Children with CLN2 disease

Natural history

CLN2 disease follows a devastatingly rapid course – symptoms and functional loss progress with age

Timeline of classic CLN2 disease symptom onset and loss of function1-6

Timeline of CLN2 disease symptom onset
Age ranges depicted are averages for the classic late-infantile phenotype. Atypical phenotypes of CLN2 disease can vary in age of onset, rate of progression and disease manifestation.

Ages 0 to 2

  • Lysosomal accumulation of lipopigments is thought to begin in the prenatal period, yet children appear to develop normally until the onset of presenting symptoms2
  • The first symptom in the majority of cases is early language delay, as shown in recent clinical findings7
  • In a minority of cases, other developmental delays, motor difficulties, or ataxia may be the first sign4,5
    • Often these can occur together with language delay

Ages 2 to 4

  • Even though language delay may appear earlier, seizures (which occur around age 3) are the symptom that most often leads parents to seek medical attention for CLN2 disease2,8
  • Multiple types of seizures can be observed, including generalised tonic-­clonic, absence, myoclonic, atonic, clonic and tonic2,4
    • Although seizures are most often unprovoked, febrile seizures may occur4
  • Onset of ataxia often occurs during this stage of the disease5

Ages 4 to 7

  • Symptoms compound with age, and there is a dramatic loss of previously attained skills. During this age range, children with CLN2 disease typically experience:1,2,8,9
    • Language regression
    • Myoclonic seizures, both epileptic and non-epileptic
    • Severe motor function impairment with eventual loss of voluntary movements
    • Movement disorders such as myoclonus, spasticity, dystonia and chorea
    • Visual deterioration which leads to blindness by age 6 or 7
  • Eventually, there is a complete loss of language and ability to walk and children become wheelchair-dependent, bedridden, and completely reliant on carers2

Ages 8 to 12

  • CLN2 disease is characterised by premature death and the majority of children rarely survive past early adolescence1

Blindness is an early symptom in other NCLs, but occurs in the later stage of CLN2 disease.6,9

Dr Paul Gissen, MBChB, PhD, FRCPCH
University College London
Great Ormond Street Hospital for Children
NHS Foundation Trust

An overview of the predictable nature of CLN2 disease and when symptoms develop throughout the lives of affected children.

The CLN2 disease clinical rating scale is an efficient way to assess disease progression in 2 major functional areas: motor and language ability

The standardised scoring system can be used to quantitatively assess disease progression at diagnosis and track loss of function over time6

  • Each functional area is scored on a scale of 3 (grossly normal) to 0 (profoundly impaired)6
  • The highest possible score when assessing motor and language function is 67

Functional performance ability is rated as follows:6

CLN2 disease rating scale motor and language function chart

In addition to motor and language function assessments, there are also functional domains (each with a 3­-point scale) to assess vision and the frequency of seizures.6

*In some children, normal motor and/or language development was never present. In such cases, the best performance achieved by the child was considered normal. When that performance level became recognisably worse, the child was rated a 2 for slightly abnormal motor function and/or language development.

Dr Alfried Kohlschuetter, MD
Professor of Paediatrics
Department of Paediatrics
University Medical Center Hamburg-Eppendorf
Hamburg, Germany

Hear how the CLN2 disease clinical rating scale was created to help physicians quantitatively track disease progression, and learn more about the important role carers play in providing disease progression insights as they track and monitor routine functions in their child with CLN2 disease.

Recognising CLN2 disease is a race against time

The majority of children with CLN2 disease experience a consistent loss of motor and language function, as measured by the CLN2 disease clinical rating scale7

CLN2 natural history curve
Longitudinal data from 58 subjects with CLN2 disease in DEM-CHILD registry.
  • Average age of first seizure: ~3 years
  • Average age of CLN2 disease diagnosis: ~5 years
  • Average loss per year: 2 points
  • Average age of death: 10.1 years
With a rapid rate of progression, 2 years to diagnosis is too long.

References: 1. Mole SE et al. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics. 2005;6:107-126. 2. Chang M 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. 3. Schulz A et al. NCL diseases – clinical perspectives. Biochimica et Biophysica Acta. 2013;1832:1801–1806. 4. Pérez-Poyato 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. 5. Worgall S et al. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther. 2008;19:463-474. 6. 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;112:347-354. 7. Nickel M 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. 8. Schulz A et al. Neuronal ceroid lipofuscinosis-2 (CLN2) disorder, a type of Batten disease caused by TPP1 enzyme deficiency: current knowledge of the natural history from international experts. Poster session presented at: The Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium; September 2015; Lyon, France. 9. Mole SE and Williams RE. Neuronal ceroid-lipofuscinoses. 2001 Oct 10 [Updated 2013 Aug 1]. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [internet]. Seattle, WA: University of Washington; 1993-2016.