Paucar, M. | bioRxiv Science

bioRxiv2021

Cerebrospinal fluid amyloid beta and glial fibrillary acidic protein concentrations in Huntingtons disease

IntroductionHuntingtons disease (HD) is a genetic incurable lethal disease. Biomarkers are needed for objective assessment of disease progression. Evidence supports both complex protein aggregation and astrocyte activation in HD. This study assesses the 42 amino acid long amyloid beta (A{beta}42) and glial fibrillary acidic protein (GFAP) as potential biomarkers in the cerebrospinal fluid (CSF) of HD mutation carriers. MethodsCSF was obtained from manifest HD patients (ManHD), premanifest HD-gene-expansion carriers (PreHD) and gene-negative controls (controls). Disease Burden Score (DBS) and Total Functional Capacity (TFC) were calculated. Protein concentrations were measured by enzyme-linked immunosorbent assays (ELISA) and intergroup differences were analysed using Mann-Whitney U test. Spearman correlations were calculated to assess disease stage association. Age-adjustment was included in the statistical tests. ResultsThe study enrolled 27 ManHD and 13 PreHD subjects. The number of controls differed in the analysis of A{beta}42 and GFAP (n = 19, and 8 respectively). A{beta}42 levels were higher in ManHD (mean 741 ng/l, SD 361) compared with PreHD (mean 468 ng/l, SD 184) (p = 0.025). Likewise GFAP concentration was higher in ManHD (mean 435 ng/l, SD 255) compared with both PreHD (mean 266 ng/l, SD 92.4)(p = 0.040) and controls (mean 208 ng/l, SD 83.7)(p = 0.011). GFAP correlated with DBS (r = 0.361, p = 0.028), TFC (r = - 0.463, p = 0.005), and 5-year risk of onset in PreHD (r = 0.694, p = 0.008). In contrast, there was no correlation between A{beta}42 concentration and DBS, TFC or 5-year risk of onset. ConclusionCSF A{beta}42 levels did not correlate with disease stage suggesting no A{beta}aggregation in HD. GFAP is a potential biomarker in HD with association to disease stage. Validation in larger HD cohorts and potential correlations with clinical phenotype would be of interest.

neuroscience↗

bioRxiv2020

Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia

BackgroundDevelopmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. MethodsHere, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify single nucleotide variants or copy number variations of importance for DD and SI. ResultsIndividual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): c.7502G>C;p.(R2501P), a previously reported variant predicted to be damaging and c.12043T>G;p.(Y4015D), a novel variant predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A>G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified. ConclusionsWe identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD, but further studies into the association are warranted.

genetics↗