Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinoses (NCL) represent a group of common progressive encephalopathies of children which have a global incidence of 1 in 12,500. These severe brain diseases are divided into three autosomal recessive subtypes, assigned to different chromosomal loci. The infantile subtype of NCL (INCL), linked to chromosome 1p32, is characterized by early visual loss and rapidly progressing mental deterioration, resulting in a flat electroencephalogram by 3 years of age; death occurs at 8 to 11 years, and characteristic storage bodies are found in brain and other tissues at autopsy. The molecular pathogenesis underlying the selective loss of neurons of neocortical origin has remained unknown. Here we report the identification, by positional candidate methods, of defects in the palmitoyl-protein thioesterase gene in all 42 Finnish INCL patients and several non-Finnish patients. The most common mutation results in intracellular accumulation of the polypeptide and undetectable enzyme activity in the brain of patients.