Zellweger Spectrum Disorders: Beyond the Peroxisome

Zellweger spectrum disorders (ZSDs) are rare autosomal recessive peroxisomal biogenesis disorders caused by pathogenic variants in PEX genes encoding peroxins, proteins essential for peroxisome assembly, maintenance, and matrix protein import.Defective peroxisome biogenesis disrupts multiple metabolic pathways, resulting in accumulation of very-long-chain fatty acids (VLCFAs), phytanic and pristanic acids, pipecolic acid, and bile acid (BA) intermediates, together with impaired plasmalogen and docosahexaenoic acid (DHA) synthesis.These biochemical abnormalities produce a severe multisystem disorder involving the central nervous system, liver, kidneys, eyes, ears, adrenal glands, and skeleton.Clinical manifestations range from the classic neonatal Zellweger syndrome with profound hypotonia, refractory seizures, feeding difficulties, hepatic dysfunction, characteristic craniofacial features, and early mortality, to milder phenotypes that survive into childhood or adulthood.This review summarizes current knowledge regarding the epidemiology, molecular genetics, pathophysiology, developmental biology, and evolutionary conservation of peroxisomes, emphasizing the pivotal roles of peroxins, particularly peroxin 5 (PEX5), in peroxisomal protein import.Recent advances in understanding neuronal migration defects, oligodendrocyte maturation, microglial dysfunction, oxidative stress, mitochondrial-peroxisomal interactions, epigenetic regulation, and non-coding RNA (ncRNA) responses are discussed to provide an integrated view of disease mechanisms.Characteristic laboratory abnormalities, neuroimaging findings, ultrastructural changes, and molecular diagnostic strategies are reviewed, together with emerging concepts including uniparental disomy (UPD), genotype-phenotype correlations, and phylogenetic conservation of PEX genes.Although treatment remains largely supportive and multidisciplinary, improvements in biochemical testing, next-generation sequencing, newborn diagnosis, and comprehensive clinical care have expanded recognition of milder disease and improved long-term outcomes for selected patients.Continued advances in molecular biology, systems genomics, and targeted therapeutic development are expected to refine diagnosis, enhance prognostic assessment, and provide opportunities for future disease-modifying interventions in this complex group of inherited peroxisomal disorders.