Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant.

[alexander disease]

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 .Since mutations in the alpha isoform of glial fibrillary acidic protein , GFAP -Î±, 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 .Exome-NGS revealed a mutation in a previously neglected GFAP isoform , GFAP -Ïµ , 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 .Exome-NGS is an unbiased approach that not only helps identify new disease genes , but may also contribute to elucidate phenotypic expression .

Diseases
Validation

Diseases presenting "fibrillary acidic protein" symptom

alexander disease

canavan disease

erdheim-chester disease

hirschsprung disease

hydrocephalus with stenosis of the aqueduct of sylvius

von hippel-lindau disease

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