Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives

Abstract

The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 PEX genes; defects in 14 of these have been shown to cause PBD. Three broad phenotypic groups are described on a spectrum of severity: Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate and infantile Refsum disease is less severe. Another group is Rhizomelic chondrodysplasia punctata spectrum. Recently, atypical phenotypes have been described, indicating that the full spectrum of these disorders remains to be identified. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome functions and PEX gene sequencing. There are no targeted therapies, although management protocols have been suggested and research endeavors continue. In this review we will discuss peroxisome biology and PBD, and research contributions to pathophysiology and treatment.

Pex35 is a regulator of peroxisome abundance

“…It is not surprising therefore that malfunction of peroxisomes leads to peroxisome-specific diseases (Braverman et al, 2013;Weller et al, 2003) and contributes to the pathology of Alzheimer's and Parkinson's diseases, aging, cancer, type 2 diabetes and heart failure (Beach et al, 2012;Colasante et al, 2015;Fransen et al, 2013;Islinger et al, 2012;Trompier et al, 2014). A useful distinction divides peroxisomal diseases into two groups: those in which single enzymatic functions are defective, and those where peroxisome biogenesis is defective per se.…”

Unique double-ring structure of the peroxisomal Pex1/Pex6 ATPase complex revealed by cryo-electron microscopy

“…In these diseases, proteins fail to be imported from the cytosol into peroxisomes. Affected children have neurodevelopmental defects and multisystemic symptoms, including hepatic dysfunction, and they often die before puberty (31). Pex1 and Pex6 have also been implicated in the fusion of peroxisome precursor vesicles (32)(33)(34).…”

Severe early onset retinitis pigmentosa in a Moroccan patient with Heimler syndrome due to novel homozygous mutation of PEX1 gene

“…and rhizomelic chondrodysplasia punctata (OMIM: 215100), which is not necessarily more slowly progressive than Zellweger (Zeharia et al, 2007;Regal et al, 2010;Ebberink et al, 2011). These conditions are characterized by a wide phenotypic pleiotropy, including leukodystrophy, developmental delay, seizures, peripheral neuropathy, SNHL, retinopathy, skeletal and craniofacial abnormalities and other organ damage (liver, heart, kidneys) (Braverman et al, 2013). Clinical manifestations are variable from severe, early-childhood lethal Zellweger syndrome to milder more slowly progressive phenotypes in rhizomelic chondroplasia punctata (Motley et al, 2002;Ebberink et al, 2011).…”