Zellweger’s disease

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. 

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

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

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. 

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). 

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. 

Poulos, A., Sharp, R, Fellenberg, A.J. Danks, D.M. (1985)/7io i. Genet. 70, 172-177. Cerebto-hepato-renal (Zellweger) syndrome, adrenoleukodystrophy, and Relsum s disease plasma changes and skin fibroblast phytanic acid oxidase. 

Schram, A.W., Strijland, A., Hashimoto, T., Wanders, R.J.A., Schutgens, R.B.H., van den Boseh, H. Tager, J.M. (1986) Proc. Natl. Acad Sci. U. S. A. 16, 6156-6158. Biosynthesis and maturation of peroxisomal beta-oxidation enzymes in fibroblasts in relation to the Zellweger syndrome and infantile Refsum disease. 

---