A timeline of symptom onset and disease progression in CLN3 disease

Abstract

Background: CLN3 disease, or Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), is a rare, genetic neurodegenerative condition, typically manifesting in the first decade of life and progressing in severity, with death typically occurring in early adulthood. Despite two decades of natural history research, a clear timeline of CLN3 disease symptom onset and progression remains poorly defined, limiting optimal patient management and therapeutic development. We conducted a literature review and analysed the natural history data to better understand the age of core symptom onset and chronological disease progression.

Methods: A literature review was undertaken using a pre-defined search strategy focused on CLN3 disease natural history studies, where age at onset for one or more core symptoms was reported in cohorts of ≥ 15 subjects. For each symptom, weighted mean age at onset and weighted standard deviation were calculated, with 95% confidence intervals derived from the weighted standard error. Symptom onset ages were compared using ANOVA.

Results: We identified nine natural history studies that met our pre-defined criteria. In total, 423 discrete patients aged between 4 and 39 years were reported. Thirteen core symptoms and a weighted average age at onset and weighted standard deviation were (in years): vision loss (6.1 ± 1.6, N = 254), behavioural changes (8.5 ± 3.9, N = 194), cognitive decline (9.3 ± 3.1, N = 219), seizures (10.2 ± 3.0, N = 243), sleep disturbance (11.0 ± 6.1, N = 111), motor decline (11.0 ± 3.8, N = 108), complete blindness (11.4 ± 3.6, N = 171), speech and language impairment (12.7 ± 4.8, N = 136), Parkinsonian gait (14.1 ± 2.5, N = 111), cardiac manifestations (17.8 ± 4.4, N = 45), loss of independent walking (19.5 ± 3.2, N = 70), feeding difficulties requiring enteral feeding tube (22.0 ± 1.6, N = 35), and death (22.4 ± 4.4, N = 95).

Conclusion: This comprehensive summary of available natural history data illustrates mean age at onset of 13 core symptoms of CLN3 disease, and characterises a chronological timeline of disease progression. These results provide much-needed practical, anticipatory guidance to those involved in caring for individuals with CLN3 disease, and serve to highlight the critical importance of collecting globally standardised, quantifiable, longitudinal data for optimising patient management and advancing therapeutic approaches for CLN3 disease.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13023-025-04174-5.

Keywords: Batten disease; CLN3 disease; Epilepsy; JNCL; Juvenile Neuronal Ceroid Lipofuscinosis; Natural history; Neurodegenerative; Retinopathy.

Fig. 1

Timeline of disease progression in classical CLN3 disease. (A) Timeline of weighted mean age and 95% confidence interval for the initial onset of the core clinical symptoms in CLN3 disease. # Unable to walk without assistance or daily use of wheelchair; † Requiring enteral feeding tube. (B) Results of ANOVA test for all pairwise comparisons of weighted mean age at onset for core clinical symptoms of CLN3 disease. Size of the asterisk indicates adjusted P value as described in panel key; for each symptom, N ranges from 35–254 participants, derived from 1–4 studies. (C) Weighted mean ages ± weighted standard deviation of initial onset for vision loss and epileptic seizures were compared for males (N = 63; open circles) and females (N = 54–55; black squares) using a 2-way ANOVA test; **** = P < 0.0001, ns = P > 0.05