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Understanding CLN2 (a form of Batten disease)

Have you seen a child with new-onset unprovoked seizures, language regression, or a gradual loss of motor skills?

Are these symptoms progressing faster than expected, without a clear explanation?

These features can be early indicators of a group of rare, inherited neurodegenerative conditions known as neuronal ceroid lipofuscinoses (NCLs) — sometimes referred to collectively as Batten disease.1,2

What are neuronal ceroid lipofuscinoses/NCLs?

  • NCLs are a family of rare inherited lysosomal storage disorders, and are a leading cause of childhood dementia3
  • NCLs are caused by pathogenic variants in different genes, each leading to deficiency of specific proteins involved in cellular waste processing3
  • NCLs vary in presentation but are often associated with seizures, progressive loss of motor and cognitive abilities, vision impairment, and early-onset neurodegeneration4,5

Classification and characteristics of NCLs6-8

Adapted from Mole & Cotman, 2015.4

NCLs share a host of aetiological and clinical characteristics3

  • Severe and progressive neurodegeneration9
  • Debilitating triad of symptoms – seizures, dementia and vision loss3
  • Neuronal and retinal accumulation of ceroid lipofuscin10
    • NCLs feature distinct inclusion bodies, including granular, curvilinear, and fingerprint profiles11
    • In CLN2, the distinct curvilinear structure of ceroid lipofuscin is evident under microscopy11
  • Classic and atypical presentations with varying age of onset, symptoms and disease course based on type and phenotype3


Ultrastructural appearances of different forms of NCL:

Source: Haltia, 2003.11

What is CLN2 Disease?

CLN2 disease (late-infantile NCL type 2), an NCL subtype, is an autosomal recessive disorder caused by pathogenic variants in the TPP1 gene which codes for the TPP1 enzyme.9

CLN2 disease at a glance:

  • Rare, autosomal recessive, neurodegenerative lysosomal storage disorder9
  • Caused by variants in the TPP1 gene9
  • Early symptoms include new-onset unprovoked seizures and early language delay or regression12
  • Psychomotor regression and functional loss become more prominent as CLN2 disease progresses12
  • Early suspicion of CLN2 can expedite diagnosis, optimise clinical care and improve outcomes8,13

What is the pathogenesis of CLN2 disease?

CLN2 disease is caused by mutations in the TPP1 gene, which result in deficient activity of the tripeptidyl peptidase 1 (TPP1) enzyme. TPP1 is a protease that cleaves N-terminal tripeptides from substrates in lysosomes.8–10

The absence or reduced activity of the TPP1 enzyme is associated with an accumulation of ceroid lipofuscin storage material in the lysosomes.10,14

Over time, cell dysfunction, cell death and atrophy occur.2,9

Lysosomal accumulation of ceroid lipofuscin in CLN2 disease is thought to begin in the prenatal period, yet children appear to develop normally until the onset of presenting symptoms.14

How does CLN2 disease present?

CLN2 disease presents on a spectrum with phenotypic heterogeneity. Classic CLN2, the most common form of CLN2 disease, typically presents between two and four years of age with language delay, motor decline, and seizures.3,6 Atypical CLN2 disease is less common, and often has delayed symptom onset and a protracted natural history compared with the classic form.14


*Historically, Jansky-Bielschowsky disease.

Children with CLN2 disease can experience a range of symptoms and complications that require specific types of care. Guidelines recommend a multidisciplinary team approach to CLN2 disease management, in which various specialists work together to holistically address these symptoms and optimise care.13,15

When should CLN2 disease be suspected?

CLN2 disease should be considered in a child with:

  • New-onset unprovoked seizures
  • Early language delay or regression
  • Gradual loss of motor skills or ataxia
  • Developmental regression

Up to 83% of children with CLN2 disease experience delay of early language development. In a minority of cases, other developmental delays or ataxia may be the first sign, though these can often occur along with the language delay.12,21

Why is early diagnosis critical?

Due to the rapid rate of CLN2 progression, effective management of CLN2 disease depends on early recognition of the condition.15 Recognising CLN2 disease is a race against time.

  • Typically, there is a 2-year delay in diagnosis from initial onset of seizures13
  • Without a family history, children are rarely diagnosed before irreversible neurodegeneration has occurred15
  • Seizures are the symptom that most often leads families to seek help, even though language delay often occurs first12,14

For more information on early diagnosis of CLN2 disease, click here.

When unprovoked seizures present, probe for early language delay and perform diagnostic testing for CLN2 disease8,12

How does CLN2 disease progress?

Classic CLN2 disease follows a rapidly progressive course. Early symptoms such as language delay, seizures and motor decline are followed by continued loss of motor and language abilities, developmental regression and progressive neurodegeneration.12,22

Adapted from Nickel et al, 201812 and Specchio et al, 2020.22
*Age ranges represent those typical of the classic late-infantile phenotype. Atypical phenotypes of CLN2 disease can vary in age of onset, rate of progression and disease manifestation.22

The CLN2 disease clinical rating scale is an efficient way to assess disease progression in two major functional areas: motor and language ability.23

CLN2 disease clinical rating scale

CLN2 disease progression can be assessed using the CLN2 clinical rating scale, a modified version of the Hamburg Scale. This scale comprises four domains, which can be evaluated to give a total score (between 0 and 12). 24–26

  • Each functional area is scored on a scale of 3 (grossly normal) to 0 (profoundly impaired)23
  • The motor–language score, which is the sum of the motor and language domains, is often a primary measure of disease progression in clinical trials24,26
  • The highest possible score when assessing motor and language function is 612

Adapted from Specchio et al, 2024.24

What is the differential diagnosis of CLN2 disease?

CLN2 disease can be challenging to recognise.8 Early symptoms can overlap with several other epileptic encephalopathies and other progressive paediatric neurological disorders​.14

CLN2 disease is often initially misdiagnosed, delaying accurate diagnosis. Delayed diagnosis means substantial disease progression can occur before treatment is initiated.12,22 Recognising when CLN2 disease should be considered is essential to support accurate diagnosis.

The differential diagnosis of CLN2 disease varies depending on the stage of disease progression.

Early in the disease course:14

  • Since seizures and myoclonus are the most prominent symptom, CLN2 disease may initially be mistaken for focal epilepsy, myoclonic epilepsy syndromes/myoclonic-astatic epilepsies such as Doose syndrome, Dravet syndrome, Lennox-Gastaut syndrome; or other epilepsy syndromes

Later in the progression of CLN2 disease:14

  • As psychomotor regression and functional loss become more prominent, differential diagnoses may include inflammatory or infectious disorders, tumours, mitochondrial disorders, and other lysosomal storage diseases including other NCL types

A comprehensive diagnostic algorithm for CLN2 disease is available.

A combination of genetic and enzyme testing is used to confirm a diagnosis of CLN2 disease.

Adapted from Fietz et al, 2016.8
*Absence of EEG findings should not preclude follow-on testing for epilepsy syndromes, CLN2 disease or other NCLs.8
†Additional clinical assessments may be warranted, such as brain MRI, OCT/VEP/ERG/FA, EM biopsy.8
‡TPP1 is included in many gene panels; ensure the one you select tests for it.
§TPP1 enzyme activity may be measured in sample types such as dried blood spots or saliva. PPT1 enzyme activity (CLN1 disease) is useful to assess with TPP1.8
‖TPP1 enzyme activity testing in other sample types can also be diagnostic.8
#Includes single gene sequencing, gene panels, or whole exome sequencing.8

Early suspicion of CLN2 can expedite diagnosis, optimise clinical care, and improve outcomes8,13

Reduce the time to diagnosis by combining EEG or MRI findings with genetic or enzymatic testing8,25

Resources

This website provides educational information for healthcare professionals who may be assessing children with unexplained developmental regression or seizure onset.

Looking for more information? Explore the Resources page to access a range of educational materials, clinical resources, expert-led webinars, case studies, and on-demand content relating to CLN2 disease.

Abbreviations

CI, confidence interval; CLN1, neuronal ceroid lipofuscinosis type 1; CLN2, neuronal ceroid lipofuscinosis type 2; EEG, electroencephalogram; EM, electron microscopy; ERG, electroretinography; FA, fluorescein angiography; IPS, intermittent photic stimulation; MRI, magnetic resonance imaging; NCL, neuronal ceroid lipofuscinosis; OCT, optical coherence tomography; PPT1, palmitoyl-protein thioesterase 1; SCAR7, spinocerebellar ataxia, autosomal recessive 7; TPP1, tripeptidyl peptidase 1; VEP, visually evoked potential.

References:

  1. Mole SE, et al. The Neuronal Ceroid Lipofuscinoses (Batten Disease), 2nd ed. Oxford University Press; 2011.
  2. Haltia M. The neuronal ceroid-lipofuscinoses: from past to present. Biochim Biophys Acta. 2006;1762(10):850–856.
  3. Schulz A, et al. NCL diseases – clinical perspectives. Biochim Biophys Acta Mol Basis Dis. 2013;1832(11):1801–1806.
  4. Mole SE, Cotman SL. Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochim Biophys Acta Mol Basis Dis. 2015;1852(10 Pt B):2237–2241.
  5. Gardner E, et al. The neuronal ceroid lipofuscinoses (Batten disease): a review of clinical and molecular features. J Inherit Metab Dis. 1999;22(4):469–484.
  6. Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology. 2012;79:183–191.
  7. Kousi M, et al. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat. 2012;33:42–63.
  8. Fietz M, et al. Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis. Mol Genet Metab. 2016; 119(1–2):160–167.
  9. Mole SE, Williams RE. Neuronal Ceroid-Lipofuscinoses. In: Adam MP, et al., eds. GeneReviews®. 2013.
  10. Mole SE, et al. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics. 2005;6:107–126.
  11. Haltia M. The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol. 2003; 62(1):1–13.
  12. Nickel M, et al. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child Adolesc Health. 2018;2(8):582–590.
  13. Williams RE, et al. Management strategies for CLN2 disease. Pediatr Neurol. 2017;69:102–112.
  14. Chang M, et al. CLN2. In: Mole S, et al. eds. The neuronal ceroid lipofuscinoses (Batten disease). 2nd ed. Oxford, United Kingdom: Oxford University Press; 2011:80–109.
  15. Mole SE, et al. Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients. Orphanet J Rare Dis. 2021;16(1):185.
  16. Di Giacopo R, et al. Protracted late infantile ceroid lipofuscinosis due to TPP1 mutations: Clinical, molecular and biochemical characterization in three sibs. J Neurol Sci. 2015;356(1-2):65–71.
  17. Dy ME, et al. TPP1 deficiency: Rare cause of isolated childhood-onset progressive ataxia. Neurology. 2015;85(14):1259–1261.
  18. Elleder M, et al. Atypical CLN2 with later onset and prolonged course: a neuropathologic study showing different sensitivity of neuronal subpopulations to TPP1 deficiency. Acta Neuropathol. 2008;116(1):119–124.
  19. Sun Y, et al. Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease). Hum Mutat. 2013;34(5):706–713.
  20. Lourenço, CM, et al. Revealing the clinical phenotype of atypical neuronal ceroid lipofuscinosis type 2 disease: Insights from the largest cohort in the world. J Paediatr Child Health. 2001;57:519–525.
  21. Nickel M, et al. Language delay in patients with CLN2 disease: Could it support earlier diagnosis? Neuropediatrics. 2023;54(6):402–406.
  22. Specchio N, et al. Changing times for CLN2 disease: The era of enzyme replacement therapy. Ther Clin Risk Manag. 2020;16:213–222.
  23. Steinfeld R, et al. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet. 2002;112(4):347–354.
  24. Specchio N, et al. Exploring concurrent validity of the CLN2 Clinical Rating Scale: Comparison to PedsQL using cerliponase alfa clinical trial data. PLoS One. 2024;19(5):e0302382.
  25. Sampaio LPB, et al. Clinical management and diagnosis of CLN2 disease: consensus of the Brazilian experts group. Arq Neuropsiquiatr. 2023;81(3):284–295.
  26. Schulz A, et al. Study of intraventricular cerliponase alfa for CLN2 disease. N Engl J Med. 2018;378(20):1898–1907.

COM-ET-3024 | September 2026