Zellweger spectrum disorder (ZSD) is a rare, debilitating genetic disorder of peroxisome biogenesis that affects multiple organ systems and presents with broad clinical heterogeneity. Although severe, intermediate, and mild forms of ZSD have been described, these designations are often arbitrary, presenting difficulty in understanding individual prognosis and treatment effectiveness. The purpose of this study is to conduct a scoping review and meta-analysis of existing literature and a medical chart review to determine if characterization of clinical findings can predict severity in ZSD. Our PubMed search for articles describing severity, clinical findings, and survival in ZSD resulted in 107 studies (representing 307 patients) that were included in the review and meta-analysis. We also collected and analyzed these same parameters from medical records of 136 ZSD individuals from our natural history study. Common clinical findings that were significantly different across severity categories included seizures, hypotonia, reduced mobility, feeding difficulties, renal cysts, adrenal insufficiency, hearing and vision loss, and a shortened lifespan. Our primary data analysis also revealed significant differences across severity categories in failure to thrive, gastroesophageal reflux, bone fractures, global developmental delay, verbal communication difficulties, and cardiac abnormalities. Univariable multinomial logistic modeling analysis of clinical findings and very long chain fatty acid (VLCFA) hexacosanoic acid (C26:0) levels showed that the number of clinical findings present among seizures, abnormal EEG, renal cysts, and cardiac abnormalities, as well as plasma C26:0 fatty acid levels could differentiate severity categories. We report the largest characterization of clinical findings in relation to overall disease severity in ZSD. This information will be useful in determining appropriate outcomes for specific subjects in clinical trials for ZSD.

Background: Owing to their low prevalence, rare diseases are poorly addressed in the scientific literature and clinical practice guidelines. Thus, health care workers are inadequately equipped to provide timely diagnoses, appropriate treatment, and support for these poorly understood conditions. These clinical tribulations are experienced as moral challenges by patients, jeopardizing their life trajectories, dreams, and aspirations. Objective: This paper presents an ethical action plan for rare disease care and the process underlying its development. Methods: This action plan was designed through an ethical inquiry conducted by the Ethics and Rare Diseases Working Group, which included 3 patient partners, 2 clinician researchers, and 1 representative from Québec’s rare disease association. Results: The plan is structured into 4 components. Component A presents the key moral challenges encountered by patients, which are the lack of knowledge on rare diseases among health care workers, the problematic attitudes that it sometimes elicits, and the distress and powerlessness experienced by patients. Component B emphasizes a vision for patient partnership in rare disease care characterized by open-mindedness, empathy, respect, and support of patient autonomy from health care workers. Component C outlines 2 courses of action prompted by this vision: raising awareness among health care workers and empowering patients to better navigate their care. Component D compares several interventions that could help integrate these 2 courses of action in rare disease care. Conclusions: Overall, this action plan represents a toolbox that provides a review of multiple possible interventions for policy makers, hospital managers, practitioners, researchers, and patient associations to critically reflect on key moral challenges experienced by patients with rare diseases and ways to mitigate them. This paper also prompts reflection on the values underlying rare disease care, patient experiences, and health care workers’ beliefs and behaviors. Health care workers and patients were the primary beneficiaries of this action plan.

Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme whose function is important for the biosynthesis of purines, pyrimidines, and pyridines. Importantly, while missense mutations of PRPS1 have been identified in neurological disorders such as Arts syndrome, how they contribute to neuropathogenesis is still unclear. We identified the Drosophila ortholog of PRPS (dPRPS) as a direct target of RB/E2F in Drosophila, a vital cell cycle regulator, and engineered dPRPS alleles carrying patient-derived mutations. Interestingly, while they are able to develop normally, dPRPS mutant flies have a shortened lifespan and locomotive defects, common phenotypes associated with neurodegeneration. Careful analysis of the fat body revealed that patient-derived PRPS mutations result in profound defects in lipolysis, macroautophagy, and lysosome function. Significantly, we show evidence that the nervous system of dPRPS mutant flies is affected by these defects. Overall, we uncovered an unexpected link between nucleotide metabolism and autophagy/lysosome function, providing a possible mechanism by which PRPS-dysfunction contributes to neurological disorders. Phosphoribosyl pyrophosphate synthetase (PRPS) is an important enzyme in nucleotide synthesis: the building blocks of DNA and RNA and other important metabolites. Importantly, while PRPS is mutated in neurological disorders such as Arts syndrome, Charcot-Marie-Tooth disease, and nonsyndromic sensorineural deafness, it is currently unclear why PRPS dysfunction leads to neurological disorders. In this study, we engineered a Drosophila model of ARTS syndrome and discovered that PRPS mutations result in defects in lysosome-mediated and autophagy processes, which are known to be important for neuronal homeostasis. Our study provides crucial insights into the way that PRPS mutations contribute to neurological disorders.

Background: Zellweger Spectrum Disorder (ZSD) is caused by bi-allelic defects in any of 13 PEX genes, resulting in failure to form functional peroxisomes. Individuals manifest a wide spectrum of clinical phenotypes and severity, but almost all have retinal degeneration leading to blindness. The onset, extent and progression of retinal findings has not been well-described and there are no therapies for treating vision loss. With expanding research and trials on retinal gene therapy for genetic disorders, it is now crucial to understand the natural history of vision loss in ZSD for defining reliable endpoints for upcoming interventional trials. Here we describe ophthalmic findings in the largest number of ZSD patients to date. Methods: We reviewed ophthalmology records from our retrospective longitudinal cohort of 66 patients, and cross-sectional ophthalmic findings from 79 patients reported in the literature. We divided patients by severe, intermediate or mild disease based on genotypes or their reported disease severity. Results: We found that visual acuity (VA) declines slowly (+0.01 Logmar/year) with a mean of 0.93 Logmar (0 = normal vision, 1 = legal blindness) in all 53 intermediate-mild patients with available data. Longitudinal VA data revealed slow loss over time and legal blindness onset at average age 7.8 years. Fundoscopy showed retinal pigmentation, macular abnormalities, small or pale optic discs and attenuated vessels with higher prevalence in milder severity groups and did not change with age. Electroretinogram (ERG) tracings were diminished in 93% of patients, 40% of which were extinguished. ERG responses did not change over time in patients with multiple ERGs. Optical coherence tomography (OCT), reported only in milder patients, revealed cystoid macular edema or macular schisis in 16/21 (age 1.8-30 years). Serial OCTs showed evolution or stable macular edema. Conclusions: Although limited by retrospective data, we highlight several useful conclusions (1) VA slowly deteriorates and is without clear association with disease severity, (2) serial ERGs are not useful for documenting vision loss progression and (3) intraretinal cysts may be common in ZSD. This study indicates that systematically reporting multiple measures will be required for accurately assessing visual function in the ZSD population, including measures of functional vision.