Peroxisome Biogenesis Disorders-
Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms. In patients with PBD-ZSD, pathogenic variants in the PEX family of genes disrupt normal peroxisomal function, impairing α- and β-oxidation of very-long-chain
fatty acids and synthesis of
bile acids, resulting in increased levels of toxic
bile acid intermediates and multisystem organ damage. The spectrum of severity in PBD-ZSD is variable, with some patients dying in the first year of life, while others live into adulthood. Symptoms of mild PBD-ZSD include various combinations of developmental delay, craniofacial dysmorphic features,
visual impairment,
sensorineural hearing loss,
liver disease, and
adrenal insufficiency.
Disease progression in mild PBD-ZSD is generally slow, and may include extended periods of stability in some cases. The presence and extent to which symptoms occur in mild PBD-ZSD represents a diagnostic challenge that can cause delays in diagnosis with potential significant implications related to disease monitoring and treatment. There is some support for the pharmacologic
therapies of
Lorenzo's oil, docosohexanoic
acid, and
batyl alcohol in altering symptoms; however, systematic long-term studies are lacking.
Cholic acid (CA)
therapy has demonstrated treatment efficacy in patients with PBD-ZSD, including decreased toxic
bile acid intermediates,
transaminase levels, and liver
inflammation, with improvement in growth parameters. However, these responses are most apparent in patients diagnosed and treated at a young age. Advanced
liver disease may limit the efficacy of CA, underscoring the need to diagnose and treat these patients before significant liver damage and other related complications occur. Here we discuss the signs and symptoms of PBD-ZSD in patients with mild disease, standard diagnostic tools, factors affecting disease management, and available pharmacological interventions.