Resolving neuronal ceroid lipofuscinoses Neuronal ceroid lipofuscinoses (NCLs) are incurable neurodegenerative disorders that are the leading cause of childhood dementia in Europe. NCLs cause visual loss, dementia, epilepsy and progressive physical decline leading to death. Health © misfire_asia, Shutterstock The EU-backed project DEM-CHILD (A treatment-oriented research project of NCL disorders as a major cause of dementia in childhood) was initiated to rapidly and cost-effectively detect as well as combat NCL. The DEM-CHILD consortium consisted of expert scientists, clinicians and ethicists, high-tech SMEs, and NCL patient and family associations. Noteworthy is the development of a novel network that includes experienced NCL clinicians from Europe and India. This helped in collecting the largest clinically and genetically best-characterised set of natural history data on NCL patients. An online DEM-CHILD patient database consortium has been developed that will continually be updated even after the project ends. A major accomplishment was development of the NCL diagnostic algorithm, the focus of two peer-reviewed journal publications. DEM-CHILD successfully devised a cost-effective and rapid gene-based diagnostic tool that can detect all NCL forms. NCLs have been associated with gene mutations such as CLN1, CLN2 and CLN3. Researchers successfully developed an automated high-throughput enzyme activity testing method based on mass spectrometry to detect CLN1, CLN2 and CLN10 gene mutations from dry blood spots. They also identified modifiers and biomarkers of CLN3 and CLN1 diseases. Scientists identified a novel signalling pathway associated with CLN3 disease that could be a potential target for therapy. Using animal models, researchers ascertained biochemical changes that are specific to CLN1. They also identified a to-date unknown NCL disease gene called ATP13A2/CLN12. DEM-CHILD carried out preclinical tests to evaluate the possibility of vision recovery via innovative gene therapies as well as intravitreal transplants using modified neural stem cells. Results were encouraging, suggesting further research into neuroprotective approaches could prove successful in restoring vision. Project outcomes were disseminated through DEM-CHILD teaching seminars, the project website, workshops, conferences, publications, articles, a diagnostic handout and a teaching video. The DEM-CHILD patient database could be used for assessing efficacy of palliative care as well as validation of experimental therapies. NCL diseases are heartbreaking for both patients and their families. Prenatal testing for NCL using DEM-CHILD tools could identify NCL cases and prevent the incidence of more such cases in affected families. Keywords Neuronal ceroid lipofuscinoses, neurodegenerative, dementia, DEM-CHILD, gene-based diagnostic tool
