Zellweger Spectrum Disorder: Ophthalmic Findings from a New Natural History Study Cohort and Scoping Literature Review.

Purpose: Individuals with Zellweger spectrum disorder (ZSD) manifest a spectrum of clinical phenotypes but almost all have retinal degeneration leading to blindness. The onset, extent, and progression of retinal findings have not been well described. It is crucial to understand the natural history of vision loss in ZSD to define reliable endpoints for future interventional trials.

Clinical, neuroradiological, and molecular characterization of patients with atypical Zellweger spectrum disorder caused by PEX16 mutations: a case series.

Peroxisome biogenesis disorders-Zellweger spectrum disorders (PBD-ZSD)-are primarily autosomal recessive disorders caused by mutations in any of 13 PEX genes involved in peroxisome assembly. Compared to other PEX-related disorders, some PEX16 defects are associated with an atypical phenotype consisting of spasticity, cerebellar dysfunction, preserved cognition, and prolonged survival. In this case series, medical records and brain MRIs from 7 patients with this PEX16 presentation were reviewed to further characterize this phenotype.

AAV-mediated gene augmentation improves visual function in the PEX1-Gly844Asp mouse model for mild Zellweger spectrum disorder.

Patients with Zellweger spectrum disorder (ZSD) commonly present with vision loss due to mutations in genes required for peroxisome assembly and function. Here, we evaluate retinal gene augmentation therapy in a mouse model of mild ZSD bearing the murine equivalent (PEX1-p[Gly844Asp]) of the most common human mutation. Experimental adeno-associated virus 8.

The biochemical basis of mitochondrial dysfunction in Zellweger Spectrum Disorder.

Peroxisomal biogenesis disorders (PBDs) are genetic disorders of peroxisome biogenesis and metabolism that are characterized by profound developmental and neurological phenotypes. The most severe class of PBDs-Zellweger spectrum disorder (ZSD)-is caused by mutations in peroxin genes that result in both non-functional peroxisomes and mitochondrial dysfunction. It is unclear, however, how defective peroxisomes contribute to mitochondrial impairment.

A longitudinal study of retinopathy in the PEX1-Gly844Asp mouse model for mild Zellweger Spectrum Disorder.

Zellweger Spectrum Disorder (ZSD) is an autosomal recessive disease caused by mutations in any one of 13 PEX genes whose protein products are required for peroxisome assembly. Retinopathy leading to blindness is one of the major untreatable handicaps faced by patients with ZSD but is not well characterized, and the requirement for peroxisomes in retinal health is unknown. To address this, we examined the progression of retinopathy from 2 to 32 weeks of age in our murine model for the common human PEX1-p.

Zellweger spectrum disorder patient-derived fibroblasts with the PEX1-Gly843Asp allele recover peroxisome functions in response to flavonoids.

Zellweger spectrum disorder (ZSD) results from biallelic mutations in PEX genes required for peroxisome biogenesis. PEX1-G843D is a common hypomorphic allele in the patient population that is associated with milder disease. In prior work using a PEX1-G843D/null patient fibroblast line expressing a green fluorescent protein (GFP) reporter with a peroxisome-targeting signal (GFP-PTS1), we demonstrated that treatments with the chemical chaperone betaine and flavonoid acacetin diacetate recovered peroxisome functions.

An enhanced immune response of Mclk1⁺/⁻ mutant mice is associated with partial protection from fibrosis, cancer and the development of biomarkers of aging.

The immune response is essential for survival by destroying microorganisms and pre-cancerous cells. However, inflammation, one aspect of this response, can result in short- and long-term deleterious side-effects. Mclk1⁺/⁻ mutant mice can be long-lived despite displaying a hair-trigger inflammatory response and chronically activated macrophages as a result of high mitochondrial ROS generation.