Neuronal ceroid lipofuscinoses (NCLs) or Batten disease is a group of neurodegenerative disorders involving lysosomal storage. A gene mutation affects the lysosome's ability to function, leading to a buildup of material inside the cell. Mutations in one of 13 genes can result in Batten disease. Symptoms depend on the gene that is affected, but many overlap.
The gene mutations in Batten disease prevent cellular lysosomes from functioning properly, which means the breakdown of molecules like proteins, carbohydrates, and old cell parts doesn't happen. This malfunction causes a cascade of problems, with the symptom severity and when they appear varying from person to person. Batten disease originally referred to only one subset of NCLs, but it is now used to describe all forms.
Symptoms of Batten disease usually begin in childhood, though the age of onset varies significantly based on the specific mutation causing the gene. Initial symptoms include behavioral changes, learning difficulties, and slow or involuntary movements. Over time, these symptoms progress to seizures and loss of language, motor skills, and intellectual abilities. Eventually, children with this disease lose all cognitive function and motor skills.
There are 14 subtypes of Batten disease, named CLN1 to CLN14. Different mutations cause each subtype, and while there are many overlapping symptoms, each subset is unique. For example, CLN1 is known as infantile Batten disease. Symptoms start at around 18 months of age, whereas symptoms of CLN2 start between ages 2 and 4. CLN4 is the only variant caused by an autosomal dominant genetic pattern, with symptoms beginning around age 30. People with the CLN8 variant can live into their 50s, while the life expectancy for CLN10 is only days after birth.
There is no cure for Batten disease, and only one form, CLN2, has an approved treatment. Children with Batten disease have a short life expectancy, with the length directly linked to how early the symptoms appear. In the variants that do not appear until adulthood, symptoms tend to be milder and may have less impact on life expectancy.
Batten disease is considered an autosomal recessive disease, which means that children who have it inherit a defective gene from both parents. People who only have one copy of the defective gene do not develop the disease, but they are carriers. When two people who are carriers have a baby, there is a one in four chance that the child will develop Batten disease. The biggest risk factors for Batten disease are a parent with the disease or one who is a carrier.
Symptoms vary from person to person, but like other neurodegenerative diseases, Batten disease commonly manifests with significant and progressive neurological and motor problems. Specific symptoms include retinal abnormalities leading to vision loss, weak muscle tone, metabolic abnormalities, movement disorders, loss of developmental milestones, and speech impairments.
Batten disease is very rare. By some estimates it affects two to four out of 100,000 children in the United States. This rarity makes getting a diagnosis challenging. Doctors typically look at symptoms, medical history, and lab results. Batten disease can occur in more than one person in a family that carries the mutated gene, resulting in a faster diagnosis.
While there is only one approved treatment for one subtype of Batton disease, there is a lot of ongoing research into effective treatments. Some lab results have been promising. For example, enzyme replacement therapy has had positive results in mouse and canine versions of CLN2, including delaying the onset of symptoms and extending life span. Researchers are also studying immunomodulatory agents to suppress inflammation and degeneration in CLN6 in sheep and CLN1 and CLN3 in mice.
Researchers are also exploring stem cell therapy as a treatment for Batten disease. Scientists believe that stem cells from a healthy donor can differentiate inside the brain to secrete working lysosomal enzymes. Although research showed positive results in mice, results of a clinical trial involving two patients with CLN1 and four with CLN2 were not as promising.
Gene therapy has shown positive results in animals, though they vary based on the specific treatment. Some show improvements in behavior and a reduction in neurodegeneration but no increase in lifespan, while others saw improved motor skills, neurological function, and longevity. Clinical trials suggest a possible slowing of the disease progression in humans. Research and additional phases of human clinical trials are still ongoing.
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