Autosomal dominant palatal myoclonus and spinal cord atrophy.
ABSTRACT We report a new family with palatal myoclonus, pyramidal tract signs, cerebellar signs, marked atrophy of the medulla oblongata and spinal cord, and autosomal dominant inheritance. These findings were almost identical with those in patients previously reported to have histopathologically confirmed adult-onset Alexander disease. Recently, heterozygous point mutations in the coding region of glial fibrillary acidic protein (GFAP) in patients with an infantile form of Alexander disease have been reported. We found a new heterozygous amino acid substitution, Val87Gly in exon 1 of GFAP, in the affected individuals in this family but not in 100 spinocerebellar ataxia (SCA) patients and 100 controls. Therefore, this family might have new clinical entities related to adult-onset Alexander disease and GFAP mutation.
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ABSTRACT: Alexander disease (AxD) is an astrogliopathy that primarily affects the white matter of the central nervous system (CNS). AxD is caused by mutations in a gene encoding GFAP (glial fibrillary acidic protein). The GFAP mutations in AxD have been reported to act in a gain-of-function manner partly because the identified mutations generate practically full-length GFAP. We found a novel nonsense mutation (c.1000 G>T, p.(Glu312Ter); also termed p.(E312*)) within a rod domain of GFAP in a 67-year-old Korean man with a history of memory impairment and leukoencephalopathy. This mutation, GFAP p.(E312*), removes part of the 2B rod domain and the whole tail domain from the GFAP. We characterized GFAP p.(E312*) using western blotting, in vitro assembly and sedimentation assay, and transient transfection of human adrenal cortex carcinoma SW13 (Vim(+)) cells with plasmids encoding GFAP p.(E312*). The GFAP p.(E312*) protein, either alone or in combination with wild-type GFAP, elicited self-aggregation. In addition, the assembled GFAP p.(E312*) aggregated into paracrystal-like structures, and GFAP p.(E312*) elicited more GFAP aggregation than wild-type GFAP in the human adrenal cortex carcinoma SW13 (Vim(+)) cells. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of GFAP that is associated with AxD and paracrystal formation.European Journal of Human Genetics advance online publication, 23 April 2014; doi:10.1038/ejhg.2014.68.European journal of human genetics: EJHG 04/2014; DOI:10.1038/ejhg.2014.68 · 4.23 Impact Factor
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ABSTRACT: Le leucodistrofie dell’adulto costituiscono un vasto campo diagnostico. La principale analisi è sapere se si è in presenza di una leucodistrofia di origine vascolare o meno. A favore di un’origine vascolare si considerano l’interessamento dei nuclei grigi e della parte mediana del ponte e le microemorragie in gradient eco. In una tale situazione, la patologia più frequente è rappresentata dal CADASIL il cui gene mutato è Notch3. In caso contrario, deve essere ricercata una leucodistrofia non vascolare che può essere dovuta a un difetto biochimico o a una mutazione genetica. L’aspetto neuroradiologico è uno degli elementi fondamentali per raggiungere una tale diagnosi.01/2009; 9(3):1–8. DOI:10.1016/S1634-7072(09)70510-0