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  • Updated 01.16.2021
  • Released 12.28.1993
  • Expires For CME 01.16.2024

Disorders of peroxisome assembly and function



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 author describes the two clinical spectra of peroxisome assembly defects and highlights the marked strides in understanding the molecular pathology. In addition, the author reviews some commonly confused single enzyme peroxisomal disorders.

Key points

Peroxisomal assembly and biogenesis disorder can present with:

• Neuronal abnormalities (ie, migration defects and germinal cysts, polyneuropathy, ataxia, and leukodystrophy)

• Retinal abnormalities (ie, dystrophy) and hearing loss (sensorineural)

• Bone formation abnormalities

• Liver dysfunction

• Nonfamilial features (including high forehead, epicanthal folds, micrognathia, very large fontanelles, and shallow supraorbital ridges)

• Age of onset often corresponds with severity.

Historical note and terminology

Peroxisomes are single-layer lipid biolayer organelles found in the cytosol that play a role in beta oxidation and reduction of reactive oxygen species, among other things, by their ability to contain oxidases and catalase.

Microbodies were first described in mouse kidney by Rhodin in 1958, and these purified microbodies from rat liver were then found to be active in peroxide-linked oxidation reactions, leading to the name "peroxisomes" (31). The ubiquitous presence of these single-membraned organelles, their role in fatty acid oxidation, and their absence in patients with Zellweger syndrome (23) 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 (37).

The failure to assemble normal peroxisomes and the impaired ability to import peroxisome matrix proteins result in multiple deficiencies of peroxisomal enzymes (peroxisome biogenesis and assembly disorder). Disorders of peroxisome assembly can be divided into 2 classes: the Zellweger syndrome spectrum and rhizomelic chondrodysplasia punctata. The peroxisome biogenesis disorders may affect the brain, retina, craniofacies, kidney, and skeleton (64; 12; 31).

Zellweger spectrum is defined by the clinical disorders of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease and is characterized as severe, intermediate, and mild. These disorders were described before the relationship to peroxisome deficiency was known; thus, the terms do not relate directly to the underlying gene defect.

The genes associated with these disorders are referred to as the PEX genes. 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 (38). Many PEX genes were subsequently identified by screening human cDNA libraries (18). PEX genes encode proteins referred to as peroxins. In sum, 12 PEX genes are associated with Zellweger spectrum disorders (ranging from mild to severe in phenotype) (53; Steinberg et al 2019). In contrast, rhizomelic chondrodysplasia type 1 is associated exclusively with a defect in the PEX7 gene (10).

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 due to their physical characteristics but were later shown to have assembly defects (20; 47). Others have been diagnosed with Krabbe disease, spinal muscular atrophy type 1 (06), or Prader-Willi syndrome due to their severe hypotonia and were found to have peroxisomal disorders. Still others were initially thought to have Down syndrome based on facial features and decreased tone until normal karyotype was obtained and further testing done.

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