Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses

Abstract

The neuronal ceroid lipofuscinoses (NCL) are a group of disorders defined by shared clinical and pathological features, including seizures and progressive decline in vision, neurocognition, and motor functioning, as well as accumulation of autofluorescent lysosomal storage material, or 'ceroid lipofuscin'. Research has revealed thirteen distinct genetic subtypes. Precisely how the gene mutations lead to the clinical phenotype is still incompletely understood, but recent research progress is starting to shed light on disease mechanisms, in both gene-specific and shared pathways. As the application of new sequencing technologies to genetic disease diagnosis has grown, so too has the spectrum of clinical phenotypes caused by mutations in the NCL genes. Most genes causing NCL have probably been identified, underscoring the need for a shift towards applying genomics approaches to achieve a deeper understanding of the molecular basis of the NCLs and related disorders. Here, we summarize the current understanding of the thirteen identified NCL genes and the proteins they encode, touching upon the spectrum of clinical manifestations linked to each of the genes, and we highlight recent progress leading to a broader understanding of key pathways involved in NCL disease pathogenesis and commonalities with other neurodegenerative diseases.

Keywords: Autophagy; Batten disease; Lysosomal storage disease; NCL; Neurodegenerative disease; Neuronal ceroid lipofuscinosis.