Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles

CL2, the neuronal ceroid lipofuscinosis (NCL) with a classical late infantile onset (LINCL or Jansky-Bielschowsky disease, MIM 204500) is among the most common childhood neurodegenerative disorders.Usually, affected children show generalised tonic-clonic and/or myoclonic seizures starting by 2 to 3 years of age as the initial, and the most noticeable, clinical symptom.This is followed by regressive cognitive dysfunction, including speech delay, slow learning, and mental retardation; neuromotor dysfunction, including ataxia and inability to walk; vision problems; behavioural changes and eventual dementia.Pathological studies by electron microscopy (EM) examination of peripheral blood "buffy coats" and/or tissue biopsy (including skin, conjunctiva, rectal, muscle, brain, or peripheral nerve) have found lysosomal curvilinear (CV) inclusions.These CV inclusions reflect the typical ultrastructural profile of autofluorescent lipofuscin storage materials that consist predominantly of mitochondrial ATP synthase (ATPase) subunit C.Such EM observations are the common basis for the clinical diagnosis of LINCL. 1 Genetically, the gene CLN2 underlying NCL2 has been mapped to chromosome 11p15.2 It consists of 13 exons spanning 6.65 kb of genomic DNA 3 and encodes a 46 kDa protein, lysosomal tripeptidyl peptidase 1 (TPP1), which cleaves tripeptides from amino termini of peptides that bear free α-amino groups.4 Mutations in CLN2 abolish TPP1 enzymatic activity in NCL2 patients.5 A total of 42 mutations, which include 10 small deletions/insertions, 20 missense and four nonsense point mutations, and eight splicing errors have been identified (http://www.ucl.ac.uk/ncl).6 We have reported that the heterogeneity of NCL with late infantile onset results from missense mutations in CLN2 that cause atypical onset and clinical symptoms.7 NCL with late infantile onset has been reported to be common in the population in Newfoundland, Canada, 8 but detailed genetic studies are lacking.Here we report molecular genetic analyses of 23 Canadian families that were clinically diagnosed with late infantile onset NCL. MATERIALS AND METHODS NCL familiesFamilies that were clinically diagnosed as affected by late infantile onset NCL were collected from Canada, 21 from the Newfoundland area and two from the Toronto area.Informed consent signed by the participants' parent(s) and guardian(s) and clinical information, including age at onset, initial neurological symptoms, and ultrastructural profiles, were obtained through health care professionals. Molecular studiesMolecular analyses for mutations in genes CLN1, CLN2, and CLN3 were conducted with the two phase approaches we described earlier.7 9-11 Clinically suspected cases were first analysed for common mutations in the CLN2 gene, which account for about two-thirds of late infantile onset NCL cases globally.* Novel mutations identified in this study have been deposited in the NCL mutation database (http://www.ucl.ac.uk/ncl).?: information is not available.