We report the first known case in Israel of a patient with an early childhood onset of ceroid-lipofuscinosis who is homozygous to a mutation of the CLN8 gene.
The late-infantile-onset forms of neuronal ceroid lipofuscinosis (LINCL) are the most genetically heterogeneous group among the autosomal recessive neuronal ceroid lipofuscinoses (NCLs), with causative mutations found in CLN1, CLN2, CLN5, CLN6, CLN7 (MFSD8), and CLN8 genes.
The NCLs include eight forms that result from genetic deficiency on genes CLN(1) to CLN(8), respectively: four classic forms with clinical onset at varying ages-infantile (INCL), late-infantile (LINCL), juvenile (JNCL), and adult (ANCL)-and four variants of late-infantile onset-the Finnish variant LINCL (fLINCL), Portuguese variant LINCL (pLINCL), Turkish variant LINCL (tLINCL), and progressive epilepsy with mental retardation (EPMR).
Patients with CLN8 mutations usually present as the late-infantile-onset neuronal ceroid lipofuscinosis phenotype and are mostly Turkish and Italian, but three patients from Israel, Pakistan, and Germany were also reported.
Our findings expand the variant diversity of CLN8 and demonstrate the tremendous diagnosis value of targeted next-generation sequencing for pediatric NCLs.
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.
Neuropathological findings have shown that EPMR is a new member (CLN8) of the neuronal ceroid lipofuscinosis (NCL) group of neurodegenerative disorders.The CLN8 gene was identified recently.
Loss of function mutations in CLN8 causes neuronal ceroid-lipofuscinosis, but our results indicate that its increased expression may protect against severe GD1.
It displays 82% nucleotide identity with CLN8, conservation of the codon harbouring the human mutation and is localized to the same region as the motor neuron degeneration mouse, mnd, a naturally occurring mouse NCL (ref.4).
In five of the eight NCL variants distinguished at present, genes associated with the disease process have been isolated and characterized (CLN1, CLN2, CLN3, CLN5, CLN8).