PEROXISOMAL DYSFUNCTION IN A HETEROGENEOUS GROUP OF CHONDRODYSPLASIA PUNCTATA (CP) SYNDROMES

Abstract

Peroxisomal dysfunction is found in a growing number of bone dysplasias in which CP is one of the characteristics. This includes (1) the rhizomelic type of CP (RCDP) that is characterised clinically by dwarfing, congenital cataracts, skeletal malformations and psychomotor retardation (2); the recently recognised dihydroxyacetone-phosphate acyl-transferase (DHAPAT) deficiency that is clinically identical to RCDP and (3) a new type of CP (NTCP) (Poll-Thé et al, J Inner Met Dis 14, 1991, 361) with bilateral cataracts but normal psychomotor development and normal skeletal radiography except for CP.Sofar we identified 34 RCDP patients, 2 patients with DHAPAT deficiency and 1 NTCP patient. Moreover, in 11 pregnancies at risk for RCDP, 6 affected fetuses were identified prenatally by the finding of an impaired plasmalogen metabolism in cultured chorionic villous cells. In RCDP and NTCP patients biochemical abnormalities include a deficiency of the peroxisomal enzymes DHAP-AT and alkyl-DHAP-synthase and of phytanic acid oxidase and abnormal (precursor) peroxisomal thiolase enzyme protein. In DHAP-AT deficiency only an isolated deficiency of DHAP-AT is found. Genetic heterogeneity between classical RCDP and DHAPAT deficiency was observed in complementation studies. These findings are important for the understanding of the pathogenesis in these disorders.