neurodegenerative diseases. Amongst the identified genetic causes, mutations in genes encoding motor proteins such as kinesins have been involved in various HSP clinical isoforms. Mutations in KIF1C are responsible for autosomal recessive spastic paraplegia type 58 (SPG58) and spastic ataxia 2 (SPAX2). Bovines also develop neurodegenerative diseases, some of them having a genetic aetiology. Bovine progressive ataxia was first described in the Charolais breed in the early 1970s in England and further cases in this breed were subsequently reported worldwide. We can now report that progressive ataxia of Charolais cattle results from a homozygous single nucleotide polymorphism in the coding region of the KIF1C gene. In this study, we show that the mutation at the heterozygous state is associated with a better score for muscular development, explaining its balancing selection for several decades, and the resulting high frequency (13%) of the allele in the French Charolais breed. We demonstrate that the KIF1C bovine mutation leads to a functional knock-out, therefore mimicking mutations in humans affected by SPG58/SPAX2. The functional consequences of KIF1C loss of function in cattle were also histologically reevaluated. We showed by an immunochemistry approach that demyelinating plaques were due to altered oligodendrocyte membrane protrusion, and we highlight an abnormal accumulation of actin in the core of demyelinating plaques, which is normally concentrated at the leading edge of oligodendrocytes during axon wrapping. We also observed that the lesions were associated with abnormal extension of paranodal sections. Moreover, this model highlights the role of KIF1C protein in preserving the structural integrity and function of myelin, since the clinical signs and lesions arise in young-adult Charolais cattle. Finally, this model provides useful information for SPG58/SPAX2 disease and other demyelinating lesions.


Assuntos
Doenças dos Bovinos/genética , Bovinos/genética , Cinesina/metabolismo , Bainha de Mielina/metabolismo , Degenerações Espinocerebelares/veterinária , Sequência de Aminoácidos , Animais , Doenças dos Bovinos/diagnóstico , Modelos Animais de Doenças , Feminino , Heterozigoto , Homozigoto , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/veterinária , Cinesina/genética , Masculino , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/genética , Espasticidade Muscular/veterinária , Mutação de Sentido Incorreto , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Atrofia Óptica/veterinária , Polimorfismo de Nucleotídeo Único , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/veterinária , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/veterinária , Degenerações Espinocerebelares/diagnóstico , Degenerações Espinocerebelares/genética , Sequenciamento Completo do Genoma
14.
Curr Osteoporos Rep ; 16(5): 554-560, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30116976

RESUMO

PURPOSE OF REVIEW: Homocystinuria is a congenital metabolic disorder in which cystathionine ß-synthase deficiency results in a prominent increase in homocysteine (serum levels > 100 µM), causing mental retardation, atherosclerotic cerebral infarction, and osteoporosis accompanied by fragility fractures. Encountering a case with excessive homocysteinemia such as that seen in hereditary homocystinuria is unlikely during usual medical examinations. However, in individuals who have vitamin B or folate deficiency, serum homocysteine concentrations are known to increase. These individuals may also have a polymorphism in methylenetetrahydrofolate reductase, MTHFR (C677T: TT type), which regulates homocysteine metabolism. These changes in homocysteine levels may elicit symptoms resembling those of homocystinuria (e.g., Alzheimer's disease, atherosclerosis, osteoporosis). RECENT FINDINGS: High serum homocysteine has been shown to have detrimental effects on neural cells, vascular endothelial cells, osteoblasts, and osteoclasts. Homocysteine is also known to increase oxidative stress, disrupt cross-linking of collagen molecules, and increase levels of advanced glycation end products, which results in reduced bone strength through a mechanism that goes beyond low bone density and increased bone resorption. Therefore, high serum homocysteine may be regarded as a factor that can reduce both bone mass and impair bone quality. In this review, we outline the epidemiology and pathophysiology of osteoporosis associated with hyperhomocysteinemia.


Assuntos
Osso e Ossos/metabolismo , Homocisteína/metabolismo , Hiper-Homocisteinemia/metabolismo , Osteoporose/metabolismo , Colágeno/metabolismo , Deficiência de Ácido Fólico/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Homocistinúria/complicações , Homocistinúria/genética , Homocistinúria/metabolismo , Humanos , Hiper-Homocisteinemia/complicações , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Espasticidade Muscular/complicações , Espasticidade Muscular/genética , Espasticidade Muscular/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporose/etiologia , Polimorfismo Genético , Transtornos Psicóticos/complicações , Transtornos Psicóticos/genética , Transtornos Psicóticos/metabolismo , Deficiência de Vitaminas do Complexo B/metabolismo
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(4): 507-510, 2018 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-30098244

RESUMO

OBJECTIVE: To detect potential mutations of the spastic ataxia of Charlevoix-Saguenay (SACS) gene in a pedigree affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). METHODS: Genomic DNA was extracted from peripheral blood samples of the proband and her family members. All exons and flanking sequences of the SACS gene were analyzed by high-throughput sequencing. Suspected mutations were verified with Sanger sequencing. RESULTS: Next generation sequencing revealed novel compound heterozygous mutations of the SACS gene, namely c.13085T to G (p.I4362R) and c.5236dupA (p.T1746fs), in the proband, which were respectively derived from her parents. The mutations were confirmed by Sanger sequencing. CONCLUSION: The c.5236dupA (p.T1746fs) and c.13085T to G (p.I4362R) mutations of the SACS gene probably underlie the ocular symptoms and hearing loss in the proband.


Assuntos
Proteínas de Choque Térmico/genética , Espasticidade Muscular/genética , Ataxias Espinocerebelares/congênito , Análise Mutacional de DNA , Feminino , Humanos , Mutação , Linhagem , Ataxias Espinocerebelares/genética
16.
Stem Cell Res ; 31: 249-252, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30144656

RESUMO

The human iPSC cell line, ARS-FiPS4F1 (ESi063-A), derived from dermal fibroblast from the patient autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) caused by mutations on the gene SACSIN, was generated by non-integrative reprogramming technology using OCT3/4, SOX2, CMYC and KLF4 reprogramming factors. The pluripotency was assessed by immunocytochemistry and RT-PCR. Differentiation capacity was verified in vitro. This iPSC line can be further differentiated toward affected cells to better understand molecular mechanisms of disease and pathophysiology.


Assuntos
Células-Tronco Pluripotentes Induzidas/metabolismo , Espasticidade Muscular/genética , Ataxias Espinocerebelares/congênito , Adolescente , Linhagem Celular , Humanos , Masculino , Mutação , Ataxias Espinocerebelares/genética
17.
Neuropediatrics ; 49(5): 330-338, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29940663

RESUMO

BACKGROUND: Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. METHODS: Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. RESULTS: We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. CONCLUSIONS: PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.


Assuntos
Encéfalo/patologia , Deficiências do Desenvolvimento , Progressão da Doença , Epilepsia Resistente a Medicamentos , Erros Inatos do Metabolismo , Microcefalia , Espasticidade Muscular , Paresia , Monoéster Fosfórico Hidrolases , Criança , Pré-Escolar , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Epilepsia Resistente a Medicamentos/etiologia , Epilepsia Resistente a Medicamentos/genética , Feminino , Ligação Genética , Humanos , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/patologia , Erros Inatos do Metabolismo/fisiopatologia , Microcefalia/etiologia , Microcefalia/genética , Espasticidade Muscular/etiologia , Espasticidade Muscular/genética , Mutação de Sentido Incorreto , Paresia/etiologia , Paresia/genética , Linhagem , Monoéster Fosfórico Hidrolases/deficiência , Monoéster Fosfórico Hidrolases/genética , Sequenciamento Completo do Exoma
18.
Cerebellum ; 17(5): 692-697, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29949095

RESUMO

Mutations in the potassium channel gene KCNC3 (Kv3.3) cause the autosomal dominant neurological disease, spinocerebellar ataxia 13 (SCA13). In this study, we expand the genotype-phenotype repertoire of SCA13 by describing the novel KCNC3 deletion p.Pro583_Pro585del highlighting the allelic heterogeneity observed in SCA13 patients. We characterize adult-onset, progressive clinical symptoms of two afflicted kindred and introduce the symptom of profound spasticity not previously associated with the SCA13 phenotype. We also present molecular and electrophysiological characterizations of the mutant protein in mammalian cell culture. Mechanistically, the p.Pro583_Pro585del protein showed normal membrane trafficking with an altered electrophysiological profile, including slower inactivation and decreased sensitivity to the inactivation-accelerating effects of the actin depolymerizer latrunculin B. Taken together, our results highlight the clinical importance of the intracellular C-terminal portion of Kv3.3 and its association with ion channel function.


Assuntos
Espasticidade Muscular/genética , Espasticidade Muscular/fisiopatologia , Deleção de Sequência , Canais de Potássio Shaw/genética , Ataxias Espinocerebelares/congênito , Adulto , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células CHO , Cricetulus , Feminino , Humanos , Masculino , Toxinas Marinhas/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Espasticidade Muscular/diagnóstico por imagem , Fenótipo , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/fisiopatologia , Tiazolidinas/farmacologia
19.
J Biol Chem ; 293(33): 12832-12842, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29945973

RESUMO

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease that is caused by mutations in the SACS gene. The product of this gene is a very large 520-kDa cytoplasmic protein, sacsin, with a ubiquitin-like (Ubl) domain at the N terminus followed by three large sacsin internal repeat (SIRPT) supradomains and C-terminal J and HEPN domains. The SIRPTs are predicted to contain Hsp90-like domains, suggesting a potential chaperone activity. In this work, we report the structures of the Hsp90-like Sr1 domain of SIRPT1 and the N-terminal Ubl domain determined at 1.55- and 2.1-Å resolutions, respectively. The Ubl domain crystallized as a swapped dimer that could be relevant in the context of full-length protein. The Sr1 domain displays the Bergerat protein fold with a characteristic nucleotide-binding pocket, although it binds nucleotides with very low affinity. The Sr1 structure reveals that ARSACS-causing missense mutations (R272H, R272C, and T201K) disrupt protein folding, most likely leading to sacsin degradation. This work lends structural support to the view of sacsin as a molecular chaperone and provides a framework for future studies of this protein.


Assuntos
Proteínas de Choque Térmico/química , Mutação de Sentido Incorreto , Dobramento de Proteína , Substituição de Aminoácidos , Cristalografia por Raios X , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Espasticidade Muscular/genética , Espasticidade Muscular/metabolismo , Domínios Proteicos , Ataxias Espinocerebelares/congênito , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo
20.
Mol Biol Rep ; 45(4): 621-624, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29855758

RESUMO

Deep vein thrombosis (DVT) is a common disease, especially among elderly patients, which is associated with high costs of treatment and high rates of recurrence. The risk factors for venous thrombosis are primarily related to hypercoagulability, which can be genetic or acquired, or because of immobilization and venous stasis. Among relevant genetic markers are a number of common polymorphisms and mutations in the genes coding for Factor V leiden and methylenetetrahydrofolate reductase. Differential associations of these polymorphisms have been reported in different populations with DVT due to ethnic variations. However, no study has been reported with respect to these polymorphisms in DVT in Iran. Thus, the aim of the present study is to determine the prevalence of FVL, MTHFR C677T and MTHFR A1298C gene polymorphisms in patients with DVT in central Iran. In the present cross-sectional study, a total of 100 patients with first and recurrent episodes of DVT and age less than 70 years were recruited during 2016-2017. Blood sample was collected from the recruited patients and FVL mutation was screened using ARMS-PCR method, MTHFR C677T and MTHFR A1298C mutations were screened using PCR-RFLP method. The results revealed that MTHFR A1298C gene polymorphism in both homozygote and heterozygote form was found to be most frequent i.e. 77% among cases, followed by MTHFR C677T (67%) and FVL (17%). The study highlights the importance of screening of these genetic markers among patients with DVT in this region.


Assuntos
Fator V/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Trombose Venosa/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos Transversais , Fator V/metabolismo , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Genótipo , Homocistinúria/genética , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Espasticidade Muscular/genética , Mutação , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Transtornos Psicóticos/genética , Fatores de Risco , Trombose Venosa/etiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA