A novel CLN8 mutation underlies a late Infantile variant of neuronal ceroid lipofuscinosis in Latin America

Abstract

Introduction: Neuronal ceroid lipofuscinosis (NCL), inherited neurodegenerative diseases of all ages, presents with storage of lipofuscin-like lipopigments in cerebral neurons and peripheral tissues. Mutations in CLN8 gene causing epilepsy progressive with mental retardation (EPMR) of Scandinavia and late infantile variant (vLI) phenotype in other countries had not yet been described in Latin America. The change p.Pro229Ala, found in the DNA of 2 individuals from Argentina and Mexico, was not validated as a mutation. Aim: To analyze and to validate changes in CLN8 gene in individuals suspected of vLI NCL. Participants: Fifteen individuals with normal palmitoyl protein thioesterase 1 (PPT1) and tripeptidyl peptidase 1 (TPP1) enzymes, positive electronic microscopy, and lack of mutations in other NCL genes. Method: Polymerase chain reaction, sequencing, and bioinformatics analyses were performed on the coding region of CLN8 gene, and validation of mutations was carried out on 200 control alleles. Result: The novel mutation c.1A>G, p.Met1Val, was validated for an Argentinean child with clinical suspicion of vLI who presented at the age of 3 years with onset of seizures, psychomotor retardation, myoclonus, cortical and cerebellar atrophy, and electronic microscopy with fingerprint and curvilinear profiles. Ocular disorders have not been studied. She died at 12 years of age. The changes p.Pro229Ala and p.Pro3Pro were validated as polymorphisms of the local population, which have been found, respectively, in 10 of 100 (1 in homozygous state) and 1 of 100 controls. Conclusion: The girl with vLI phenotype is the first confirmed CLN8 (vLI) case in Latin America. In the future, CLN8 should be considered in the search of possible mutations in individuals with vLI in the region.