Peroxisome biogenesis disorders.

Abstract

Peroxisome biogenesis disorders (PBD) are a group of conditions caused by a partial or generalized defect in peroxisome biogenesis. They encompass two phenotypic groups: 1. the Zellweger spectrum disorders (ZSD) including severe, intermediate and milder forms [previously known respectively as Zellweger syndrome (ZS), Neonatal Adrenoleukodystrophy (NALD) and Infantile Refsum Disease (IRD)] and 2. Rhizomelic Chondrodysplasia Punctata type 1 (RCDP1), as well as the variant phenotypes now being described for both groups. PBD represent the paradigm for metabolic malformation syndromes. In a little over 50 years, an intense, concerted multidisciplinary effort has led to elucidating the fundamental biochemical, pathophysiological and molecular bases for these disorders effectively paving the way for therapeutic interventions and trials. Peroxisomes are membrane bound organelles derived from the endoplasmic reticulum, numbering up to several hundred per mammalian cell, mostly spherical in shape, up to 1μm in diameter. They are indispensable for normal life and highly conserved throughout evolution amongst most eukaryotes. Peroxisomes were first identified by biochemist Christian DeDuve in the 1960 s, as cytoplasmic particles containing hydrogen peroxide-generating oxidases [1]. Later, the neurologist Hans Zellweger reported a group of children with similar craniofacial dysmorphism and malformations in the brain, eye, liver, and kidney [2]. These cases, initially described under the eponym of “cerebro-hepato-renal-syndrome”, were subsequently termed Zellweger syndrome (ZS) [3]. ZS is considered today the prototype for ZSD. The reported absence of morphologically identifiable peroxisomes in hepatocytes and renal tubular cells of affected individuals using the peroxisomal matrix enzyme marker, catalase, [4] demonstrated a connection between ZS and peroxisome dysfunction. However, the etiological connection was not recognized until the identification of multiple peroxisomal enzymes and their deficiencies in affected patients. Similar findings were later demonstrated in the intermediate and milder ZSD phenotypes and RCDP1, which were also being reported at that time [5–7].