Ether lipid synthesis and its deficiency in peroxisomal disorders.

This paper deals with the discovery of plasmalogen deficiency in the cerebro-hepato-renal (Zellweger) syndrome and discusses how this has led to the development of postnatal and prenatal diagnostic procedures for this and a number of related peroxisomal disorders in man that show a general impairment in the biosynthesis of ether glycerophospholipids. The results have clearly shown an indispensable role for peroxisomes in the total process of ether lipid synthesis as evidenced by a description of the cellular topography of this process. Platelet-activating factor is a bioactive phospholipid in which the glycero-ether linkage is essential for its biological activities.

Prenatal and perinatal diagnosis of peroxisomal disorders.

Peroxisomes play an essential role in human cellular metabolism. Peroxisomal disorders, a group of genetic diseases caused by peroxisomal dysfunction, can be classified into three groups: (1) disorders of peroxisome biogenesis with a generalized loss of peroxisomal functions (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, hyperpipecolic acidaemia); (2) disorders with a loss of multiple peroxisomal functions (rhizomelic chondrodysplasia punctata and Zellweger-like syndrome; (3) disorders with loss of a single peroxisomal function (X-linked adrenoleukodystrophy, peroxisomal thiolase deficiency, bifunctional protein deficiency, acyl-CoA oxidase deficiency, classic Refsum disease, hyperoxaluria type I and acatalasaemia). Prenatal diagnosis is indicated in all these genetic disorders with the exception of classic Refsum disease, most types of hyperoxaluria type I and acatalasaemia.

Peroxisomal functions in classical Refsum's disease: comparison with the infantile form of Refsum's disease.

The infantile and classical forms of Refsum's disease are generally considered to belong to the newly recognized group of peroxisomal disorders. In this study we carried out a detailed investigation into different peroxisomal functions in classical Refsum's disease by analyses of plasma (very long chain fatty acids, di- and trihydroxycoprostanoic acid and pipecolic acid) and cultured skin fibroblasts from the patients (de novo plasmalogen biosynthesis, very long chain fatty acid oxidation and amount of particle-bound catalase). The results obtained indicate that, except for a deficient phytanic acid oxidation, peroxisomal functions were found to be normal in classical Refsum's disease in contrast with the findings in infantile Refsum's disease, in which there is a general impairment of peroxisomal functions.

Plasmalogen biosynthesis in peroxisomal disorders: fatty alcohol versus alkylglycerol precursors.

In recent years a growing number of inherited diseases have been recognized to originate from an impairment in one or more peroxisomal functions. Since it is well established that the first two steps in the biosynthesis of plasmalogens proceed in peroxisomes, we studied the biosynthesis of plasmalogens in cultured skin fibroblasts from patients with different peroxisomal and related disorders. When de novo plasmalogen biosynthesis was studied by growing the cells in the presence of [14C]hexadecanol, impaired plasmalogen biosynthesis was found in rhizomelic chondrodysplasia punctata, cerebrohepatorenal (Zellweger) syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

Aberration in de novo ether lipid biosynthesis in peroxisomal disorders.

The Zellweger syndrome is a rare inborn error of metabolism characterized by the absence of morphologically distinguishable peroxisomes. As a consequence tissues and cells from Zellweger patients contain severely reduced levels of ether phospholipids. These are replaced by diacylphospholipids while keeping the polar headgroup composition of the cellular phospholipids constant.