TPP1 gene

Also known as: CLN2 disease; Ceroid lipofuscinosis neuronal 2, variable age at onset; Jansky-Bielschowsky disease


1. The Disease:

CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1).

2. The symptoms:

CLN2 is a clinically and genetically heterogeneous group of neurodegenerative disorders, with the age of onset predominantly in childhood. Lack of early signs or symptoms does not exclude the diagnosis.

Multiple forms of CLN2 disease exist. In the more common form of the disease patients present with slowing of development and psychomotor regression, language delay and typically followed by epilepsy between the ages of 2 and 4, subsequently developing retinal degeneration and blindness by 5 or 6 years of age.

Left untreated, life expectancy is between 6 years-old and early teenage years.

Around 13% of patients have a later symptom onset [31], more protracted or mild disease course sometimes with the absence of epilepsy and preservation of visual function and a longer life expectancy.

3. Actions to take in case of early diagnosis:  

  • Biochemical correlation is important by determination the TPP1 enzyme activity.
  • CLN2 is a lifelong disease requiring lifetime management and regular follow-up with a Paediatric Neurology Center Management is provided by multidisciplinary team.
  • Various supportive therapeutic approaches (physiotherapy, speech therapy) are recommended.
  • Various treatment strategies are under clinical development for the treatment of CLNs, although to date, there is only one clinically approved drug for CLN2 disease.
  • Recombinant human TPP1 (cerliponase alfa, Brineura™) is an enzyme replacement therapy (ERT) that slows the decline of motor and language function in CLN2 patients. The approval of cerliponase alfa (2017) in the European Union (EU) covers all ages. Clinical trial evidence revealed that the therapy is well tolerated. As in other enzyme replacement therapies, the development of anti-drug antibodies (ADA) represents a constant risk for allergic reactions and—if anti-bodies are neutralising—for loss of treatment efficacy. Although ADA production was detected in the cerebro-spinal fluid (CSF) and serum, of 25% and 79% patients, respectively, this was not associated with neutralising antibodies, any incidence of hypersensitivity adverse reactions, or reduced therapeutic response.
  • Cerliponase alfa is administered every two weeks via slow intracerebroventricular (ICV) infusion. This technique requires device implantation under general anaesthesia, by an experienced paediatric neurosurgeon.
  • Potentially future gene therapy for treatment of CLN2 disease is likely to impose new challenges as life expectancy increases.
  • Genetic counselling should be offered to at-risk family members.

4. For more information:


Biblio: Mole SE, Schulz A, Badoe E, et al. Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients. Orphanet J Rare Dis. 2021;16(1):185. PMID: 33882967.