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CLN2 Disease

CLN2 disease is a rare and rapidly progressing pediatric neurodegenerative genetic disorder1,2

CLN2 disease:

  • Is an autosomal recessive lysosomal storage disorder (LSD)2
  • Is one of the most common forms of neuronal ceroid lipofuscinosis (NCL)2
  • Has an estimated incidence of ~0.5 per 100,000 live births3
  • Most commonly presents as the late–infantile phenotype4
  • Mutations in the CLN2/TPP1 gene, which is located on chromosome 11p15 [63], result in deficient lysosomal activity of tripeptidyl-peptidase 1 (TPP1)

CLN2 disease presents both classically and atypically4

CLN2 disease, classic phenotype4:

  • Late–infantile onset
    • The majority of diagnosed cases present with this phenotype and progress in a rapid and predictable manner

CLN2 disease, atypical phenotype4-8:

  • Age of onset, rate of progression, and symptom progression vary, for example:
    • Infantile, with onset under the first year
    • Late–infantile onset with a protracted progression and patients may live into their 20s
    • Juvenile onset with a classic progression
  • Residual TPP1 enzyme activity is more common in atypical CLN2 phenotypes

CLN2 disease experts have identified a new path to expedite earlier diagnosis in children with CLN2 disease based on probing around early language development9

CLN2 disease should be suspected in children aged 2 to 4 with new-onset, unprovoked seizures preceded by early language delay

  • In CLN2 disease, onset of unprovoked seizures typically occurs between ages 2 and 4; febrile seizures may also occur1,10
  • 83% of children with CLN2 disease experienced delay of early language development11
  • In a minority of cases, other developmental delays or ataxia may be the first sign, though these can often occur along with the language delay5
Probing on early language development in children who have had seizures can enable earlier diagnosis of CLN2 disease and access to specific care.

References: 1. Schulz A, Kohlschütter A, Mink J, Simonati A, Williams R. NCL diseases–clinical perspectives. Biochimica et Biophysica Acta. 2013;1832:1801-1806. 2. Mole SE, Williams RE. Neuronal ceroid-lipofuscinoses. 2001 Oct 10 [Updated 2013 Aug 1]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [internet]. Seattle, WA: University of Washington; 1993-2016. 3. Claussen M, Heim P, Knispel J, Goebel HH, Kohlschütter A. Incidence of neuronal ceroid-lipofuscinoses in West Germany: variation of a method for studying autosomal recessive disorders. 1992;42:536-538. 4. Mole SE, Williams RE, and Goebel HH. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics. 2005;6:107-126. 5. Chang M, Cooper JD, Davidson BL, et al. CLN2. In: Mole S, Williams R, and Goebel H, eds. The neuronal ceroid lipofuscinoses (Batten Disease). 2nd ed. Oxford, United Kingdom: Oxford University Press; 2011:80-109. 6. Williams RE, Aberg L, Autti T, et al. Diagnosis of the neuronal ceroid lipofuscinoses: an update. Biochimica et Biophysica Acta. 2006;1762:865-872. 7. Steinfeld R, Heim P, von Gregory H, et al. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet. 2002;112:347-354. 8. Kousi M, Lehesjoki A-­E, Mole SE. 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. 9. Fietz M, Giugliani R, AlSayed M, et al. Expert recommendations for the laboratory diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): diagnostic algorithm and best practice guidelines for a timely diagnosis. Poster session presented at: The 12th Annual WORLD Symposium; February – March 2016; San Diego, CA. 10. Pérez-Poyato MS, Marfa MP, Abizanda IF, et al. Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients. J Child Neurol. 2013;28:470-478. 11. Nickel M, Jacoby D, Lezius S, et al. Natural history of CLN2 disease: quantitative assessment of disease characteristics and rate of progression. Poster session presented at: The 12th Annual WORLD Symposium; February – March 2016; San Diego, CA.