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.

Molecular networking in the neuronal ceroid lipofuscinoses: insights from mammalian models and the social amoeba Dictyostelium discoideum

“…The neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease, are devastating forms of neurodegeneration that affect the global population [1]. Mutations have been documented in 13 genetically distinct genes (CLN1-CLN8, CLN10-CLN14), each of which causes a specific subtype of the disease (e.g., mutations in CLN3 cause CLN3 disease) [2,3]. While the NCLs affect all ages and ethnicities, the disease is recognized as the most common form of childhood neurodegeneration [1].…”

CLN5 and CLN3 function as a complex to regulate endolysosome function

“…Mutations in the gene encoding for CLN3 results in the juvenile variant of NCL (JNCL), commonly known as Batten disease. JNCL is the most common cause of childhood dementia, and has an age of onset between 5 to 10 years (Butz et al, 2019). CLN3 is a protein of 438 amino acids with six transmembrane domains, whose N-and C-terminal ends are located in the cytosol.…”

Endosomal Trafficking in Alzheimer's Disease, Parkinson's Disease, and Neuronal Ceroid Lipofuscinosis

“…The childhood forms present clinically as progressive mental and motor deterioration and loss of vision with shortened life expectancy, while the rare adult-onset forms are dominated by dementia. To date, 13 genetically distinct forms of NCL have been identified (Table 1), all characterized by the accumulation of abnormal lipofuscin-like material in the lysosomes of nerve cells, associated with progressive and selective destruction of neurons, particularly in the cerebral and cerebellar cortex and in the retina (58)(59)(60)(61). Historically, NCL has been classified into four distinctive forms, based on the clinical manifestation, morphologic features, and age of onset: infantile (INCL), late-infantile (LINCL), juvenile (JNLC), and adult type NCL (ANLC) (59).…”

“…Of the 13 genes causing NCL, four have been linked to retromer function: CLN1, CLN3, CLN5, and CLN10 (cathepsin D, or CTSD) (55,(61)(62)(63)(64)(65)(66). These NCL variants cause pathological changes that seem to share an endolysosomal dysfunctional pathway.…”