THE MOLECULAR-GENETICS OF PEDIATRIC LIPID DISORDERS - RECENT PROGRESSAND FUTURE-RESEARCH DIRECTIONS

Over the last 10 years, the explosion of molecular biology and molecul ar genetic techniques have allowed major advances in the diagnosis and management of a wide variety of human disorders. These range from acc urate and simple screening for carriers of thalassemia (Old JM, Varawa lla NY, Weatherall DJ: Lancet 2:834-837, 1990) to the use of preimplan tation diagnosis of embryos at risk for untreatable congenital defects (Monk M, Holding C: Lancet 1:985-988, 1990) and the development of ge ne therapy for treatment of disorders such as adenosine deaminase defi ciency (Sharp D: Lancet 1:1277-1278, 1991). These same molecular techn iques have also been applied to pediatric lipid disorders with some no table successes, both in their diagnosis and understanding the mechani sms of the resulting pathology, including the recent experiments (Wils on JM, Grossman M, Wu CH, Chowdhury NR, Wu GY, Chowdhury JR:J Biol Che m 267:963-967, 1992) that have led to proposals to treat homozygous fa milial hypercholesterolemia by gene therapy. The purpose of this revie w is to detail this molecular genetic progress for two of the disorder s that result in disturbed triglyceride metabolism in infants, lipopro tein lipase deficiency and apo CII deficiency, and four disorders that lead to disturbed cholesterol levels in infancy, abetalipoproteinemia , hypobetalipoproteinemia, familial defective apo B, and familial hype rcholesterolemia. We will also address the question of how knowledge o f the mutation causing the defect in a particular patient could be cli nically useful and highlight areas of research for the future.