MUTATIONS IN THE PALMITOYL PROTEIN THIOESTERASE GENE CAUSING INFANTILE NEURONAL CEROID-LIPOFUSCINOSIS

NEURONAL ceroid lipofuscinoses (NCL) represent a group of common progr essive encephalopathies of children which have a global incidence of 1 in 12,500 (ref. 1). These severe brain diseases are divided into thre e autosomal recessive subtypes, assigned to different chromosomal loci (2-4). The infantile subtype of NCL (INCL), linked to chromosome 1p32, is characterized by early visual loss and rapidly progressing mental deterioration, resulting in a pat electroencephalogram by 3 years of a ge; death occurs at 8 to 11 years(5), and characteristic storage bodie s are found in brain and other tissues at autopsy(6). The molecular pa thogenesis underlying the selective loss of neurons of neocortical ori gin has remained unknown. Here we report the identification, by positi onal candidate methods, of defects in the palmitoyl-protein thioestera se gene in all 42 Finnish INCL patients and several non-Finnish patien ts. The most common mutation results in intracellular accumulation of the polypeptide and undetectable enzyme activity in the brain of patie nts.