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

Abstract

Aim: To address disease progression in a cohort of patients with childhood-onset neuronal ceroid lipofuscinosis (NCL), a group of genetic disorders leading to progressive dementia.

Method: In this retrospective study, selected clinical features (age at onset, at death, and disease duration) and pathogenicity of individual genotypes were selected and matched from the database of the Italian network of NCLs. A cohort of 152 children with molecularly diagnosed NCL were grouped by age at onset and subdivided according to the associated mutated gene. Clinical features were assessed by descriptive statistics and the significance level by non-parametric tests. The pathogenicity of patients' genotypes in each NCL form was categorized following the guidelines of the American College of Medical Genetics (ACMG) and matched with the phenotypes.

Results: The median age at onset was 4 years; the median age at death was 17 years. The earliest disease onset was related to the shortest lifespan (6 years). Earlier onset and short survival were associated with mutated genes encoding for lysosomal enzymes. High percentages of pathogenic variants were identified and associated with 79.3% of genotypes. The evaluated clinical parameters were not necessarily linked to the genotype.

Interpretation: The age of onset is a good indicator of the expected lifespan of a child with NCL. The ACMG classes of variant partly foresee the outcome of NCL phenotypes.