Clinical bottom line
Rare inherited disorders of peroxisomal biogenesis and function, collectively termed peroxisome biogenesis disorders (PBDs), represent a heterogeneous group of multisystem diseases with variable severity and onset. These disorders, including neonatal adrenoleukodystrophy and Zellweger spectrum disorders, are characterized by defective peroxisome assembly leading to impaired metabolism of very-long-chain fatty acids, plasmalogens, and other substrates. Clinical manifestations range from severe neonatal presentations with craniofacial dysmorphism and profound neurological impairment to milder, later-onset phenotypes. Diagnosis relies on biochemical assays and genetic testing, while management remains largely supportive and symptomatic, emphasizing multidisciplinary care. Emerging insights into disease mechanisms and lipidomic profiles may inform future therapeutic strategies but currently no curative treatments exist (Nyhan et al., 2020; Shimozawa et al., 2019).
What the evidence shows
Peroxisomal disorders arise from mutations in PEX genes responsible for peroxisome biogenesis, leading to a spectrum of clinical phenotypes collectively known as Zellweger spectrum disorders (ZSDs), including neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (Wanders et al., 2004). The severity correlates with residual peroxisomal function, with the most severe forms presenting in the neonatal period with hypotonia, seizures, hepatomegaly, and characteristic craniofacial features (Nyhan et al., 2020). Biochemically, patients exhibit elevated plasma very-long-chain fatty acids (VLCFAs), deficient plasmalogens, and impaired bile acid synthesis (Shimozawa et al., 2019).
Diagnosis integrates clinical suspicion with biochemical screening, including VLCFA quantification and plasmalogen levels, followed by confirmatory molecular genetic testing (Shimozawa et al., 2019). Advances in lipidomics have refined understanding of peroxisomal lipid metabolism abnormalities, potentially aiding diagnosis and monitoring (Hama et al., 2019). Neuroimaging often reveals leukodystrophy patterns consistent with peroxisomal leukodystrophy, contributing to differential diagnosis (Poggi-Travert et al., 1995).
Management is predominantly supportive, addressing feeding difficulties, seizures, hearing and vision impairment, and adrenal insufficiency when present. Multidisciplinary care involving neurology, metabolic specialists, nutritionists, and rehabilitation services is essential (Nyhan et al., 2020). Experimental approaches, such as dietary restriction of VLCFAs and supplementation with docosahexaenoic acid, have shown limited and inconsistent benefit (Wanders et al., 2004). Hematopoietic stem cell transplantation and gene therapy remain investigational.
Caveats and uncertainty
The rarity and phenotypic heterogeneity of PBDs complicate natural history characterization and clinical trial design. Many published data derive from case series and retrospective cohorts, limiting generalizability. Biochemical markers can overlap with other peroxisomal and non-peroxisomal disorders, necessitating comprehensive diagnostic evaluation (Shimozawa et al., 2019). The lack of disease-modifying therapies underscores the need for further research into pathophysiology and therapeutic targets.
Lipidomic profiling, while promising, requires validation in larger cohorts to establish clinical utility. The variable expressivity and incomplete genotype-phenotype correlations challenge prognostication and counseling (Hama et al., 2019). Current management guidelines are consensus-based rather than evidence-driven due to limited clinical trial data.
How this may change practice
Heightened awareness of PBDs among clinicians can facilitate earlier diagnosis through targeted biochemical and genetic testing, enabling timely supportive interventions. Incorporation of advanced lipidomic assays may enhance diagnostic accuracy and disease monitoring as these technologies become more accessible. Multidisciplinary care models should be prioritized to address the complex multisystem involvement.
Ongoing research into molecular mechanisms and peroxisomal lipid metabolism may yield novel biomarkers and therapeutic candidates. Clinicians should remain alert to emerging clinical trials and experimental therapies to offer patients potential access under appropriate protocols. Genetic counseling remains a critical component for affected families given the autosomal recessive inheritance pattern.