Asunto(s)
Destreza Motora , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatología , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/clasificación , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Adulto JovenRESUMEN
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.
Asunto(s)
Debilidad Muscular/genética , Atrofia Muscular Espinal/genética , Mutación/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Atrofias Musculares Espinales de la Infancia/genética , Preescolar , Mapeo Cromosómico , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Lactante , Masculino , Atrofia Muscular Espinal/diagnóstico , Países Bajos , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Atrofias Musculares Espinales de la Infancia/diagnóstico , Factores de Transcripción/genéticaRESUMEN
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.
Asunto(s)
Anomalías Múltiples/genética , Ensamble y Desensamble de Cromatina/genética , Proteínas de Unión al ADN/genética , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Micrognatismo/genética , Factores de Transcripción/genética , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Cara/anomalías , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Cuello/anomalías , Eliminación de Secuencia , Trastornos del Habla/genéticaRESUMEN
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.
Asunto(s)
Corteza Cerebral/anomalías , Malformaciones del Desarrollo Cortical/genética , Mutación , Tubulina (Proteína)/genética , Adolescente , Adulto , Sustitución de Aminoácidos , Corteza Cerebral/embriología , Corteza Cerebral/patología , Preescolar , Femenino , Enfermedades Fetales/genética , Variación Genética , Humanos , Lisencefalia/genética , Malformaciones del Desarrollo Cortical/patología , Piamadre/anomalías , Piamadre/embriología , Piamadre/patología , EmbarazoRESUMEN
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.