Towards genomic database of Alexander disease to identify variations modifying disease phenotype

Abstract

Alexander disease (AxD) is an extremely rare neurodegenerative disorder caused by glial fibrillary acidic protein (GFAP) gene mutations. Compared with the cerebral type, which is characterized by infantile onset, the bulbospinal type and intermediate form are associated with a late onset, spanning from juveniles to the elderly, and more diverse clinical spectrum, suggesting the existence of factors contributing to phenotypic diversity. To build a foundation for future genetic studies of this rare disease, we obtained genomic data by whole exome-sequencing (WES) and DNA microarray derived from thirty-one AxD patients with the bulbospinal type and intermediate form. Using this data, we aimed to identify genetic variations determining the age at onset (AAO) of AxD. As a result, WES- or microarray-based association studies between younger (<45 years; n = 13)- and older (≥45 years; n = 18)-onset patients considering the predicted GFAP-mutation pathogenicity identified no genome-wide significant variant. The candidate gene approach identified several variants likely correlated with AAO (p < 0.05): GAN, SLC1A2, CASP3, HDACs, and PI3K. Although we need to replicate the results using an independent population, this is the first step towards constructing a database, which may serve as an important tool to advance our understanding of AxD.

Metabolic Enzyme Alterations and Astrocyte Dysfunction in a Murine Model of Alexander Disease With Severe Reactive Gliosis

“…Consistent with these previous reports, increases were detected in proteins associated with reactive astrocytes (Gfap, Vim, Cd44) ( 23 ), RFs (Cryab, Rps27a, Hsp27 (also known as Hspb1), Ddx3x, Ccnd2, Rack1) ( 22 , 33 , 34 ), and autophagy (Sqstm1) ( 35 ). Gan, which targets Gfap for proteasomal degradation ( 36 ), was also elevated and has gene variants correlated with the age of clinical onset in AxD patients ( 37 ). Heightened levels of Stat3 were also detected in GFAP Tg ; Gfap +/ R236H mice, a phosphorylated transcription factor activated in reactive gliosis ( 38 ).…”

Psychiatric Onset Alexander Disease: An Important Challenge in Neuropsychiatric Diagnosis: A Case Report

“…Many pathogenic mutations have been reported in AxD, Majority of them is point mutation and indels. (Quinlan, Brenner, Goldman, & Messing, 2007;Yasuda et al, 2019) Alexander disease is considered a gain-of function disorder in the sense that the GFAP mutations produce consequences that differ dramatically from those caused by the absence of GFAP (like that case in this study).Although the main cause of sever and lethal AxD is accumulation of toxic defective proteins in astrocytes as a consequence of point mutation in GFAP gene; but, in this case with deletion of 1-9 exons, GFAP protein is produced from intact allele with less than 50% performance-This phenomenon is called haploinsufficiencybesides, previous studies demonstrated that deletion of some exons like exon 5. (Green, 2018) After a pathogenic mutation is discovered, it is preferred to assess mutation in other family members, whom could be asymptomatic or minimally affected.…”

Clinical and radiological characteristics of older‐adult‐onset Alexander disease

“…Given the fact that bulbospinal ALXDRD, which is more common in adulthood, shows a milder phenotype and slower progression than cerebral ALXDRD, which is more common in infancy [1], it is logical to speculate that the low number of reports of older‐adult‐onset ALXDRD may be due to their milder phenotype with slower progression or asymptomatic status. Furthermore, even among bulbospinal ALXDRD cases, older‐age‐at‐onset cases (≥45 years old) tend to show a more severe phenotype than younger‐age‐at‐onset cases (<45 years old) [21]. Therefore, to assess the association between disease progression and severity depending on the age at onset, we compared older‐adult‐onset cases with younger‐adult‐onset cases, as control cases, whose clinical classification and period from onset to diagnosis were matched.…”

“…In ALXDRD, the younger the onset age, the more severe the clinical phenotype tends to be [1,21]. Thus, we hypothesized that older-adult-onset ALXDRD would be associated with a much milder phenotype than younger-adult-onset ALXDRD.…”