Genetic Diseases Caused by Peroxisomal Dysfunction. New Findings in Clinical and Biochemical Studies

Peroxisomes play an essential role in human cellular metabolism. Peroxisomal disorders, a group of genetic diseases caused by peroxisomal dysfunction, can be classified in three groups namely a group of disorders with a general peroxisomal dysfunction (Zellweger syndrome; infantile type of Refsum's disease; neonatal adrenoleukodystrophy, hyperpipecolic acidemia), a group with an impairment of some, but not all peroxisomal functions (rhizomelic chondrodysplasia punctata) and a group with impairment of only a single peroxisomal function (acatalasemia, X-linked adrenoleukodystrophy/adrenomyeloneuropathy; adult type of Refsum's disease; peroxisomal thiolase deficiency; peroxisomal acyl-CoA oxidase deficiency; hyperoxaluria type I). In this paper we report the typical findings in ophthalmological examinations of patients suspected of Zellweger syndrome contributing to the clinical diagnosis of this disorder. In biochemical studies using a rapid gaschromatographic detection method for plasmalogens we confirmed that plasmalogens are severely deficient in all tissues of Zellweger patients studied. Moreover, using a recently developed radiochemical method, de novo plasmalogen biosynthesis was found to be impaired in fibroblasts from patients with Zellweger syndrome, infantile Refsum's disease, neonatal adrenoleukodystrophy or rhizomelic chondrodysplasia punctata, this in contrast to X-linked chondrodysplasia in which a normal plasmalogen biosynthesis was found. From the literature it is known that peroxisomal beta-oxidation with both long-chain (C16:0) and very long-chain (C24:0; C26:0) fatty acids is deficient in Zellweger syndrome, infantile Refsum's disease and neonatal adrenoleukodystrophy. In contrast, in X-linked adrenoleukodystrophy only the peroxisomal beta-oxidation of the very long chain fatty acids is impaired. As a result very long-chain fatty acids accumulate in tissues, plasma, fibroblasts and amniotic fluid cells from patients with Zellweger syndrome, infantile Refsum's disease, neonatal and X-linked adrenoleukodystrophy, but not in rhizomelic chondrodysplasia punctata or X-linked chondrodysplasia. Finally we confirmed that the peroxisomal enzyme alanine glyoxylate aminotransferase is severely deficient in liver from a patient that died because of the neonatal type of hyperoxaluria type I, but not in liver from Zellweger patients.