Background: NCLs (Neuronal Ceroid Lipofuscinoses) are neurodegenerative diseases, characterized by dementia, motor decline, vision loss and epilepsy. All except one are without any approved treatment option. Early diagnosis and exact knowledge of the natural history are important for evaluation of urgently needed experimental therapies. Since only few expert centers across the world follow NCL patients regularly, an international effort is necessary to describe the progression of disease, leading to the development of an evaluation tool for current and future experimental therapy studies.
Aims: (1) Collecting the world’s largest, clinically and genetically best characterized set of CLN2 patients. (2) Analyzing disease prevalence, time of onset and character of first symptoms and providing quantitative longitudinal data on disease progression using an established clinical rating scale (Steinfeld et al., 2002).
Results: 74 CLN2 patients were analyzed longitudinally. (1) Mean age at symptom onset and diagnosis were 35 and 54 months, respectively, indicating diagnosis occurred on average 19 months after onset of first symptoms, reported as seizures (70%), loss of language (57%) or motor abilities (41%). However, a systematic review of early language development in 36 patients revealed that 83% had a significant delay in language development preceding the onset of other symptoms. (2) Our cohort showed a highly homogeneous, rapid decline in motor-language summary scores from normal (score 6) to no function (score 0), which occurred over approximately 36 months with a mean rate of decline of −1.8 units per year.
Conclusions: This international collaboration represents the largest set of quantitative longitudinal data on the natural history of CLN2 disease to date. Delayed language acquisition frequently precedes the onset of more typical symptoms. The course of disease is highly predictable. These data served as historical controls for the evaluation of treatment efficacy in clinical trials of intraventricular enzyme replacement therapy for CLN2 and were successfully audited and approved by US and European Medical Agencies (FDA, EMA).