By: Sofia Arreguin
What is CLN2?
CLN2 is the gene responsible for producing TPP1, an enzyme responsible for removing waste, such as protein and fats, from cells through its production of the enzyme tripeptidyl peptidase 1. Situated in every cell is a lysosome, which possesses enzymes that decompose and recycle certain materials within the cell; TPP1 is one of those enzymes. Within the lysosomes, TPP1 works to recycle and break down peptides, such as protein fragments, into amino acids, or their initial building blocks (National Library of Medicine, 2016). This waste removal allows for the maintenance of healthy cells and, therefore, a healthier body. However, an abnormality within the CLN2 gene could cause a decline in the amount of functioning TPP1 enzymes, resulting in what many refer to as a late infantile-onset form of Batten’s Disease (NIH, 2024).
CLN2-Related Epilepsy
Named Ceroid Lipofuscinosis Neuronal 2, the manifestation of CLN2-related epilepsy within an individual originates from a mutation in the TPP1 gene. Primarily affecting children ages two to four, this rare genetic disorder prohibits the TPP1 gene from producing the enzyme tripeptidyl peptidase 1. Considered to be a form of lysosomal storage disorder, because of its lack of a ‘protein-severing’ enzyme, these unremoved macromolecules, like lipids and proteins, begin to accumulate in the child’s neurons and cells, especially in the eyes and brain (What is CLN2 disease, n.d.). Rather than breaking down these materials, lysosomes store them, eventually leading to neurodegeneration and defective cell function. As a result, a series of symptoms begin to appear, such as recurrent and worsened seizures, muscle twitches, poor motor skills and coordination, vision impairment, a loss of formerly developed skills, and worsened intellectual disability (National Library of Medicine, 2016). Many affected children seldom survive past their teenage years, typically passing away at ages six to twelve.
Their unfortunate deaths stem from the fact that this rare disease is inherited, passed down through families. When a child is born, they inherit two copies of the CLN2 gene: one from their mother and the other from their father. However, those who develop CLN2 disease, a type of epilepsy, inherit mutated versions of the gene, categorizing this condition as an autosomal recessive disorder, a circumstance in which a child inherits a copy of a mutated gene from each parent (What is CLN2 disease, n.d.). In this case, parents are identified as carriers of the genetic abnormality by possessing one mutated CLN2 gene. While they remain healthy, the likelihood of handing down CLN2 disease to their children rises. For example, if both parents carry the mutation, there is a 25% chance their child will acquire the mutation, a 25% chance they won’t retain the mutation, and a 50% chance of the child remaining healthy, but carrying the one mutated gene of the CLN2 disease (What is CLN2 disease, n.d.).
Research and Treatment
One of the most well-known and approved treatments for CLN2 disease is Cerliponase alfa, an enzyme replacement therapy supplying TPP1 directly to the child’s brain. Advertised as BioMarin by the U.S., this treatment involves surgically implanting intracerebroventricular devices (ICV) through the skull to allow for the administration of medication into the brain’s ventricles (Batten Disease Family Association, n.d.). Children receive this treatment every two weeks, with each session occupying about four hours and thirty minutes of their time. While this treatment works to delay the progression of a loss of mobility, it cannot cure or reverse any existing damage. Medical professionals may also prescribe antiepileptic medications (AEDs) to prevent or regulate the occurrence of seizures and hallucinations. Other types of therapy or treatment can present themselves in the form of occupational and mental health counseling. For instance, occupational therapy may help alleviate a child’s muscle spasms and maintain mobility, while mental health counseling can provide support to individuals in coming to terms with the concept of an early death and managing grief (Batten Disease, 2024).
In terms of diagnosis, physicians often employ the use of testing, such as genetic testing and biopsies. With genetic testing, blood and saliva samples are collected and delivered to labs, where they are analyzed for signs of genetic changes to the DNA (Batten Disease, 2024). This testing is often conducted to verify a Batten’s Disease diagnosis. With a biopsy, tissue samples of the child’s skin are scrutinized under the lens of a microscope, in search of extensive clusters of lipofuscin (Batten Disease, 2024). Described as being ‘yellowish-brown,’ these groupings consist of proteins and lipids, both of which accumulate within the skin and other tissues. As mentioned, an accumulation of proteins and fats is a significant factor in the development of CLN2 disease.
While the life expectancy of a child with this condition varies based on severity, it is important to note that the sooner the symptoms begin to appear, the briefer the lifespan. If someone is affected by this rare genetic condition, it may be beneficial to offer support, comforting them with the knowledge that there are treatments that offer a better quality of life, such as slowing the progression of the disease’s symptoms.
References
Batten Disease. (2024, September 30). Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/6018-batten-disease
Batten Disease Family Association. (n.d.). CLN2 Disease, Late-Infantile. https://bdfa-uk.org.uk/batten-disease/types-batten-disease/cln2
National Institute of Neurological Disorders and Stroke. (2024, December 4). Cerliponase alfa (Brineura®) – Ceroid lipofuscinosis 2 (CLN2 disease). https://www.ninds.nih.gov/about-ninds/what-we-do/impact/ninds-contributions-approved-therapies/cerliponase-alfa-brineurar-ceroid-lipofuscinosis-2-cln2-disease
National Library of Medicine. (2016, November 1). CLN2 Disease. MedlinePlus. https://medlineplus.gov/genetics/condition/cln2-disease/
What is CLN2 disease?. (n.d.) CLN2family.com. https://www.cln2family.com/what-is-cln2-disease/
