LATE INFANTILE NEURONAL CEROID-LIPOFUSCINOSIS AND ITS VARIANTS

Objectives: To review the molecular epidemiology of Neuronal Ceroidolipofuscinoses (NCLs) of childhood onset in Italy. NCLs are a group of rare, progressive neurodegenerative disorders related to the endolysosomial storage of autofluorescent ceroid and lipofuscin. Most cases have onset within the first decade of life and are recessively inherited. They were classified according to the age of onset and the features of the storage material but advances in NCLs genetic have improved the diagnosis and outlined the phenotypic heterogeneity within each form.

Methods: Clinical, ultrastructural, biochemical, and molecular genetic analyses were performed during the past 7 years in 44 NCL patients of childhood onset.

Results: Mutations in CLN2 were detected in 14 cases (32%), whereas CLN1, CLN6, CLN8 were mutated in 10 vLINCL children (23%). In 12 children no mutations in these genes were detected. TPP-I and PTT1 biochemistry was also performed in 22 cases. Ultrastructural examination of peripheral tissues was performed in 83% of children: cytosome features from blood lymphocytes and/or skin biopsy were predictive of classical LINCL and CLN1-associated vLINCL, whereas heterogeneous cytosomes were observed in three CLN8 patients. In all children major clinical features, such as severe myoclonic epilepsy, psychomotor deterioration and ataxic gait, were present; a more protracted course was observed among both CLN1- and CLN8-variants.

Conclusion: LINCL (including vLINCL) is the most frequent NCL form in this study. Identification of variant forms is necessary to offer appropriate genetic counselling. However, the disease severity and progression do not relate to the type of mutation in both classical and vLINCL.

Keywords: NCL; LINCL variants; LINCL genes