Batten disease and genetics
Batten disease, also known as neuronal ceroid lipofuscinosis (NCL), is an inherited genetic disorder characterized by the accumulation of lipopigments in the body's tissues, leading to a range of neurological symptoms. The juvenile form of this condition, commonly referred to as Batten disease, typically manifests between the ages of five and eight and progresses less rapidly compared to other forms of NCL. Genetic mutations in several specific genes, including CLN3, CLN1, CLN2, and CLN5, are responsible for various types of Batten disease, which are inherited in autosomal recessive or dominant patterns.
Symptoms include vision loss, motor coordination difficulties, seizures, and cognitive decline, with the severity and progression of the disease varying by type. Diagnosis can be challenging due to its rarity and often begins with eye examinations. Currently, there is no cure for Batten disease, and treatments focus on managing symptoms and improving quality of life. While research is ongoing, including experimental therapies like stem cell treatment and dietary interventions, no definitive prevention measures exist. Families with a history of Batten disease may benefit from genetic counseling when considering future pregnancies.
Batten disease and genetics
ALSO KNOWN AS: Neuronal ceroid lipofuscinosis
DEFINITION Batten disease is the most common form of a group of rare disorders known as neuronal ceroid lipofuscinoses (NCLs). Batten disease is an inherited genetic disorder that causes a buildup of lipopigments in the body’s tissue. “Batten disease” refers to the juvenile form of NCL, but the other forms of NCL can also be referred to as “Batten disease.” About 2 to 4 of every 100,000 births are affected, according to the Batten Disease Support and Research Association. The forms of NCL include infantile NCL, late infantile NCL, juvenile NCL, and adult NCL.
Risk Factors
Since Batten disease is an inherited condition, people at risk include children of parents with Batten disease and children of parents not afflicted with Batten disease, but who carry the abnormal genes that cause the disease.
Etiology and Genetics
The infantile, late infantile, and juvenile forms of Batten disease, while caused by mutations in three different genes, are all inherited in an autosomal recessive manner. Both copies of the particular gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected, but two-thirds of the unaffected children will be carriers like their parents. A simple blood test is available to screen for and identify the most common carrier for juvenile Batten disease.
Adult NCL, which can be caused by mutations in at least two different genes, is inherited as either an autosomal recessive or in an autosomal dominant fashion. In autosomal dominant inheritance, a single copy of the mutated gene is sufficient to cause full expression of the disease. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children.
The juvenile form of Batten disease is caused by mutations in the CLN3 gene, found on the long arm of chromosome 16 at position 16p12.1. The CLN3 protein, also known as palmitoyl-protein delta-9 desaturase, has been shown to participate in the membrane-associated modification of proteolipids. Lack of this activity may result in the accumulation of proteolipids in cells, leading to the neurodegeneration that is characteristic of the disorder.
Candidate genes associated with the infantile and late infantile forms of the disease have also been identified, and these have been named CLN1 and CLN2, respectively. CLN1, which is found on the short arm of chromosome 1 at position 1p32, encodes a protein called palmitoyl-protein thioesterase. CLN2, located on the short arm of chromosome 11 at position 11p15.5, encodes an acid protease, an enzyme that hydrolyzes specific proteins.
In 2023, the Canadian Institutes of Health Research published research about the CLN5 subtype of Batten disease, which causes the lysosome to malfunction. This means that waste material in a cell cannot be broken down or cannot be removed. The CLN5 protein regulates how the lysosome functions, so mutations in this protein affect how the cell processes and breaks down material. Researchers used a microbe as a model. They introduced genetic mutations into the microbe. These mutations mimic those found in Batten disease. They planned to study how these mutations affect cell behavior, which would lead to a better understanding of the disease.
Symptoms
Symptoms of Batten disease include vision loss (an early sign) and blindness, muscle incoordination, mental retardation or decreasing mental function, emotional disturbances or difficulties, seizures, muscle spasms, deterioration of muscle tone, and movement problems.
These symptoms are similar in each type of the disease. However, the time of appearance, severity, and rate of progression of symptoms can vary depending on the type of the disease.
In infantile NCL (Santavuori-Haltia disease), symptoms begin to appear between the ages of six months and two years and progress rapidly. Children with this type generally live until midchildhood (about age five), though some survive in a vegetative state a few years longer.
In late infantile NCL (Jansky-Bielschowsky disease), symptoms begin to appear between ages two and four and progress rapidly. Children with this type usually live until ages eight through twelve. Symptoms of juvenile NCL (Batten disease) begin to appear between ages five and eight and progress less rapidly. Those afflicted usually live until their late teens or early twenties and, in some cases, into their thirties.
Symptoms of adult NCL (Kufs disease or Parry disease) usually begin to appear before age forty. Symptoms progress slowly and are usually milder. However, this form of the disease usually does shorten a person’s life span.
Screening and Diagnosis
Batten disease is often difficult to diagnose because it is so rare. Vision problems are often the first symptoms. Therefore, an initial diagnosis may result from an eye exam. To confirm the diagnosis, tests are taken. These include testing to look for evidence of a buildup of lipopigments, such as blood tests, urine tests, and tissue biopsies examined with an electron microscope.
Imaging tests can look for specific brain abnormalities. These include a magnetic resonance imaging (MRI) scan, which uses magnetic waves to make pictures of the inside the body; a computed tomography (CT) scan, a type of X-ray that uses a computer to take pictures inside the body; and an electroencephalogram (EEG), a test that records the brain’s activity by measuring electrical currents through the brain. Electrical studies of the eyes can look for vision problems associated with the disease, while deoxyribonucleic acid (DNA) analysis can look for the abnormalities that may cause this disease.
Treatment and Therapy
There is no known treatment that will stop the progression or effects of Batten disease. Therefore, treatment aims to reduce symptoms.
Patients who have seizures can be given anticonvulsant medications to help control seizures. In addition, physical and/or occupational therapy can help people continue functioning for a longer period of time.
One experimental therapy is supplementation with vitamins C and E combined with a diet low in vitamin A. This may slow the progression of the disease in children; however, there is no evidence that it will halt the ultimate progression of the disease. Parents should talk to their child’s doctor before trying this therapy.
Very early trials of stem cell treatment for infantile and late infantile disease are now underway. There is hope that these or other forms of gene therapies may have an effect on the progression of Batten and Jansky-Bielschowsky diseases.
Prevention and Outcomes
There is no known way to prevent Batten disease. Individuals who have Batten disease or have a family history of the disorder can talk to a genetic counselor when deciding to have children.
Bibliography
Adams, Heather R., et al. "Experience, Knowledge, and Opinions About Childhood Genetic Testing in Batten Disease." Molecular Genetics & Metabolism 111.2 (2014): 197–202. Print.
Dawson, G., and S. Cho. “Batten’s Disease: Clues to Neuronal Protein Catabolism in Lysosomes.” Journal of Neuroscience Research 60.2 (April 15, 2000): 133–40. Print.
Dolisca, Sarah-Bianca, et al. "Batten Disease: Clinical Aspects, Molecular Mechanisms, Translational Science, and Future Directions." Journ. of Child Neurology 28.9 (2013): 1074–1100. Print.
EBSCO Publishing. Health Library: Batten Disease. Ipswich: Author, 2009. Print.
Huber, Dr. Robert. "Uncovering the Mystery of Batten Disease." Canadian Institutes of Health Research, 31 May 2023, cihr-irsc.gc.ca/e/53498.html. Accessed 10 Sept. 2024.
Maria, Bernard L. "Batten Disease: Current Understanding and Future Directions." Journ. of Child Neurology 28.9 (2013): 1072–73. Print.
Mole, S. E. “Batten’s Disease: Eight Genes and Still Counting?” Lancet 354.9177 (1999): 443–45. Print.
Sondhi, D., et al. “Feasibility of Gene Therapy for Late Neuronal Ceroid Lipofuscinosis.” Archives of Neurology 58.11 (2001): 1793–98. Print.
Taupin, P. “HuCNS-SC (StemCells).” Current Opinion in Molecular Therapeutics 8.2 (2006): 156–63. Print.
Wisniewski, Krystyna E., and Nanbert Zhong, eds. Batten Disease: Diagnosis, Treatment, and Research. San Diego: Academic Press, 2001. Print.