Current State of Clinical and Morphological Features in Human NCL

Abstract

The neuronal ceroid lipofuscinoses (NCL) are a large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Previously, diagnosis of NCL was based on age at onset and clinicopathological (C-P) findings described 4 forms, classified as infantile (INCL) (2), late-infantile (LINCL) (5), juvenile (JNCL) (6), and adult (ANCL) (12). Most patients with NCL have progressive ocular and cerebral dysfunction, including cognitive/motor dysfunction and uncontrolled seizures. After reviewing 520 patients with NCL, we found that about 104 (20%) did not fit this classification of NCL. With further research, 4 additional forms have been recognized: Finnish (13), Gypsy/Indian (14), Turkish (15)--variants of LINCL, and Northern epilepsy (16), also known as progressive epilepsy with mental retardation. These eight NCL forms resulted from 151 different mutations in genes CLN1 to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl). The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1. The diagnosis of NCL is based on clinicopathological (C-P) findings, enzymatic assay, and molecular genetic testing. Ultrastructural studies must be performed to confirm the presence and nature of lysosomal storage material (fingerprint or curvilinear profiles, or granular osmiophilic deposits) before doing biochemical testing. Pheno/genotypic correlation studies are discussed.

Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6

“…NCL is a genetically and phenotypically heterogeneous group of progressive neurodegenerative disorders with at least eight subtypes (28). Clinical features variably include progressive mental and visual decline, motor disturbances, epilepsy, and premature death (18). As in Clcn6 Ϫ/Ϫ mice, genes involved in inflammatory response and microglial activation were up-regulated in NCL (29).…”

“…No autofluorescent material was seen in liver, heart, or kidney. Autofluorescent material (lipofuscin) within neurons is a hallmark of NCL, a subtype of lysosomal storage disease (18).…”

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

“…Clinical symptoms include progressive vision loss, severe cognitive and motor decline, and seizures (Dyken, 1988;Goebel and Wisniewski, 2004;Weleber, 1998;). In the later stages of the disease affected children become severely handicapped.…”

“…In humans, there are a number of forms of NCL that differ from one another in the age at which symptoms first appear, the rate of disease progression, and the patterns of symptoms (Dyken, 1988;Goebel and Wisniewski, 2004;. Almost all NCL patients exhibit severe vision loss and progressive cognitive impairment that reflects progressive pathological changes in the central nervous system, including engorgement of neurons with storage material, brain and retinal atrophy, and generalized neuronal degeneration (Goebel and Wisniewski, 2004). Currently there are no known treatments to delay or halt the progression of the NCLs; the development of therapeutic interventions has been impeded by the lack of defined objective markers of disease status.…”

“…Currently there are no known treatments to delay or halt the progression of the NCLs; the development of therapeutic interventions has been impeded by the lack of defined objective markers of disease status. In humans, the different forms of NCL result from mutations in at least eight distinct genes (Goebel and Wisniewski, 2004;Siintola et al, 2006;Siintola et al, 2007;Steinfeld et al, 2006;). …”