Dementia in children – is that possible? Yes: as a side effect of a fatal metabolic disease. There is no treatment yet, but that could change soon.
dementia It is considered a disease of old age, which usually only occurs after the age of 60. In rare cases, however, children and adolescents can also be affected. These childhood dementias include neuronal ceroid lipofuscinoses (NCL or CLN). An international research team led by scientists from the University of Göttingen and the University of Zurich (UZH) has now examined the processes involved in the development of a specific subtype of the disease in more detail. The results could be a first step in the development of new treatment approaches for this form of dementia.
CLN5: How does the disease come about?
CLN is a group of rare, genetically determined metabolic diseases that lead to severe changes in the brain and have not yet been cured. About one in 30,000 newborns is affected. “There are a total of 13 different subtypes that differ in the type of genetic defect,” explains Prof. Robert Steinfeld. He is Professor of Pediatric Neurology at the University of Zurich and one of the senior authors of the study.
“Depending on the subtype, those affected develop abnormalities shortly after birth, in early childhood or in young adulthood. They lag behind in language, motor and cognitive development, have epileptic seizures and suffer from retinal degeneration with progressive poor eyesight, which over time can lead to total blindness.” The type and severity of symptoms can vary with the type of disease. The course of the disease is usually they will advance and life expectancy is significantly reduced. There is progressive cognitive decline and most of those affected die in adolescence or early adulthood.
All CLN forms have in the Neurons Storage material on that the name Ceroid-Lipofuszine carries. It is currently unclear whether this storage material is causally linked to the death of nerve cells or is a side effect of neurodegeneration. A research team around Robert Steinfeld and Ralph Krätzner from the University of Zurich and the Clinic for Pediatric and Adolescent Medicine at the University Medical Center Göttingen (UMG) has now identified the causes of Finnish late infantile neuronal ceroid lipofuscinosis, a specific subtype of the disease, examined more closely. Their results are recently in the journal Science Advances appeared. “Children with this variant, in which there is a mutation in the CLN5 gene, become conspicuous from the age of about four and die in their teens,” explains Steinfeld.
| follow the channel Thrill for more neurology topics. consequences Are you also interested in news from other medical fields? Discover here other DocCheck channels. |
More precise biochemical understanding
Until now, little was known about how the mutations affect the CLN5 protein. “In the new study, we have now succeeded in gaining a more in-depth structural biological and biochemical understanding of CLN5,” reports Steinfeld. The research team was able to crystallize CLN5 protein produced in a cell culture and thus determine its three-dimensional structure. Using the structural data, the scientists also found out that the protein is a Enzymes acts, that Palmitatreste cleaved from proteins. The activity of the enzyme was greatly reduced in variants of the CLN5 protein into which the disease-causing mutation had been introduced.
“Our results make it clear that processes of protein lipidation and De-palmitoylation play an important role in the development of the disease,” explains the neuroscientist. “A malfunction of the enzyme can apparently cause both early childhood and late-onset neurodegenerative disease processes that lead to loss of function and the death of nerve cells.”
A specific CLN5 variant (p.Asn320Ser) is associated with a familial form of Alzheimer’s disease associated. It is possible that the functional restriction of CLN5 leads to increased palmitylation of cellular proteins. “One possible candidate is the enzyme BACE1, which in its palmitylated form can split amyloid precursor protein (APP) into beta-amyloid to a greater extent,” explains Robert Steinfeld. “Since the occurrence of Beta-Amyloid is associated with Alzheimer’s disease, reduced de-palmitylation may thus favor the neurodegenerative process.”
Basis for further studies – and possible therapies
The researchers see the new findings as a basis for further studies that are intended to clarify the mechanisms by which the CLN5 mutation leads to the neuronal degradation processes in detail. “This includes, for example, finding out which proteins are actually depalmitoylated by the enzyme,” says the neurologist. “A next important step would then be to use these findings to develop new therapies for CLN5 and other forms of CLN.”
For a CLN variant, namely CLN2, there has been one since May 2017 medical therapy available, which can at least delay the progression of symptoms in about two-thirds of patients. It is an enzyme replacement therapy Cerliponase alfa, in which patients receive a corresponding bioengineered enzyme to replace the missing enzyme. However, the therapy is complex and can be stressful for the patient. The substance has to be introduced into the liquor space with a catheter every 14 days and side effects such as fever, vomiting or cramps and inflammation at the access point can occur. The costs are also very high – they are around 750,000 euros per year. The therapy has been approved by the EU Commission and the costs are covered by statutory health insurance in Germany for patients who meet the indication criteria for this treatment.
Analogously, the missing enzyme in CLN5 could also be produced biotechnically and introduced into the cerebrospinal fluid space. “That could help delay the disease. However, it does not lead to a cure,” says Robert Steinfeld. “In my view, therefore, one Gene therapy the more promising treatment approach. Although these do not yet exist, there are already promising developments.”
Currently, many patients and their families are left with only treatment approaches aimed at relieving symptoms and improving quality of life. This includes regular psychological support, pain relief and palliative medicine Approaches. However, Steinfeld is optimistic that an effective therapy for neuronal ceroid lipofuscinosis will be available in 10 to 20 years. “Our new study is at least a small step in the right direction,” says the neuroscientist.
Image source: Kevin Gentunsplash