Zellwegers disease

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. 

IRD, infantile Refsum s disease NALD, neonatal adrenoleukodystrophy ZS, Zellweger s syndrome. 

Zellweger-spectrum-like Late onset neuropathy Refsum s disease... 

Enzyme defects are also known to exist in the minor pathways of fatty acid degradation. In Refsum disease, the methyl-branched phytanic acid (obtained from vegetable foods) cannot be degraded by a-oxidation. In Zellweger syndrome, a peroxisomal defect means that long-chain fatty acids cannot be degraded. 

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. 

A second important difference between mitochondrial and peroxisomal fi oxidation in mammals is in the specificity for fatty acyl-CoAs the peroxisomal system is much more active on very-long-chain fatty acids such as hexacosanoic acid (26 0) and on branched-chain fatty acids such as phytanic acid and pristanic acid (see Fig. 17-17). These less-common fatty acids are obtained in the diet from dairy products, the fat of ruminant animals, meat, and fish. Their catabolism in the peroxisome involves several auxiliary enzymes unique to this organelle. The inability to oxidize these compounds is responsible for several serious human diseases. Individuals with Zellweger syndrome are unable to make peroxisomes and therefore lack all the metabolism unique to that organelle. In X-linked adrenoleukodystrophy (XALD), peroxisomes fail to... 

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... 

Cholesterol and phospholipids. Most lipids found in myelin are common to other cellular membranes. Cholesterol content is high and cholesterol esters are not present in normal myelin. Phospholipids are also common to other cellular membranes, except for the great quantity of ethanolamine phosphoglycerides in the plasmalogen form. The synthesis of plasmalogens is modified in Zellweger syndrome which is a peroxisomal syndrome that also increases VLCFA. This syndrome and other peroxisomal diseases may cause demyelination (Powers, 2005). 

Amyloidosis, fatty liver, glycogenoses, Wolman s syndrome, hyperchylomicronaemia, Wilson s disease, Zellweger s cerebrohepato renal syndrome, Niemann-Pick disease, mucopolysaccharidoses, etc. 

Wilson s disease Wolman s disease Zellweger syndrome... 

Martinez, M. (1991) Developmental profiles of polyunsaturated fatty acids in the brain of normal infants and patients with peroxisomal diseases severe deficiency of docosahexaenoic acid in Zellweger s and pseudo-Zellweger s syndomes. World Rev. Nutr. Diet. 66 87-102. 

Cerebrohepatorenal (Zellweger s) syndrome Infantile Refsum s disease Neonatal adrenoleukodystrophy Rhizomelic chondrodysplasia punctata Hyperpipecolic acidemia Genetic diseases with generalized impairment of peroxisomal function but normal number of peroxisomes... 

Elevated plasma levels of THCA have also been found very recently in three young children with another inherited disease, infimtile Re um s disease (P14). This condition has in common many of the clinical and biochemical features of the Zellweger syndrome, so that the metabolic defect in these two diseases may be similar (P13). 

P13. Poulos, A., Sharp, P., and Whiting, M. J., In ntile Refiium s disease (phytanic acid storage disease). A variant of Zellweger s syndrome CUn. Genet. 26, 579-586 (1984). 

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. 

Hanson et al. [105] found increased amounts of 3a,7a,12a-trihydroxy-5 -choIes-tan-26-oic acid, 3a,7a-dihydroxy-5]3-chotestan-26-oic acid, and varanic acid in the urine of 3 infants with Zellweger s syndrome [106]. The same observation was reported by Mathis et al. in 2 other patients with this syndrome [107]. Furthermore, Monnens et al. found an increased amount particularly of the trihydroxy t Uc acid and also of the dihydroxy C27 bite acid in bile and serum from 2 infants with this syndrome [108]. The increased concentrations of higher bile acids may be explained by mitochondrial abnormalities in the liver of patients with Zellweger s syndrome [109]. More recent studies indicate that the occurrence of Q- i acids is related to the absence of peroxisomes in this disease (cf. Chapter 9). 

Peroxisomal Diseases. Peroxisomal diseases are caused by mutations affecting either the synthesis of functional peroxisomal enzymes or their incorporation into peroxisomes. For example, adrenoleukodystrophy probably involves a mutation that decreases the content of a transporter in the peroxisomal membrane. Zellweger s syndrome is caused by the failure to complete the synthesis of peroxisomes. 

A number of inherited deficiencies of peroxisomal enzymes have been described. Zellweger s syndrome, which results from defective peroxisomal biogenesis, leads to complex developmental and metabolic phenotypes affecting principally the liver and the brain. One of the metabolic characteristics of these diseases is an elevation of C26 0, and C26 1 fatty acid levels in plasma. Refsum s disease is caused by a deficiency in a single peroxisomal enzyme, the phytanoyl CoA hydroxylase that carries out a-oxidation of phytanic acid. Symptoms include retinitis pigmentosa, cerebellar ataxia, and chronic polyneuropathy. Because phytanic acid is obtained solely from the diet, placing patients on a low-phytanic acid diet has resulted in marked improvement. 

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