Study Provides More Insight into Early Signs, Progression of CLN5 Disease

In children with late infantile neuronal ceroid lipofuscinosis 5 (CLN5), cognitive difficulties are early clinical markers of this condition, and severe mutations are associated with a more rapid decline of neurological function, a study has found.

The study, “Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5,” was published in the journal Developmental Medicine and Child Neurology.

CLN5 is a rare form of neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease. It is caused by mutations in the CLN5 gene, which provides instructions for making the pCLN5 protein, whose function is not yet fully understood.

Although adolescent and adult onset cases of CLN5 have been reported, it is mainly considered to be a disease of late infantile onset, often developing in children between 2 and 8 years old.

There is limited information on CLN5, particularly on the survival and natural history of the disease. This information is necessary to assess the effectiveness of new treatments currently in development.

To characterize disease features in a group of children with CLN5, records of 15 children, including nine males and six females, with CLN5 from either the DEM-CHILD International NCL Registry or a collaboration of international clinical experts were analyzed.

A new scale, ranging from zero (complete loss of function) to four (normal), was used to assess clinical symptoms and included parameters concerning motor, vision, language, behavior, learning, cognition, and epilepsy.

Assessment was carried out at disease onset, during the early course of the disease (less than three years after onset) and at later stages, at three to five years and six to 10 years after onset.

Patients also underwent brain magnetic resonance imaging (MRI) and analysis of the skin and white blood cells.

Median disease onset was at preschool age, with a median age of 4 years old, and impairments related to cognitive, learning abilities, and motor function were the most common early clinical symptoms, while impaired visual function and seizure onset occurred relatively late, at three to four years after disease onset.

Other features observed included behavior disturbances, hyperactivity, and aggression. As the disease progressed, patients also showed signs of anxiety, obsessive activities, and hallucinations.

Genetic analysis revealed nine different mutations in the CLN5 gene. There was no difference in the rate of clinical decline between patients with different mutations during the first three years. However, after that time frame, mutation severity was correlated to clinical decline.

“The findings of a possible genotype–phenotype relationship in CLN5 disease, late infantile, requires further exploration, but may suggest that within the first 3 years of the disease there may be a temporal window of opportunity for experimental or novel disease-modifying treatments,” the researchers wrote.