Therapeutic developments in peroxisome biogenesis disorders

Abstract

Clinically, peroxisome biogenesis disorders (PBDs) are a group of lethal diseases with a continuum of severity of clinical symptoms ranging from the most severe form, Zellweger syndrome, to the milder forms, infantile Refsum disease and rhizomelic chondrodysplasia punctata. PBDs are characterised by a number of biochemical abnormalities including impaired degradation of peroxide, very long chain fatty acids, pipecolic acid, phytanic acid and xenobiotics and impaired synthesis of plasmalogens, bile acids, cholesterol and docosahexaenoic acid. Treatment of PBD patients as a group is problematic since a number of patients, especially those with Zellweger syndrome, have significant neocortical alterations in the brain at birth so that full recovery would be impossible even with postnatal therapy. To date, treatment of PBD patients has generally involved only supportive care and symptomatic therapy. However, the fact that some of the milder PBD patients live into the second decade has prompted research into possible treatments for these patients. A number of experimental therapies have been evaluated to determine whether or not correction of biochemical abnormalities through dietary supplementation and/or modification is of clinical benefit to PBD patients. Another approach has been pharmacological induction of peroxisomes in PBD patients to improve overall peroxisomal biochemical function. Well known rodent peroxisomal proliferators were found not to induce human peroxisomes. Recently, our laboratory demonstrated that sodium 4-phenylbutyrate induces peroxisome proliferation and improves biochemical function (very long chain fatty acid β-oxidation rates and very long chain fatty acid and plasmalogens levels) in fibroblast cell lines from patients with milder PBD phenotypes. Dietary supplementation and/or modification and pharmacological induction of peroxisomes as treatment strategies for PBD patients will be the subject of this review.

• 4-phenylbutyrate
• infantile Refsum disease
• neonatal adrenoleukodystrophy
• peroxisome
• peroxisome biogenesis disorder
• therapy
• Zellweger syndrome