Molecular Genetics of the Neuronal Ceroid Lipofuscinoses

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are a group of clinically and genetically heterogenenous neurodegenerative disorders characterised by the accumulation of autofluorescent storage material in many cell types. Most display autosomal recessive inheritance. More than 400 mutations have been described in 13 genes: PPT1 , TPP1 , CLN3 , CLN5 , CLN6 , MFSD8 , CLN8 , CTSD, GRN, ATP13A2, KCTD7, CTSF and DNAJC5 , and none show obvious mutation hotspots. The functions of most of these genes remain elusive. The majority of the genetic defects identified are private, but there are geographically widespread or localised common founder mutations. The NCLs exemplify both phenotypic convergence and divergence, and there can be very wide disease severity caused by mutations in the same gene. Some recently identified mutations are in genes that are associated with other diseases. The recent expansion of knowledge in the genetic understanding of the NCLs is leading to improved diagnostic approaches, and the recent adoption of a new nomenclature. Key Concepts: More than 400 mutations are known across 13 genes causing disease in families diagnosed with NCL. Most NCLs are autosomal recessive. NCLs are a heterogenous group of disorders with common features of progressive degeneration of the brain, and often the retina, and intracellular storage of material similar to ceroid and lipofuscin. NCLs are monogenic disorders. One type of NCL is autosomal dominant. There remain families diagnosed with NCL in which the genetic cause is not yet determined.

Regulation of the Prickle1 and Prickle2 genes and their role in autism spectrum disorders

“…Recent work identified recessive genes involved in a subset of the progressive myoclonic epilepsy (PME) syndromes, characterized by varying degrees of neurodegeneration, generalized seizures and myoclonus. These include CSTB in Unverricht and Lundborg disease (43,44), EPM2A, NHLRC1 (EPM2B) (45,46) in Lafora disease, SCARB2 with and without renal failure (47,48), mitochondrial t-RNA genes in epilepsy with ragged-red fibers (MERRF) (49)(50)(51), and CLNF4, PPT1 and CLN1-8 in neuronal ceroid lipofuscinoses (52)(53)(54)(55)(56)(57)(58).…”