Here we report successful reprograming of patient fibroblasts into induced pluripotent stem cells (iPSCs) for the two most common NCL subtypes: classic late-infantile NCL, caused by TPP1(CLN2) mutation, and juvenile NCL, caused by CLN3 mutation.
Extraneuronal pathology in a canine model of CLN2neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression.
Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder.
The results of linkage analyses in Finnish variant CLN2 families using the markers linked to CLN1 revealed an exclusion; i.e., this form of CLN is caused by a locus different from that of CLN1.
Four sub-types of childhood NCL were identified: infantile NCL (INCL) with granular osmiophilic inclusions (GROD) and PPT1 deficiency (1/26), classical LINCL with curvilinear (CV) inclusions and tripeptidyl peptidase (TPP1) deficiency (3/26), variant late infantile NCL (LINCL) with fingerprint/curvilinear (FP/CV) inclusions and normal TPP1 enzyme activity (11/26) and juvenile NCL (JNCL) with a mix of FP/CV (11/26).
We have conducted proteomic analyses of brain and cerebrospinal fluid (CSF) from mouse models of the most frequently diagnosed NCL diseases: CLN1 (infantile NCL), CLN2 (classical late infantile NCL) and CLN3 (juvenile NCL).
The two most prevalent forms of neuronal ceroid lipofuscinosis (NCL) are the juvenile form (Batten disease, CLN3) and late infantile form (Jansky-Bielschowsky disease, CLN2).
Gemfibrozil has shown efficacy in an animal model of NCL known as CLN2 (late infantile classic juvenile) and has been shown to be safe for lowering lipids in children.
We have examined mRNA levels of the CLN1, CLN2, and CLN3 genes, which are associated with the infantile, late infantile, and juvenile forms of NCL in 64 different human tissues, and have grouped the results into gastrointestinal tract, central nervous system, glandular/secretory, muscle, and carcinoma tissue types. mRNA levels for CLN3 are highest in gastrointestinal tissue and are also high in glandular/secretory tissue, whereas mRNA levels for CLN1 and CLN2 do not appear to be preferentially elevated in any tissue type.
Thus, our study indicates that some mutations in the CLN1, CLN2, and CLN3 genes may be associated with late onset of the disease process, may have a more benign clinical course, and clinic overlap with other forms of neuronal ceroid lipofuscinosis.
CLN2 disease is a genetic disorder caused by dysfunction of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) that belongs to the neuronal ceroid lipofuscinoses (NCL) and leads to epilepsy, dementia, and death in young persons.