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Defects in PEX3 are associated with a severe neonatal-lethal form of Zellweger spectrum disorder. We report two moderately affected siblings whose clinical and biochemical phenotypes expand the reported spectrum of PEX3-related disease. Genome sequencing of an adolescent male with progressive movement disorder, spasticity and neurodegeneration, and previous non-diagnostic plasma very-long chain fatty acid analysis, revealed a homozygous likely pathogenic missense variant in PEX3 [c.991G > A; p.(Gly331Arg)]. A younger sibling with significant motor decline since the age of three years was also subsequently found to be homozygous for the familial PEX3 variant. A comprehensive review of the scientific literature identified three additional families with non-lethal infantile- or childhood-onset PEX3-related disease, which together with this clinical report illustrate the potential for highly variable disease severity. Our findings demonstrate the diagnostic utility of genome-wide sequencing for identifying clinically and biochemically heterogeneous inherited metabolic disorders such as the peroxisome biogenesis disorders.

Zellweger spectrum disorders (ZSD) are rare, debilitating genetic diseases of peroxisome biogenesis that affect multiple organ systems and present with broad clinical heterogeneity. Although many case studies have characterized the multitude of signs and symptoms associated with ZSD, there are few reports on the prevalence of symptoms to help inform the development of meaningful endpoints for future clinical trials in ZSD. In the present study, we used an online survey tool completed by family caregivers to study the occurrence, frequency and severity of symptoms in individuals diagnosed with ZSD. Responses from caregivers representing 54 living and 25 deceased individuals with ZSD were collected over an 8-month period. Both perception of disease severity and prevalence of various symptoms were greater in responses from family caregivers of deceased individuals compared to those of living individuals with ZSD. Compared with previous reports for ZSD, the combined prevalence of seizures (53%) and adrenal insufficiency (45%) were nearly twice as high. Overall, this community-engaged approach to rare disease data collection is the largest study reporting on the prevalence of symptoms in ZSD, and our findings suggest that previous reports may be underreporting the true prevalence of several symptoms in ZSD. Studies such as this used in conjunction with clinician- led reports may be useful for informing the design of future clinical trials addressing ZSD.

Zellweger spectrum disorders (ZSD) are rare, debilitating genetic diseases of peroxisome biogenesis that affect multiple organ systems and present with broad clinical heterogeneity. Although many case studies have characterized the multitude of signs and symptoms associated with ZSD, there are few reports on the prevalence of symptoms to help inform the development of meaningful endpoints for future clinical trials in ZSD. In the present study, we used an online survey tool completed by family caregivers to study the occurrence, frequency and severity of symptoms in individuals diagnosed with ZSD. Responses from caregivers representing 54 living and 25 deceased individuals with ZSD were collected over an 8-month period. Both perception of disease severity and prevalence of various symptoms were greater in responses from family caregivers of deceased individuals compared to those of living individuals with ZSD. Compared with previous reports for ZSD, the combined prevalence of seizures (53%) and adrenal insufficiency (45%) were nearly twice as high. Overall, this community-engaged approach to rare disease data collection is the largest study reporting on the prevalence of symptoms in ZSD, and our findings suggest that previous reports may be underreporting the true prevalence of several symptoms in ZSD. Studies such as this used in conjunction with clinician- led reports may be useful for informing the design of future clinical trials addressing ZSD., (© 2020 The Author(s).)

Zellweger spectrum disorders (ZSDs) are rare, debilitating genetic diseases of peroxisome biogenesis that require constant management and lifelong care. Nevertheless, the experience of family caregivers for children diagnosed with ZSD is not well understood. In this study, we sought to characterize the emotional experience of ZSD family caregivers. Three 90-min focus groups were conducted with thirty-seven parents (25 mothers and 12 fathers) of children with ZSD during a family advocacy conference. Focus groups were arranged by age of proband (Group 1: 0-4 years, Group 2: 5-10 years, Group 3: >11 years). Audio recordings of focus groups were transcribed and analyzed using software for coding purposes. Analyzed content was validated using peer debriefing, member checking, and method triangulation. Focus group results showed that nearly a third of ZSD caregivers described their overall emotional experience as a "rollercoaster." Additionally, three interconnected themes were identified: 1) range of emotions, 2) stressors, and 3) coping. Feeling overwhelmed and devastated were the most frequently described emotional responses. Corresponding stressors to these emotions included the burden of caregiver tasks associated with ZSD, and negative interactions with healthcare professionals. The most common coping strategies were acceptance of limitations of the diseases, redefining "normal" in the parenting experience, and advocating on behalf of the child and the patient community. This study underscores the profound emotional impact on parents who are caregivers for children with ZSDs, highlighting the utility of patient community feedback and qualitative approaches to fully characterize the overall family experience. Simple, targeted approaches focusing on improved communication between healthcare professionals and families, as well as offering resources for emotional support may greatly improve the lives of families living with ZSD and other rare pediatric diseases.