Zellweger’s syndrome

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

ALDP, DHAP, dihydroxyacetone phosphate DHAPAT, dihydroxyacetone phosphate acyltransferase NALD, neonatal adrenoleukodystrophy RCDP, rhizomelic chondrodysplasia punctata X-ALD, X-linked adrenoleukodystrophy ZS, Zellweger s syndrome. 

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. 

Eyssen, H., E ermont, E., van Eldere, J., Jaeken, J., Parmentier, G., Janssen, G. Bile acid abnormalities and the diagnosis of cerebro- hep-ato-renal syndrome (Zellweger s syndrome). Acta Paediatr. Scand. 1985 74 539-544... 

Analysis of peroxisomes in lymphoblasts Zellweger s syndrome and a patient with a deletion in chromosome 7. Pediatr. Res. 1993 33 441-444... 

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)... 

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... 

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. 

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. 

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