Disorders of peroxisome assembly

Steven J Steinberg PhD (Dr. Steinberg of Johns Hopkins University School of Medicine has no relevant financial relationships to disclose.)
Nancy E Braverman MD (Dr. Braverman of the Institute for Genetic Medicine at Johns Hopkins University School of Medicine has no relevant financial relationships to disclose.)
Raphael Schiffmann MD, editor. (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released December 28, 1993; last updated August 9, 2007; expires August 9, 2010
Notice: This article has expired and is therefore not available for CME credit.

This article includes discussion of disorders of peroxisome assembly, peroxisomal polyenzymopathies, group 1 peroxisomal disorders, disorders of peroxisome biogenesis, generalized peroxisomal disorders, disorders of peroxisome assembly, Zellweger syndrome, cerebrohepatorenal syndrome, neonatal adrenoleukodystrophy, and rhizomelic chondrodysplasia punctata. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

The peroxisome biogenesis disorders are a heterogeneous group of rare autosomal recessive diseases. The underlying defect is the failure to form functional peroxisomes, resulting in deficiencies of multiple enzymes targeted to this organelle and progressive, multisystem diseases. Two clinical categories of disease are distinguished, Zellweger spectrum and Rhizomelic chondrodysplasia punctata spectrum. The authors describe the 2 clinical spectra of peroxisome assembly defects and highlight the marked strides in understanding the molecular pathology made over the past decade.

Historical note and terminology

Microbodies were first described in mouse kidney by Rhodin in 1958. Purified microbodies from rat liver were active in peroxide-linked oxidation reactions, leading to the name "peroxisomes" (Lazarow and Moser 1995). The ubiquitous presence of these single-membraned organelles, their role in fatty acid oxidation, and their absence in patients with Zellweger syndrome (Goldfischer et al 1973) stimulated interest in peroxisome biology. A reliable assay for peroxisome dysfunction based on elevated serum very long-chain fatty acids defined a new category of human metabolic disease (Moser et al 1999).

The peroxisome biogenesis disorders may affect the brain, retina, craniofacies, kidney, and skeleton (Zellweger 1987; Brown et al 1993; Lazarow and Moser 1995). The failure to assemble normal peroxisomes and the impaired ability to import peroxisome matrix proteins result in multiple deficiencies of peroxisomal enzymes. Disorders of peroxisome assembly can be divided into 2 classes: the Zellweger syndrome spectrum and rhizomelic chondrodysplasia punctata. Zellweger spectrum is defined by the clinical disorders of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. These disorders were described before the relationship to peroxisome deficiency was known and thus the terms do not relate directly to the underlying gene defect.

In order to determine the genes involved in the peroxisome biogenesis disorders, patient fibroblast cell lines were collected and fused for biochemical complementation. This approach defined at least 13 complementation groups, each predicted to represent a different gene defect (Moser et al 1995). Many PEX genes were subsequently identified by screening human cDNA libraries (Dodt et al 1996). PEX genes encode proteins referred to as peroxins. In sum, 12 PEX genes are associated with Zellweger spectrum disorders (Steinberg et al 2004). In contrast, rhizomelic chondrodysplasia type 1 is associated exclusively with a defect in the PEX7 gene (Braverman et al 1997).

A variety of historic labels have been ascribed to the Zellweger spectrum (cerebrohepatorenal syndrome, hyperpipecolic acidemia). In addition, some patients initially diagnosed with Usher syndrome or Leber congenital amaurosis were later shown to have assembly defects (Ek et al 1986; Raas-Rothschild et al 2002).

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