Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study
Open accessAbstract
Background Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, characterised by rapid psychomotor decline and epilepsy, is caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1. We aimed to analyse the characteristics and rate of progression of CLN2 disease in an international cohort of patients.Methods We did an observational cohort study using data from two independent, international datasets of patients with untreated genotypically confirmed CLN2 disease: the DEM-CHILD dataset (n=74) and the Weill Cornell Medical College (WCMC) dataset (n=66). Both datasets included quantitative rating assessments with disease-specific clinical domain scores, and disease course was measured longitudinally in 67 patients in the DEM-CHILD cohort. We analysed these data to determine age of disease onset and diagnosis, as well as disease progression-measured by the rate of decline in motor and language summary scores (on a scale of 0-6 points)-and time from first symptom to death.Findings In the combined DEM-CHILD and WCMC dataset, median age was 35·0 months (IQR 24·0-38·5) at first clinical symptom, 37·0 months (IQR 35·0 -42·0) at first seizure, and 54·0 months (IQR 47·5-60·0) at diagnosis. Of 74 patients in the DEM-CHILD dataset, the most common first symptoms of disease were seizures (52 [70%]), language difficulty (42 [57%]), motor difficulty (30 [41%]), behavioural abnormality (12 [16%]), and dementia (seven [9%]). Among the 41 patients in the DEM-CHILD dataset for whom longitudinal assessments spanning the entire disease course were available, a rapid annual decline of 1·81 score units (95% CI 1·50-2·12) was seen in motor-language summary scores from normal (score of 6) to no function (score of 0), which occurred over approximately 30 months. Among 53 patients in the DEM-CHILD cohort with available data, the median time between onset of first disease symptom and death was 7·8 years (SE 0·9) years.Interpretation In view of its natural history, late-infantile CLN2 disease should be considered in young children with delayed language acquisition and new onset of seizures. CLN2 disease has a largely predictable time course with regard to the loss of language and motor function, and these data might serve as historical controls for the assessment of current and future therapies.Funding EU Seventh Framework Program, German Ministry of Education and Research, EU Horizon2020 Program, National Institutes of Health, Nathan's Battle Foundation, Cures Within Reach Foundation, Noah's Hope Foundation, Hope4Bridget Foundation.
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CLN2 disease causes the recessive neurodegenerative late-infantile form of neuronal ceroid lipofuscinosis, or late-infantile Batten disease.
“CLN2 disease causes the recessive neurodegenerative late-infantile form of neuronal ceroid lipofuscinosis, or late-infantile Batten disease 147 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [147]
The Introduction identifies CLN2 disease as a late-infantile form of neuronal ceroid lipofuscinosis and describes it as autosomal recessive and neurodegenerative. It does not say CLN2 disease causes that form; it says mutations in the CLN2 gene cause CLN2 disease. Our copy also does not establish the name “late-infantile Batten disease.” (LLM, conf=0.85)
Experimental — accuracy not yet measuredOnset of focal seizures or myoclonic-atonic seizures in CLN2 disease occurs at 2-4 years of age in a child with normal development or isolated language delay.
“Onset of focal seizures or myoclonic-atonic seizures occurs at 2-4 years of age in a child with normal development or isolated language delay.”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [147]
The Results report a median age of 37 months at first seizure, and the Discussion identifies seizures and language delay as common early signs. The Discussion describes variable seizure types but does not establish focal or myoclonic-atonic seizures specifically as the presenting seizures, or establish normal development at their onset. Page numbers were not provided in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCLN2 disease is followed by rapid progression to a progressive myoclonus epilepsy, severe regression, visual failure and early death.
“It is followed by rapid progression to a progressive myoclonus epilepsy, severe regression, visual failure and early death.”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [147]
The Introduction describes seizures, loss of language and psychomotor function, blindness, and premature death; the Discussion reports rapid functional decline. However, the Discussion says seizure types are highly variable and that myoclonic seizures *can* predominate as the disease progresses, rather than establishing progressive myoclonus epilepsy as the course for all patients. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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Self-citation
- Authors
- Nickel, M., Simonati, A., Jacoby, D., Lezius, S., Kilian, D., Van de Graaf, B., Pagovich, O. E., Kosofsky, B., Yohay, K., Downs, M., Slasor, P., Ajayi, T., Crystal, R. G., Kohlschütter, A., Sondhi, D., & Schulz, A.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- University of Verona (IT)
- BioMarin (United States) (US)
- Weill Cornell Medicine (US)
- NYU Langone Health (US)
- Statistics Collaborative (US)
- Corresponding author
- Schulz, Angela
- ORCID
- Venue
- The Lancet Child & Adolescent Health
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 2
- Issue
- 8
- Pages
- 582-590
- ISSN
- 2352-4642 (ISSN-L)
- PMC
- PMC7516285
- OpenAlex
- W2811299944
- Cited by
- 148
- References
- 27
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 16 · 2023: 15 · 2022: 17 · 2021: 22 · 2020: 23 · 2019: 9 · 2018: 4
- FWCI
- 9.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Child & Adolescent Health (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Seventh Framework Programme (281234)
- National Institutes of Health (1R01NS061848, U54NS065768)
- Cures Within Reach
- European Commission
- Bundesministerium für Bildung und Forschung (NCL2Treat 01GM1516C)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- late infantile neuronal ceroid lipofuscinosis, disease progression, disease onset, epilepsy, survival, natural history (disease), lysosomal storage disease, early symptoms, age at diagnosis
- MeSH terms
- Tripeptidyl-Peptidase 1, Adolescent, Child, Child, Preschool, Female, Humans, Infant, Longitudinal Studies, Male, Neuronal Ceroid-Lipofuscinoses, Cohort Studies, Disease Progression
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