Zellweger disorder

Disorders affecting the import pathways to mitochondria, peroxisomes, and the nucleus (e.g., mutations in the peroxisomal Pex proteins leading to Zellweger syndrome). 

Fatal hereditary disorder that typically presents in the neonatal period. Clinical features include an array of hepatic, renal and neurological dysfunctions. Patients with Zellweger syndrome rarely survive the first year of life. The disease is caused by mutations in the Pex proteins leading to an defective import of peroxisomal matrix proteins and consequently to a loss of most peroxisomal metabolic pathways. 

Table 41-4 shows that nine of the 12 Zellweger spectrum disorders show a considerable range of severity of clinical manifestations. Clinical and biochemical studies do not correlate with the type of gene defect. There is, however, considerable correlation between the severity of clinical manifestations and the degree to which a specific mutation compromises import function in vitro. For example in PEX1 deficiency, 75% of patients with the G843D allele, in which import is 15% retained, had the relatively mild IRD phenotype, compared to those with the C.2097insT, which abolishes import completely, where only 13% had the IRD phenotype. Such correlations also exist in patients with the PEX 7 defect [ 10]. 

Bifunctional protein deficiency. The enzyme defect involves the D-bifunctional protein. This enzyme contains two catalytic sites, one with enoyl-CoA hydratase activity, the other with 3-hydroxyacyl-CoA activity [13]. Defects may involve both catalytic sites or each separately. The severity of clinical manifestations varies from that of a very severe disorder that resembles Zellweger s syndrome clinically and pathologically, to somewhat milder forms. Table 41-6 shows that biochemical abnormalities involve straight chain, branched chain fatty acids and bile acids. Bifunctional deficiency is often misdiagnosed as Zellweger s syndrome. Approximately 15% of patients initially thought to have a PBD have D-bifunctional enzyme deficiency. Differential diagnosis is achieved by the biochemical studies listed in Table 41-7 and by mutation analysis. 

Barth, P. G., Majoie, C. B., Gootjes, J. et al. Neuroimaging of peroxisome biogenesis disorders (Zellweger spectrum) with prolonged survival. Neurology 62 439-444, 2004. 

Zellweger syndrome Is a llpid storage disorder caused by impaired peroxisome biogenesis due to deficiency or functional defect of one of eleven proteins involved in the complex mechanism of peroxisomal matrix protein import and assembly of the organelle. 

The essential amino acid lysine (2,5-diaminohexanoic acid) can be degraded via two pathways, viz. the so-called saccharopine pathway and the pipecolic acid (PA) pathway. Both pathways merge at the level of a-aminoadipic acid semialdehyde (AASA). It is generally accepted that the saccharopine pathway constitutes the major breakdown pathway. However, the PA pathway has attracted much attention since the discovery of the association between the presence of elevated PA levels and Zellweger syndrome almost 40 years ago. Mainly because the analysis of amino acids was the primary biochemical approach for studying presumed inborn errors of metabolism, PA in Zellweger syndrome was discovered even before it was realized that this disorder was based on a defect of peroxisomal functions. 

Table 3.4.1 Levels of very-long-chain fatty acids (VLCFA), pristanic acid and phytanic acid in the different peroxisomal disorders. AMACR 2-methyl acyl-CoA racemase, N normal, RCDP rhizomelic chondrodysplasia punctata, SCP-x sterol carrier protein, ZSDs Zellweger spectrum disorders,...

Peroxisomal disorders (Zellweger syndrome, Refsum s disease, neonatal adre-noleukodystrophy) are characterised by defective peroxisome biogenesis, or, being present, peroxisomes lacking / -oxidative enzymes. In the BA biosynthetic pathway, dihydroxycoprostanic acid (DHCA) and trihydroxycoprostanic acid (THCA) are /1-oxidised in peroxisomes to produce CA and CDCA, respectively, whereas peroxisomal disorders cause a defective oxidation of the BA precursor side chain, which leads to an accumulation of C27 bile acids, notably 3 ,7 -dihydroxy-5/3-cholesta-noic acid (DHCA) and 3a,7a,12a-trihydroxy-5/l-cholestanoic acid (THCA), in the plasma and urine of affected patients. 

Several genetic diseases involve the development of peroxisomes.14/35/58/59 Most serious is the Zellweger syndrome in which there are no functional peroxisomes. Only "ghosts" of peroxisomes are present and they fail to take up proteins containing the C-terminal peroxisome-targeting sequence SKL.60/60a There are many symptoms and death occurs within the first year. Less serious disorders include the presence of catalaseless peroxisomes.603... 

The elevation of VLCFA can be detected in most body tissues and fluids and forms the basis for a diagnostic assay for the identification of affected individuals.The most frequently used test is the measurement of VLCFA in plasma which has been shown to be very sensitive. Although VLCFA are increased in some of the other peroxisomal disorders, including Zellweger syndrome, infantile Refsum disease, and neonatal ALD, the clinical presentations of these disorders are very different from X-ALD, and the discrimination of... 

Peroxisomal disorders of bile acid synthesis, both in the side-chain decomposition process and at the steroid ring, can cause atrophy of the small bile ducts. This gives rise to Zellweger s syndrome with asyndromic bile-duct hypoplasia. (513) (s. pp 234, 603) (s. tabs. 13.3, 13.4)... 

Three genetic disorders Zellweger s syndrome, neonatal adrenoleukodystrophy, and childhood adrenoleukodys-trophy) exhibit defective formation of peroxisomes (in Zellweger s syndrome no morphologically detectable peroxisomes are present) or deficiency of one or more constituent enzymes. All three disorders are characterized by a marked accumulation of very long chain, saturated, unbranched fatty acids (tetracosanoic and hexacosanoic acids) in liver and central nervous system tissues, severe neurological symptoms, and early death. 

Faust PL, Hatten ME. Targeled deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder. J Cell Biol 1997 139(5) 1293-1305. 

Zellweger H. The cerebro-hepato-renal (Zellweger) syndrome and other peroxisomal disorders. Dev Med Child Neurol 1987 29(6) 821-829. 

Information concerning the relative importance of metabolic pathways may be obtained from studies on inborn errors of metabolism. Two such disorders affecting bile acid biosynthesis have been described, cerebrotendinous xanthomatosis (CTX) and Zellweger s disease (cerebro-hepato-renal syndrome). The primary defect in cerebrotendinous xanthomatosis seems to be the absence of one enzyme involved in bile acid biosynthesis. The basic defect in Zellweger s disease has not yet been defined with certainty. 

Autosomal recessive mutations that cause defective peroxisome assembly occur naturally in the human iU population. Such defects can lead to severe impairment of many organs and to death. In Zellweger syndrome and related disorders, for example, the transport of many or all proteins into the peroxisomal matrix is impaired newly synthesized peroxisomal enzymes remain in the cytosol and... 

Faust, P.L., and Hatten, M.E. (1997) Targeted Deletion of the PEX2 Peroxisome Assembly Gene in Mice Provides a Model for Zellweger Syndrome, a Human Neuronal Migration Disorder. 7. Cell. Biol. 139.1293-1305. 

Wanders, R.J.A., van Roermund, C.W.T, van Wijland, M.J.A., Schutgens, R.B.H., Heikoop, J., van der Bosch, H., Schram, AW. Tager, J.M. (1987) J. Clin. Invest, 80, 1778-1783. Peroxisomal fatty acid beta-oxidation in relation to the accumulation of very long chain fatty acids in cultured skin fibroblasts from patients with Zellweger syndrome and other peroxisomal disorders. 

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