Kousi_2012_Hum.Mutat_33_42

The neuronal ceroid lipofuscinoses (NCLs) are clinically and genetically heterogeneous neurodegenerative disorders. Most are autosomal recessively inherited. Clinical features include a variable age of onset, motor and mental decline, epilepsy, visual loss, and premature death. Mutations in eight genes (PPT1/CLN1, TPP1/CLN2, CLN3, CLN5, CLN6, MFSD8/CLN7, CLN8) have been identified and several more are predicted to exist, including two provisionally named CLN4 and CLN9. Despite excessive in vitro and in vivo studies, the precise functions of the NCL proteins and the disease mechanisms remain elusive. To date 365 NCL-causing mutations are known, with 91 novel disease-causing mutations reported. These are reviewed with an emphasis on their complex correlation to phenotypes. Different mutations within the NCL spectrum can cause variable disease severity. The NCLs exemplify both phenotypic convergence or mimicry and phenotypic divergence. For example, mutations in CLN5, CLN6, MFSD8, or CLN8 can underlie the clinically similar late infantile variant NCL disease. Phenotypic divergence is exemplified by different CLN8 mutations giving rise to two very different diseases, the mild CLN8 disease, EPMR (progressive epilepsy with mental retardation), and the more severe CLN8 disease, late infantile variant. The increase in the genetic understanding of the NCLs has led to improved diagnostic approaches, and the recent proposal of a new nomenclature.