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

Sep 29, 2026

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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: A retrospective study matched clinical features (age at onset, at death, and disease duration) and genotype pathogenicity from the Italian CLNet database for 152 molecularly diagnosed children. Results: Median age at onset was 4 years; median age at death was 17 years. Earlier onset correlated with shorter lifespan (6 years), and earlier onset/short survival aligned with lysosomal-enzyme gene mutations and 79.3% pathogenic variants. Interpretation: Age at onset predicts expected lifespan, and ACMG variant classes partly foresee NCL phenotype outcomes.

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DOI: 10. 1111/dmcn.16416 O R IG I NA L A R T I C L E Age at onset and gene variants predict lifespan and disease duration in childhood neuronal ceroid lipofuscinoses Alessandro Simonati1,* | Francesco Pezzini1,* | Nardo Nardocci2 | CLNet Consortium† | Filippo M. Santorelli3 1Department of Surgery, Dentistry, Paediatricsand Gynaecology, University of Verona, Verona, Italy 2Neurological Institute C Besta Foundation, Milan, Italy 3Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Calambrone (Pisa), Italy Correspondence Alessandro Simonati, Department of Surgery, Dentistry, Paediatrics and Gynaecology, Policlinico GB Rossi, Piazzale LA Scuro 10, 37134 Verona, Italy. Email: [alessandro.simonati@univr.it](alessandro.simonati@univr.it) Funding information Rete IRCCS-RIN; Ministero della Salute, Grant/Award Number: Ricerca Corrente 2025; Fondazione Pierfranco e Luisa Mariani, Grant/Award Number: National Network on Rare Neuropaediatric Diseases; Ministerodell'Università e della Ricerca; Regione Toscana, Grant/Award Number: Bando Ricerca Salute 2018 DEM AGING 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 4years; 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. Neuronal ceroid lipofuscinoses (NCLs), a group of genetically determined diseases, are the most common neurodegenerative disorder in childhood, and one of the main causes of childhood dementia worldwide. All NCLs share common clinical features, have a progressive course, and a fatal outcome. Epidemiological studies have shown some differences of prevalence among the forms.1–3 At present, NCL nomenclature is based on the genes harbouring variations, and 13 genetic forms are recognized; nine NCLs have childhood onset and are inherited with autosomal recessive trait.4, 5 NCL genes encode proteins of the lysosomal compartment, the endoplasmic reticulum, and one gene product is associated with cellular membranes.6, 7 Phenotypic heterogeneity is quite common among the NCLs, possibly associated with a wide spectrum of variation in the same gene having severe or milder clinical consequences.8 This original article is commented on by Mole on pages 156–157 of this issue. Abbreviations: ACMG, American College of Medical Genetics; CLNet, Italian network of neuronal ceroid lipofuscinoses; INCL, infantile neuronal ceroid lipofuscinosis; JNCL, juvenile neuronal ceroid lipofuscinosis; LINCL, late infantile neuronal ceroid lipofuscinosis; NCL, neuronal ceroid lipofuscinosis; VUS, variant of uncertain significance. *These authors contributed equally to this work. †Sel

FAQs

What is the study’s main goal for childhood neuronal ceroid lipofuscinosis?

To address disease progression by evaluating how age at onset and specific gene variants relate to lifespan and disease duration in a childhood-onset NCL cohort.

How were patients grouped and analyzed in this retrospective study?

A cohort of 152 children with molecularly diagnosed NCL was grouped by age at onset and subdivided by the associated mutated gene. Clinical features were assessed with descriptive statistics and significance tested using non-parametric methods.

What associations did the results show between age at onset, survival, and genotype?

Earlier disease onset was linked to shorter lifespan, and earlier onset/short survival were associated with mutated genes encoding lysosomal enzymes. High proportions of pathogenic variants were reported and matched with genotypes.

Sep 29, 2026

Uploaded by Jake