Assuntos
Destreza Motora , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/classificação , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Adulto JovemRESUMO
Spinal muscular atrophy with respiratory distress type 1 is an autosomal recessive disorder with early respiratory difficulties, distal muscle weakness, and contractures leading to foot deformities as the most striking clinical symptoms. Mutations of the gene encoding the immunoglobulin heavy chain µ-binding protein 2, mapped on chromosome 11q13, are the cause of the disease. We present the clinical and mutational characteristics of ten patients in the Netherlands who showed considerable clinical variability; they carried six novel mutations, including a deletion of exon 2. However, there were no clear phenotype-genotype correlations.
Assuntos
Debilidade Muscular/genética , Atrofia Muscular Espinal/genética , Mutação/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Atrofias Musculares Espinais da Infância/genética , Pré-Escolar , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença/genética , Humanos , Lactente , Masculino , Atrofia Muscular Espinal/diagnóstico , Países Baixos , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Atrofias Musculares Espinais da Infância/diagnóstico , Fatores de Transcrição/genéticaRESUMO
We identified de novo truncating mutations in ARID1B in three individuals with Coffin-Siris syndrome (CSS) by exome sequencing. Array-based copy-number variation (CNV) analysis in 2,000 individuals with intellectual disability revealed deletions encompassing ARID1B in 3 subjects with phenotypes partially overlapping that of CSS. Taken together with published data, these results indicate that haploinsufficiency of the ARID1B gene, which encodes an epigenetic modifier of chromatin structure, is an important cause of CSS and is potentially a common cause of intellectual disability and speech impairment.
Assuntos
Anormalidades Múltiplas/genética , Montagem e Desmontagem da Cromatina/genética , Proteínas de Ligação a DNA/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Fatores de Transcrição/genética , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Face/anormalidades , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pescoço/anormalidades , Deleção de Sequência , Distúrbios da Fala/genéticaRESUMO
Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also polymicrogyria malformations.
Assuntos
Córtex Cerebral/anormalidades , Malformações do Desenvolvimento Cortical/genética , Mutação , Tubulina (Proteína)/genética , Adolescente , Adulto , Substituição de Aminoácidos , Córtex Cerebral/embriologia , Córtex Cerebral/patologia , Pré-Escolar , Feminino , Doenças Fetais/genética , Variação Genética , Humanos , Lisencefalia/genética , Malformações do Desenvolvimento Cortical/patologia , Pia-Máter/anormalidades , Pia-Máter/embriologia , Pia-Máter/patologia , GravidezRESUMO
Failure to thrive, feeding difficulties, variable forms of infantile epilepsy or psychomotor developmental delay and hypotonia were the most frequent clinical disease presentations in eight children with combined oxidative phosphorylation enzyme complex deficiencies carrying mutations in the polymerase gamma (POLG1) gene. Five out of eight patients developed severe liver dysfunction during the course of the disease. Three of these patients fulfilled the disease criteria for Alpers syndrome. Most children showed deficiencies of respiratory chain enzyme complexes I and III, in combination with complex II, complex IV and/or PDHc in muscle, whereas in fibroblasts normal enzyme activities were measured. All children carried homozygous or compound heterozygous mutations in the POLG1 gene, including two novel mutations in association with mtDNA depletion. Conclusion We suggest performing POLG1 mutation analysis in children with combined oxidative phosphorylation deficiencies in muscle, even if the clinical picture is not Alpers syndrome.