Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders.

BACKGROUND: Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype-phenotype correlations and disease mechanisms remain elusive. METHODS: We report five families carrying biallelic variants in PEX13. The identified variants were initially evaluated by using a combination of computational approaches. Immunofluorescence and complementation studies on patient-derived fibroblasts were performed in two patients to investigate the cellular impact of the identified mutations. RESULTS: Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy. Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module. Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration. CONCLUSIONS: This study expands the phenotypic and mutational spectrum of PEX13-related ZSDs and also highlight a variety of disease mechanisms contributing to PEX13-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs.

Age-Related Changes in Headache Days across the Cognitive Spectrum.

Introduction: Prior studies demonstrating age-related declines in headache prevalence have not accounted for the potentially confounding effects of cognitive impairment. Our primary goal was to assess the relationship between aging and self-reported monthly headache days across the cognitive spectrum. Methods: A detailed headache questionnaire was included prospectively as part of an annual mailing to participants in the Sanders-Brown Center on Aging longitudinal cohort. Results: The overall survey response rate was 58.6%, yielding a cohort of 332 cognitively normal, 71 mild cognitive impairment (median Mini-Mental Status Examination [MMSE] score = 27, interquartile range [IQR] = 25-28), and 51 demented (median MMSE score = 24, IQR = 19-26) individuals. Current headaches were reported by 22.8%, 25%, and 27.1%, respectively, across normal, mild cognitive impairment, and dementia subgroups. A negative correlation was observed between age and average headache days in cognitively normal (ρ = -0.163, 95% confidence interval [CI] = -0.246 to -0.022, P = 0.004), mild cognitive impairment (ρ = -0.255, 95% CI = -0.274 to 0.229, P = 0.0475), and dementia groups (ρ = -0.295, 95% CI = -0.457 to 0.159, P = 0.068). Ordinary least-squares regression with backward selection identified age alone, but not gender or MMSE, as predicting headache days in the overall cohort. Conclusions: Aging is associated with a decline in headache days in the absence of any confounding cognitive pathology and is weakly predictive of headache days across the cognitive spectrum. Whether this represents a reporting bias due to dementia or has neurobiological significance warrants further investigation.

Cellular mechanics of germ band retraction in Drosophila.

Germ band retraction involves a dramatic rearrangement of the tissues on the surface of the Drosophila embryo. As germ band retraction commences, one tissue, the germ band, wraps around another, the amnioserosa. Through retraction the two tissues move cohesively as the highly elongated cells of the amnioserosa contract and the germ band moves so it is only on one side of the embryo. To understand the mechanical drivers of this process, we designed a series of laser ablations that suggest a mechanical role for the amnioserosa. First, we find that during mid retraction, segments in the curve of the germ band are under anisotropic tension. The largest tensions are in the direction in which the amnioserosa contracts. Second, ablating one lateral flank of the amnioserosa reduces the observed force anisotropy and leads to retraction failures. The other intact flank of amnioserosa is insufficient to drive retraction, but can support some germ band cell elongation and is thus not a full phenocopy of ush mutants. Another ablation-induced failure in retraction can phenocopy mys mutants, and does so by targeting amnioserosa cells in the same region where the mutant fails to adhere to the germ band. We conclude that the amnioserosa must play a key, but assistive, mechanical role that aids uncurling of the germ band.