Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5.

Aim: To characterize the phenotypic profile of a cohort of children affected with CLN5, a rare form of neuronal ceroid-lipofuscinosis (NCL), and to trace the features of the natural history of the disease.

Method: Records of 15 children (nine males, six females) were obtained from the data sets of the DEM-CHILD International NCL Registry. Disease progression was measured by rating six functional domains at different time points along the disease course. All patients underwent mutation analysis of the CLN5 gene and ultrastructural investigations of peripheral tissues. Expression of the gene product, pCLN5, was characterized in vitro in six patients.

Results: Disease onset was at 2 to 7 years 6 months of age: impaired learning and cognition were the most common early symptoms. Seizures occurred relatively late (median age 8y) and were the presenting symptoms in two children. Nine mutations were detected in 30 alleles, including six mutations predicting a truncated protein. Mixed cytosomes were observed by electron microscopy. Differences of disease progression were observed in two groups of patients and could be related to their genetic profile.

Interpretation: Clinical features in a multicentre cohort of patients with CLN5 confirm that cognitive difficulties are early clinical markers of this condition. Severe mutations were associated with a more rapid decline of neurological function.