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1.
Epilepsia ; 61(6): 1142-1155, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32452540

RESUMO

OBJECTIVE: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. METHODS: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. RESULTS: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. SIGNIFICANCE: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.


Assuntos
Variação Genética/genética , Hérnia Diafragmática/diagnóstico por imagem , Hérnia Diafragmática/genética , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/genética , Proteínas de Membrana/genética , Adulto , Sequência de Aminoácidos , Criança , Estudos de Coortes , Eletroencefalografia/métodos , Fácies , Hérnia Diafragmática/fisiopatologia , Humanos , Recém-Nascido , Deformidades Congênitas dos Membros/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Masculino
3.
J Clin Neurophysiol ; 24(6): 450-5, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18090526

RESUMO

The primary goal of this study was to identify secondary functional changes in the peripheral motor units of the paretic upper extremity (UE) in patients with severe ischemic stroke and to determine how these changes develop during the first weeks after stroke. An inception cohort of 27 consecutive patients with an acute ischemic supratentorial stroke and an initial UE paralysis was compared with 10 healthy control subjects. The ulnar nerve was electrically stimulated proximal to the wrist and electromyographic recordings were obtained from the abductor digiti minimi muscle. Hemiparetic side mean values of the compound muscle action potential (CMAP) 1 and 3 weeks after stroke were compared with the nonparetic side and with CMAP values obtained from healthy control subjects. The mean CMAP amplitude in patients was significantly lower on the paretic side compared with the nonparetic side and with control subjects. Decrease in CMAP amplitude was observed in more than half of the stroke patients, sometimes as early as 4 days after stroke, and persisted in most cases. Whenever present, it was accompanied by absence of motor recovery at that specific time after stroke. Decreased CMAP amplitude in the abductor digiti minimi muscle can be seen already in the very acute phases after stroke unrelated to peripheral neuropathy, radiculopathy, or plexopathy, and it is accompanied by absence of UMN recovery. This knowledge is important for interpreting electrophysiological data in stroke patients.


Assuntos
Isquemia Encefálica/complicações , Vias Eferentes/fisiopatologia , Mãos/inervação , Doença dos Neurônios Motores/etiologia , Neurônios Motores , Músculo Esquelético/inervação , Paralisia/etiologia , Acidente Vascular Cerebral/complicações , Nervo Ulnar/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/fisiopatologia , Estudos de Casos e Controles , Progressão da Doença , Estimulação Elétrica , Eletromiografia , Potencial Evocado Motor , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/fisiopatologia , Paralisia/fisiopatologia , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo
4.
Hum Genet ; 111(4-5): 388-93, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12384780

RESUMO

We present a linkage study in a four-generation autosomal dominant cerebellar ataxia (ADCA) family of Dutch ancestry. The family shows a clinically and genetically distinct form of ADCA. This neurodegenerative disorder manifests in the family as a relatively mild ataxia syndrome with some additional characteristic symptoms. We have identified a SCA19 locus, approved by the Human Genome Nomenclature Committee that can be assigned to the chromosome region 1p21-q21. Our mutation analysis failed to identify any mutations in the known spinocerebellar ataxia ( SCA) genes and linkage analysis excluded the remaining SCA loci. We therefore performed a genome-wide scan with 350 microsatellite markers to identify the location of the disease-causing gene in this family. Multi-point analysis was performed and exclusion maps were generated. Linkage and haplotype analysis revealed linkage to an interval located on chromosome 1. The estimated minimal prevalence of ADCA in the Netherlands is about 3:100,000. To date, sixteen different SCA loci have been identified in ADCA ( SCA1-8 and SCA10-17). However, mutation analysis has been commercially available only for the SCA1, 2, 3, 6 and 7 genes. So far, a molecular analysis in these SCA genes cannot be made in about one-third of the ADCA families. Thus, the identification of this new, additional SCA19 locus will contribute to expanding the DNA diagnostic possibilities.


Assuntos
Ataxia Cerebelar/genética , Cromossomos Humanos Par 1 , Genes Dominantes , Mapeamento Cromossômico , Análise Mutacional de DNA , Feminino , Heterogeneidade Genética , Haplótipos , Humanos , Masculino , Países Baixos , Linhagem , Fenótipo
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