Neuronal Ceroid Lipofuscinosis: Impact of Recent Genetic Advances and Expansion of the Clinicopathologic Spectrum

Abstract

Neuronal ceroid lipofuscinosis (NCL), first clinically described in 1826 and pathologically defined in the 1960s, refers to a group of disorders mostly diagnosed in the childhood years that involve the accumulation of lysosomal storage material with characteristic ultrastructure and prominent neurodegenerative features including vision loss, seizures, motor and cognitive function deterioration, and oftentimes, psychiatric disturbances. All NCL disorders evidence early morbidity, and treatment options are limited to symptomatic and palliative care. While distinct genetic forms of NCL have long been recognized, recent genetic advances are considerably widening the NCL genotypic and phenotypic spectrum, highlighting significant overlap with other neurodegenerative diseases. This review will discuss these recent advances and the expanded potential for increased awareness and new research that will ultimately lead to effective treatments for NCL and related disorders.

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

“…NCL-causing mutations were first identified in PPT1 and CLN3 and reported in 1995 [4,5]. Since then, numerous NCL patients have been found to harbor mutations not only in PPT1 and CLN3 but also in any of 11 additional NCL-associated genes (http://www.ucl.ac.uk/ncl/ mutation.shtml) [6]. A minority of NCL cases has had adult onsets and the disorder in these adult-onset cases is sometimes referred to as Kufs disease [7].…”

Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice

“…They belong to a broader group of lysosomal storage disorders (Ballabio and Gieselmann, 2009; Cotman et al, 2013). The lysosome is an important cellular organelle involved in the breakdown of macromolecules that can be transported back into the cytoplasm (de Duve, 2005).…”

Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function

“…The neuronal ceroid lipofuscinoses (NCLs) 3 are a group of inherited neurodegenerative diseases characterized by motor and cognitive decline, seizures, and typically vision loss. The NCLs are further typified by the occurrence of abnormal accumulations of protein-and lipid-containing autofluorescent storage material in both neuronal and non-neuronal cells, which most often contains abundant levels of the pore-forming subunit of the mitochondrial ATP synthase (subunit c of the F 0 -ATPase complex; hereafter referred to as subunit c) (1).…”

“…The NCLs are further typified by the occurrence of abnormal accumulations of protein-and lipid-containing autofluorescent storage material in both neuronal and non-neuronal cells, which most often contains abundant levels of the pore-forming subunit of the mitochondrial ATP synthase (subunit c of the F 0 -ATPase complex; hereafter referred to as subunit c) (1). Currently, 13 genes are known to cause different subtypes of NCL, encoding proteins of varied, often incompletely understood functions within the secretory and endosomal-lysosomal systems (2)(3)(4). In juvenile onset NCL (JNCL), autosomal recessive inheritance of loss-of-function mutations in the CLN3 gene lead to disease, with most patients carrying at least one copy of a common ϳ1-kb deletion in CLN3 (5).…”