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Neuronal Ceroid Lipofuscinosis Type 2 (CLN2)

CLN2, a form of Batten disease, is a rapidly progressing childhood neurodegenerative disease that causes seizures, dementia and loss of vision.1,2

What is CLN2 Disease?

CLN2 is a childhood neurodegenerative disease characterised by language delay, seizures, loss of motor function, dementia, blindness and early death.1 It is one of the most common forms of neuronal ceroid lipofuscinosis, a group of inherited disorders collectively known as Batten disease, however it is very rare, affecting fewer than 1 in 100,000 live births in most studied populations.1-3 CLN2 disease is a type of lysosomal storage disorder, in which a deficiency in the enzyme tripeptidyl peptidase 1 (TPP1) causes ceroid lipofuscin to build up in nerve cells.1,3 This is associated with degeneration in the brain and eyes by an as yet unknown mechanism.3

CLN2 is an autosomal recessive disease,1 which means that if both parents are carriers of an abnormal TPP1 gene, each time they have a child, there is a one in four chance of that child having CLN2 disease. Families caring for a child affected by CLN2 disease must cope with many difficult emotional and practical challenges, and can experience stress, loss of sleep, lower life satisfaction and a significant financial burden.2

Symptoms of CLN2 Disease

For around 85% of CLN2 patients, the devastating manifestations of the disease follow a predictable course.1,3 The most common first symptoms are language delay and seizures, which typically begin between the ages of two and four years.1 This is followed by a period of rapid deterioration in cognitive and motor functions, leading to the loss of speech and movement by about the age of six.1 Children with CLN2 disease experience developmental regression and worsening dementia,4 as well as becoming blind by the time they are ten years old.1 Patients become wheelchair-bound and dependent on caregivers, and usually die in late childhood or early adolescence.3 In some atypical cases, CLN2 patients may experience earlier or later symptom onset, varied symptoms, and/or slower disease progression.1

Diagnosing CLN2 Disease

Early diagnosis of CLN2 disease is critical for patients and their caregivers, allowing early initiation of disease-specific care, reducing the risk of inappropriate medications, and enabling families to make informed decisions.1 Identifying CLN2 early is challenging due to lack of disease awareness and because the initial symptoms can occur in other, more common conditions.1,3 In children suspected of having CLN2 disease, the disorder can be diagnosed by demonstration of TPP1 enzyme deficiency and/or genetic testing to detect changes in the TPP1 gene.1 In order to avoid cases being missed, it is essential that clinicians keep CLN2 disease in mind, and that hospitals test for CLN2 when a child presents with seizures and language delay.3 Historically, most children with CLN2 disease have been diagnosed at around five years of age when substantial loss of function has already occurred.1 Active disease awareness and increased access to diagnostic programmes are reducing the delay in diagnosis.5 As large-scale gene panels (which test for multiple disease mutations at once) become increasingly available, the key to early diagnosis may lie in prompt use of these next-generation techniques in patients with unexplained epilepsies or other symptoms of developmental regression, rather than waiting for a clear-cut clinical picture suggesting CLN2 disease.3

Managing CLN2 Disease

Because of the wide range of symptoms experienced by children with CLN2 and the complexity of their clinical needs as the disease rapidly progresses, a multidisciplinary approach is advocated to manage patients and support their families.1,3 Earlier on, the aim is to keep children functioning for as long as possible, particularly in terms of movement and communication.1 Understanding of CLN2 is growing and treatment is based on managing clinical signs and symptoms as well as addressing the underlying cause of the disease.3


References
  1. Williams RE et al. Management strategies for CLN2 disease. Pediatr Neurol 2017; 69:102-12.
  2. Schulz A et al. The challenges of living with and caring for a child or children affected by neuronal ceroid lipofuscinosis type 2 disease: In-depth family surveys in the United Kingdom and Germany. J Inborn Errors Metab Screen 2020;8:e20190013.
  3. Specchio N et al. Changing times for CLN2 disease: The era of enzyme replacement therapy. Ther Clin Risk Manag 2020;16:213-22.
  4. 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):160-67.
  5. Pang T et al. Update on a sponsored no-cost epilepsy gene panel for seizure onset between 24 years of age: Results from 682 tests. Poster 321. Presented at the 16th Annual WORLDSymposium, 10-13 February 2020, Orlando, FL, USA.