Novel CLN8 mutations confirm the clinical and ethnic diversity of late infantile neuronal ceroid lipofuscinosis

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited lysosomal storage diseases and the prototype of childhood onset neurodegenerative disorders. To date, 10 NCL entities (CLN1-CLN10) are known and characterized by accumulation of autofluorescent storage material, age of onset and clinical symptoms. CLN8 was first identified as the causative gene for a late-onset form with progressive epilepsy and mental retardation in Finnish patients. In addition, CLN8 phenotypes were described in Turkish, Israeli and Italian patients with a more rapid progression of visual loss, epilepsy, ataxia and mental decline. Here, we report the first mutations in German (c.611G>T) and Pakistani (c.709G>A) patients. Our findings confirm previous assumptions that the CLN8 variant can occur in many ethnic groups. So far, large CLN gene deletions are only known for the CLN3 gene. Here, we also describe a novel, large CLN8 gene deletion c.544-2566_590del2613 in a Turkish family with a slightly more severe phenotype. Our data indicate that patients with clinical signs of late infantile NCL and characteristic ultrastructural inclusions should also be screened for CLN8 mutations independent of their ethnic origin.

Variant late‐infantile neuronal ceroid lipofuscinosis due to a novel heterozygous CLN8 mutation and de novo 8p23.3 deletion

“…The initial phenotype of our patient (Table 1) appeared to be similar in severity to the v‐LINCL phenotypes with small CLN8 missense mutations. His disease‐onset was slightly later than that of the more progressive phenotype found in the two Turkish patients with relatively large CLN8 gene deletions (3).…”

“…The majority of mutations described are homozygous missense mutations. Large deletions (46‐bp with frameshift mutation resulting in truncated CLN8 protein) have only been described in two children (Turkish siblings with consanguineous parents) who had a more severe phenotype in comparison to patients with CLN8 missense mutations (3).…”

“…Variant late-infantile neuronal ceroid lipofuscinosis due to a novel heterozygous CLN8 mutation and de novo 8p23. 3…”

CLN8 disease caused by large genomic deletions

“…One Turkish family carries a 2.6 kb intragenic deletion in CLN8 that causes more severe disease than most other mutations (Reinhardt et al. ). To date, ~30 other mutations that cause CLN8 disease have been reported, of which 21 are missense mutations, one is a nonsense mutation, and five are small deletions of 1–3 bp.…”

Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

“…It is now recognized that mutations in all genes are distributed across many countries, albeit with higher incidence in some ethnic groups due to founder effects. Among the many recognized variants of NCL human forms (recent reviews in [3,6,11]), eight causal genes have been identified: CLN10/CTSD [12][13][14], CLN1/PPT1 [3,6,[15][16][17][18], CLN2/TPP1 [6,[18][19][20][21], CLN3 [22][23][24][25], CLN5 [26][27][28][29][30], CLN6 [31][32][33][34], CLN7/ MFSD8 [35][36][37][38][39], CLN8 [40][41][42]. The genes CLCN6 [43], and CLCN7 [44], and possibly SGSH [45], may also contribute to rare forms of NCL.…”