PMC:3654953 / 1618-4220 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3654953","sourcedb":"PMC","sourceid":"3654953","source_url":"https://www.ncbi.nlm.nih.gov/pmc/3654953","text":"Background\nAlexander’s disease (AD, OMIM #203450) is a rare neurological disorder characterized by a peculiar form of leukodystrophy, with infantile, juvenile and adult forms manifesting with different clinical and pathological signs [1]. AD is a sporadic or autosomal dominant condition associated in most of the cases with heterozygous mutations in the gene encoding the glial fibrillary acidic protein, GFAP, an intermediate filament component of the cytoskeleton of several cell types [2]. GFAP mutations frequently occur de novo, particularly in infantile cases, while in Adult-onset AD (AOAD) both de novo mutations and autosomal dominant transmission have been described [3]. GFAP-containing eosinophil aggregates, known as Rosenthal fibers, distributed in the white matter of the CNS, constitute the morphological hallmark of the disease [2]. Whilst the infantile form shows extensive white matter lesions and usually fatal outcome, AOAD is characterized by predominant brainstem involvement and survival into adulthood [4].\nWe here report the results of exome next-generation DNA sequencing (NGS) conducted on a family with two maternal half-siblings, affected by two distinct adult-onset neurological syndromes: mild cognitive deterioration and movement disorder in a female patient, motor-neuron disease (MND) in her half-brother. The two patients shared the same mother, but had different, unrelated fathers, suggesting either an X-linked or an autosomal dominant condition with variable penetrance and expressivity. In spite of the diversity of the clinical features, the brain MRI features were compatible with AOAD. However, standard sequence analysis of the nine canonical exons encoding the predominant isoform, GFAP-α, had previously ruled out mutations in both patients.\nNGS is a holistic, unbiased approach that generates comprehensive information on gene variance [5]. Exome NGS analysis in our family revealed a heterozygous missense mutation in an alternative exon of the GFAP gene (exon 7A), which has not previously been included in the diagnostic screening of AOAD. Additional variants in other genes included a private mutation in the X-linked gene encoding histone deacetylase 6, HDAC6, which was present in the male, but absent in the female, patients. HDAC6 was suggested to have a modulating role in different processes related to neurodegeneration, including authophagy, proteosomal degradation, aggresome formation [6,7]. We demonstrated that the mutant HDAC6 variant has reduced deacetylase activity, which could contribute to the different phenotypes of our patients.","divisions":[{"label":"title","span":{"begin":0,"end":10}},{"label":"p","span":{"begin":11,"end":1032}},{"label":"p","span":{"begin":1033,"end":1789}}],"tracks":[{"project":"AxD_symptoms","denotations":[{"id":"T4","span":{"begin":118,"end":132},"obj":"Phenotype"},{"id":"T5","span":{"begin":731,"end":747},"obj":"Phenotype"},{"id":"T6","span":{"begin":1255,"end":1272},"obj":"Phenotype"},{"id":"T7","span":{"begin":2362,"end":2379},"obj":"Phenotype"}],"attributes":[{"id":"A4","pred":"hp_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/HP_0002415"},{"id":"A5","pred":"hp_id","subj":"T5","obj":"http://purl.obolibrary.org/obo/HP_0100320"},{"id":"A6","pred":"hp_id","subj":"T6","obj":"http://purl.obolibrary.org/obo/HP_0100022"},{"id":"A7","pred":"hp_id","subj":"T7","obj":"http://purl.obolibrary.org/obo/HP_0002180"},{"subj":"T4","pred":"source","obj":"AxD_symptoms"},{"subj":"T5","pred":"source","obj":"AxD_symptoms"},{"subj":"T6","pred":"source","obj":"AxD_symptoms"},{"subj":"T7","pred":"source","obj":"AxD_symptoms"}]},{"project":"2_test","denotations":[{"id":"23634874-14572141-81641068","span":{"begin":235,"end":236},"obj":"14572141"},{"id":"23634874-17498694-81641069","span":{"begin":490,"end":491},"obj":"17498694"},{"id":"23634874-16365765-81641070","span":{"begin":679,"end":680},"obj":"16365765"},{"id":"23634874-17498694-81641071","span":{"begin":847,"end":848},"obj":"17498694"},{"id":"23634874-18684770-81641072","span":{"begin":1029,"end":1030},"obj":"18684770"},{"id":"23634874-22468856-81641073","span":{"begin":1886,"end":1887},"obj":"22468856"},{"id":"23634874-17568747-81641074","span":{"begin":2449,"end":2450},"obj":"17568747"},{"id":"23634874-21377170-81641075","span":{"begin":2451,"end":2452},"obj":"21377170"},{"id":"T21721","span":{"begin":235,"end":236},"obj":"14572141"},{"id":"T94953","span":{"begin":490,"end":491},"obj":"17498694"},{"id":"T10644","span":{"begin":679,"end":680},"obj":"16365765"},{"id":"T41820","span":{"begin":847,"end":848},"obj":"17498694"},{"id":"T41984","span":{"begin":1029,"end":1030},"obj":"18684770"},{"id":"T71222","span":{"begin":1886,"end":1887},"obj":"22468856"},{"id":"T80131","span":{"begin":2449,"end":2450},"obj":"17568747"},{"id":"T37983","span":{"begin":2451,"end":2452},"obj":"21377170"}],"attributes":[{"subj":"23634874-14572141-81641068","pred":"source","obj":"2_test"},{"subj":"23634874-17498694-81641069","pred":"source","obj":"2_test"},{"subj":"23634874-16365765-81641070","pred":"source","obj":"2_test"},{"subj":"23634874-17498694-81641071","pred":"source","obj":"2_test"},{"subj":"23634874-18684770-81641072","pred":"source","obj":"2_test"},{"subj":"23634874-22468856-81641073","pred":"source","obj":"2_test"},{"subj":"23634874-17568747-81641074","pred":"source","obj":"2_test"},{"subj":"23634874-21377170-81641075","pred":"source","obj":"2_test"},{"subj":"T21721","pred":"source","obj":"2_test"},{"subj":"T94953","pred":"source","obj":"2_test"},{"subj":"T10644","pred":"source","obj":"2_test"},{"subj":"T41820","pred":"source","obj":"2_test"},{"subj":"T41984","pred":"source","obj":"2_test"},{"subj":"T71222","pred":"source","obj":"2_test"},{"subj":"T80131","pred":"source","obj":"2_test"},{"subj":"T37983","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"AxD_symptoms","color":"#c093ec","default":true},{"id":"2_test","color":"#93eca6"}]}]}}