Age at onset and gene variants predict lifespan and disease duration in childhood neuronal ceroid lipofuscinoses

Abstract

Dementia is a worldwide public health priority associated with prolonged life expectancy and aging. It is possibly due to interacting genetic and environmental factors. There is growing evidence that the number of young adults and children affected with dementia is increasing. Neuronal ceroid lipofuscinoses (NCLs) are the most frequent diseases leading to dementia in childhood and adolescence. They are genetic disorders (gene mutations are inherited by both parents). Several symptoms are associated with the cognitive decline: vision impairment, seizures, motor dysfunction, impaired speech and deglutition, sleep disturbances, etc. A targeted treatment is available for one form (CLN2 disease), resulting in slowing down the rate of disease progression. Knowledge of the natural history of NCLs has become crucial for families and caregivers to manage the patients' disease courses and sustain their quality of life.

We investigated the relationship between age at onset and disease duration in a cohort of patients with NCL (mutated in eight NCL genes) subdivided in three groups according to the age of disease onset. Clinical data were then matched with the involved genes and the pathogenicity (the ability of an organism to cause disease) of mutations. The outcome (in terms of lifespan) was primarily related to the age at disease onset: the earliest onset meaningfully correlates with the shortest disease duration and survival. Neither the age at onset nor the survival were influenced by the kind of mutations. Most severely affected phenotypes were associated with selected genes and the impaired functions of their product (lysosomal enzymes).