Propensity for paternal inheritance of de novo mutations in Alexander disease.
ABSTRACT De novo dominant mutations in the GFAP gene have recently been associated with nearly all cases of Alexander disease, a rare but devastating neurological disorder. These heterozygous mutations must occur very early in development and be present in nearly all cells in order to be detected by the sequencing methods used. To investigate whether the mutations may have arisen in the parental germ lines, we determined the parental chromosome bearing the mutations for 28 independent Alexander disease cases. These cases included 17 different missense mutations and one insertion mutation. To enable assignment of the chromosomal origin of the mutations, six new single nucleotide polymorphisms in the GFAP gene were identified, bringing the known total to 26. In 24 of the 28 cases analyzed, the paternal chromosome carried the GFAP mutation (P < 0.001), suggesting that they predominantly arose in the parental germ line, with most occurring during spermatogenesis. No effect of paternal age was observed. There has been considerable debate about the magnitude of the male to female germ line mutation rate; our ratio of 6:1 is consistent with indirect estimates based on the rate of evolution of the sex chromosome relative to the autosomic chromosomes.
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ABSTRACT: BACKGROUND: We studied a family including two half-siblings, sharing the same mother, affected by slowly progressive, adult-onset neurological syndromes. In spite of the diversity of the clinical features, characterized by a mild movement disorder with cognitive impairment in the elder patient, and severe motor-neuron disease (MND) in her half-brother, the brain Magnetic Resonance Imaging (MRI) features were compatible with adult-onset Alexander's disease (AOAD), suggesting different expression of the same, genetically determined, condition. METHODS: Since mutations in the alpha isoform of glial fibrillary acidic protein, GFAP-alpha, the only cause so far known of AOAD, were excluded, we applied exome Next Generation Sequencing (NGS) to identify gene variants, which were then functionally validated by molecular characterization of recombinant and patient-derived cells. RESULTS: Exome-NGS revealed a mutation in a previously neglected GFAP isoform, GFAP-epsilon, which disrupts the GFAP-associated filamentous cytoskeletal meshwork of astrocytoma cells. To shed light on the different clinical features in the two patients, we sought for variants in other genes. The male patient had a mutation, absent in his half-sister, in X-linked histone deacetylase 6, a candidate MND susceptibility gene. CONCLUSIONS: Exome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression.Orphanet Journal of Rare Diseases 05/2013; 8(1):66. DOI:10.1186/1750-1172-8-66 · 3.96 Impact Factor
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ABSTRACT: RESUMEN Con el Proyecto Internacional para el Estudio de las Enfermedades de la Mielina y los nuevos conocimientos en genética molecular e imagen, se han descrito nuevas e infrecuentes leucodistrofias que no se habían identificado. Describimos el caso de un niño mexicano de nueve años de edad con antecedente de consanguinidad en la rama paterna. Padecía un síndrome de deterioro neurológico progresivo con epilepsia. Los estudios de imagen revelaron una leucoencefalopatía generalizada con megaencefalia y quistes bitemporales. En México se han documentado dos casos (Reunión Anual de la Sociedad Mexicana de Neuro-logía Pediátrica). El caso que presentamos es uno de ellos, analizamos sus características clínicas, los estudios de imagen y revisamos la literatura sobre el tema. Palabras clave: Leucodistrofias, enfermedad de Van der Knapp, leucoencefalopatía, megaencefalia, quistes bitemporales. ABSTRACT The advent of the International Project for the Study of Myelin Diseases, the current advances in molecular genetics and the imaging studies, have permitted the diagnosis of infrequent leucodystrophies, not previously identified. We describe the case of a nine year-old Mexican child with a history of parental consanguinity and a progressive deteriorative neurological syndrome associated with epilepsy. His imaging studies showed generalizad leukodystrophia with bitemporal cysts and megalencephaly. There are only 3 cases reported in Mexico. The one we report is one of them. The purpose of this paper is to alert pediatricians on the diagnosis of this condition and to analyze the clinical, imaging and laboratory characteristics compared with current information in literature.