Zellweger Syndrome


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Introduction to Zellweger Syndrome

Zellweger syndrome (ZWS) is a disorder that is a member of a family of disorders that result from defects in the biogenesis and/or functioning of the peroxisomes and are referred to as peroxisome biogenesis disorders, PBDs. Although there are characteristic clinical features to Zellweger syndrome, this disorder is not due to defects in a single gene. In fact, at least twelve different loci have been associated with the development of Zellweger syndrome and the closely related Zellweger syndrome spectrum (ZSS) disorders. These loci include:

the PEX1 gene on chromosome 7q21.2; mutations in the PEX1 gene are the most common associated with Zellweger syndrome

the PEX2 gene on chromosome 8q21.1; the PEX2 gene is also known as the peroxisomal membrane protein 3, PXMP3

the PEX3 gene on chromosome 6q24.2; encodes a critical protein involved in targeting of proteins to the peroxisomal membrane

the PEX5 gene on chromosome 12p13.31; this gene encodes the receptor for proteins containing a PTS1 sequence for targeting to the peroxisomes, see below

the PEX6 gene on chromosome 6p21.1: functions with PEX5 encoded proteins in PTS1-containing protein targeting to peroxisomes

the PEX10 gene on chromosome 1p36.32

the PEX12 gene on chromosome 17q12

the PEX13 gene on chromosome 2p15

the PEX14 gene on chromosome 1p36.22; functions to interact with PEX5 encoded proteins that are bound to a PTS1-containing protein

the PEX16 gene on chromosome 11p11.2

the PEX19 gene on chromosome 1q23.2

the PEX26 gene on chromosome 22q11.21; encoded protein anchors PEX1p and PEX6p to the peroxisomal membrane

another undefined locus on chromosome 7q11.

Zellweger syndrome was first described in 1964 by Hans Zellweger and represents the prototypical PBD. Several related, but milder forms of PBDs, are now classified as the Zellweger syndrome spectrum disorders. These other diseases are neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). Zellweger syndrome represents the extreme of the clinical manifestation of peroxisome biogenesis dysfunction with patients rarely surviving their first year of life. Zellweger syndrome is associated with either severe, moderate or mild defects in all peroxisome functions. An additional phenotypic spectrum in PBDs is represented by rhizomelic chondrodysplasia punctata, RCDP. RCDP is distinguished from the Zellweger spectrum PBDs by manifesting with more severe skeletal involvement as well as specific biochemical characteristics.

The peroxisomes are a single membrane organelle, similar to lysosomes, present in virtually all eukaryotic cells. The peroxisome is a specialized enzyme "factory" that contains in excess of 50 different enzymes involved in a variety of metabolic processes including β-oxidation of very long chain fatty acids, α-oxidation of fatty acids and synthesis of ether-lipids. Proteins that are involved in and necessary for correct peroxisome biogenesis are called peroxins (PEX). At least 15 PEX genes have been identified in humans. Enzymes that are targeted to the peroxisomes contain either of two amino acid consensus elements called peroxisome targeting sequences (PTS). The PTS1 is a C-terminal consensus sequence of –[S/A/C][K/R/H][L/M] referred to as the SKL motif. This sequence element is recognized by a cytosolic PTS1 receptor encoded by the PEX5 gene. There are two isoforms of PEX5 encoded proteins in humans identified as Pex5pS and Pex5pL (for short and long forms, respectively). The Pex5pL protein has an internal 37 amino acid insertion, hence the "long" designation. The PTS2 is an N-terminal consensus sequence of –[R/K][L/V/I/Q]XX[L/V/I/H/Q][L/S/G/A/K]X[H/Q][L/A/F]–, (where X represents any amino acid). The PTS2 receptor is encoded by the PEX7 gene and the encoded protein is referred to as Pex7p. Proteins that are targeted to the membrane of the peroxisome (called peroxisome membrane proteins, PMPs) contain a consensus sequence identified as the PEX19 binding site (PEX19BS) and this site is recognized by the membrane protein receptor encoded by the PEX19 gene.

Pex5pS, Pex5L, and Pex7p interact with newly synthesized target proteins in the cytosol and direct them to the peroxisome. On the membrane of the peroxisome is a component of the protein import machinery encoded by the PEX14 gene called Pex14p. Following interaction of Pex5pS or Pex5pL, bound to a protein containing a PTS1 sequence, with Pex14p, the PTS1 containing protein is transferred into the peroxisome. The activity of Pex7p in peroxisome protein import actually requires Pex5pL as well. PTS2 containing proteins interact with Pex7p and then, in conjunction with Pex5pL, the complex interacts with Pex14p and the PTS2 containing protein is transferred into the peroxisome. Very few proteins contain a PTS2 sequence but one enzyme of note is phytanoyl-CoA hydroxylase (PHYH) which is defective in classic Refsum disease.

Clinical Features of ZWS

Classic Zellweger syndrome is a neonatal presenting severe disorder. Zellweger syndrome is also known as cerebrohepatorenal syndrome. The involvement of the liver in ZWS is characterized by hepatic cysts and overall hepatic dysfunction contributing to elevations of copper and iron in the blood. In addition to the liver pathology the function of the kidneys is also impaired. The most common clinical manifestations of ZWS include a series of characteristic craniofacial abnormalities. These defects include hypoplastic supraorbital ridges, epicanthal folds, a small nose with anteverted nares, a broad nasal bridge, full forehead, and large anterior fontanelle.

In the severe neonatal presenting form of ZWS, infants display severe hypotonia, weakness, and seizures. These latter symptoms, in association with the facial deformities, can lead to a diagnosis of Down syndrome. Due to the lack of proper peroxisomal lipid metabolism very long-chain fatty acids and various branched-chain fatty acids accumulate in the tissues impairing their functions. Since the peroxisomes are also important in ether phospholipid and plasmalogen synthesis, which are critical lipids in brain function, there is progressive impairment of neuronal migration and neuronal positioning as well as decreased myelin production. The loss of myelin, which is associated with white matter in the brain, leads to leukodystrophy. ZWS infants also have characteristic ocular defects including cataracts, glaucoma, corneal clouding, and optic nerve dysplasia. The optic nerve dysplasia results from the loss of myelination.

Definitive diagnosis of ZWS is commonly accomplished through measurement of the levels of plasma very long-chain fatty acids. Most common observations are increased levels of C26:0 (hexacosanoic acid; also called cerotic acid) and C26:1 (hexacosenoic acid). In addition, increases in the ratios of C24/C22 and C26/C22 fatty acids is indicative of a defect in peroxisomal fatty acid metabolism. The accumulating branched-chain fatty acids include phytanmic and pristanic acid.

 

 

 

 

 

 

 

 

 

 

 


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Michael W King, PhD | © 1996–2017 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

Last modified: July 25, 2017