Epilepsy & Seizures
Myoclonic status epilepticus
Sep. 20, 2020
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What is Batten disease?
Batten disease is the common name for a broad class of rare, fatal, inherited disorders of the nervous system also known as neuronal ceroid lipofuscinoses, or NCLs. In these diseases, a defect in a specific gene triggers a cascade of problems that interferes with a cell’s ability to recycle certain molecules. The disease has several forms that share some of the same features and symptoms but vary in severity and age when symptoms first begin to appear. Each form is caused by a mutation in a different gene. Although “Batten disease” originally referred specifically to the juvenile-onset form of NCL, the term Batten disease is increasingly used to describe all forms of NCL.
Most forms of Batten disease/NCLs usually begin during childhood. Children with the disease often appear healthy and develop normally before they begin to show symptoms. Children with the infantile or late-infantile forms usually show symptoms earlier than age 1 year. Common symptoms for most of the forms include vision loss, seizures, delay and eventual loss of skills previously acquired, dementia, and abnormal movements. As the disease progresses, children may develop one or more symptoms including personality and behavior changes, clumsiness, learning difficulties, poor concentration, confusion, anxiety, difficulty sleeping, involuntary movements, and slow movement. Over time, affected children may suffer from worsening seizures and progressive loss of language, speech, intellectual abilities (dementia), and motor skills. Eventually, children with Batten disease become blind, wheelchair bound, bedridden, unable to communicate, and lose all cognitive functions. There is no cure for these disorders but a treatment for one of the forms (CLN2 disease) has been approved by the U.S. Food and Drug Administration (see Treatment section).
Children with all forms of Batten disease have a greatly shortened life expectancy. Generally, the increased risk for early death depends on the form of the disease and age of the child at disease onset. Children with infantile Batten disease die prematurely, often in early childhood, while those with later-onset forms may live into their teens to their thirties. If the disease develops in adulthood, the symptoms tend to be milder and may not affect life expectancy.
What causes Batten disease?
Batten disease is an inherited genetic disorder that appears to affect the function of tiny bodies within cells called lysosomes. Lysosomes are the “recycle bin” of the cell and regularly break down waste, proteins, and naturally occurring fatty compounds called lipids into smaller components that can be discarded out of the cell or recycled. Lipids include fatty acids, oils, waxes, and sterols. In Batten disease/NCLs, the mutated genes do not produce the proper amounts of proteins important for lysosomal function. Each gene (representing a form of the disease) provides information for a specific protein that is in turn, defective and not produced. These proteins are needed for brain cells (neurons) and other cells to work efficiently. The lack of a functional protein causes the abnormal buildup of “junk” material in the lysosomes—as well as the abnormal buildup of the residue called lipofuscin that occurs naturally as part of the lysosomal breakdown of lipids. It is not known whether the lipofuscin itself is toxic or if the buildup is a marker of impaired lysosomal function.
How are the forms of Batten disease and the NCLs classified?
The NCL disorders are classified by the gene that causes the disorder, although they are sometimes described by the child’s age at the time symptoms begin to appear. Each gene is called CLN (ceroid lipofuscinosis, neuronal) and given a different number designation as its subtype. Because of the different gene mutations, signs and symptoms range in severity and progress at different rates. The disorders generally include a combination of vision loss, epilepsy, and dementia. Some forms of the NCLs are:
How many people have these disorders?
It is not known how many people have Batten disease, but by some estimates it can be as frequent as in 1 in 12,500 people in some populations. It affects an estimated 2 to 4 out of every 100,000 children in the United States. Many more individuals may be carriers (see below) of a defective gene that can cause any of the NCL diseases. Although NCL diseases are rare, the childhood onset variants are the most common neurodegenerative disorders of childhood. Occasionally an NCL disease occurs in more than one person in families that carry the defective genes.
How are NCLs inherited?
People normally have two copies of the same gene in their cells, one comes from the father and one from the mother. This means that, in some cases, the cells have a “back up” system if only one copy is needed for the cell to function properly. Batten disease is caused when both copies (one from each parent) of the specific gene causing the disease are defective. This is known as autosomal recessive disease. People who only have one defective copy (carriers) will not develop symptoms and are usually unaware of their carrier condition. The rare exception may be for Adult NCL (see below).
If both parents carry one defective gene that causes NCL, there is a 1 in 4 chance during each pregnancy of having a child with the disease. At the same time, during each pregnancy there is 50 percent chance for the baby to inherit only one copy of the defective gene, which would make the child a “carrier” like the parent, as a normal copy will be inherited from the other parent. Carriers most often are not affected by the disease but can pass the abnormal gene to their children in a similar fashion to which they inherited it from their own parents. Finally, there is a 1 in 4 chance for the baby to inherit two completely normal genes.
At risk for any form of Batten disease are children whose parents have Batten disease, and children whose parents are carriers of an NCL gene that causes the disorder but aren’t severely affected by the disorder, if at all.
Adult NCL/Kufs disease B may be inherited as an autosomal recessive or, less often, as an autosomal dominant disorder. In autosomal dominant inheritance, everyone who inherits a defective of the disease gene develops the disease, even when they may have inherited a normal copy.
How are these disorders diagnosed?
Following a review of the person’s individual and family medical history and a neurological exam, several tests can be used to diagnose Batten disease and other neuronal ceroid lipofuscinoses. Currently, most diagnoses of Batten disease are made by genetic testing. Possible diagnostic tests include:
Is there any treatment?
No specific treatment is known that can reverse the symptoms of any form of Batten disease. In 2017 the Food and Drug Administration approved an enzyme replacement therapy for CLN2 disease (TTP1 deficiency) called cerliponase alfa (Brineura®) that has been shown to slow or halt the progression of symptoms. There are no treatments that can slow or stop disease progression for other NCL disorders.
Seizures can sometimes be reduced or controlled with antiseizure drugs. Other medicines are available to treat anxiety, depression, parkinsonism (stiffness and difficulty with walking/doing tasks), and spasticity (muscle stiffness). Additional medical problems can be treated appropriately as they arise. Physical and occupational therapy may help those with the disease retain function as long as possible. Support groups can help affected children, adults, and families to share common concerns and experiences, and to cope with the severe symptoms of the disease.
What research is being done?
The National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health (NIH), conducts research and supports studies of the brain and central nervous system through grants to major medical institutions across the country. NIH is the leading supporter of biomedical research in the world.
Much of NINDS’ research on Batten disease and the neuronal ceroid lipofuscinoses focuses on gaining a better understanding of the disease, gene therapy, and developing novel drugs to treat the disorders.
CLN1 Disease. Scientists are using a modified safe virus to deliver a replacement, functioning gene to the brain (gene therapy). In gene therapy, the correct gene code is attached to an adeno-associated virus—a small virus that causes a very slight immune reaction that doesn’t seem to be harmful to humans—and the virus allows for the gene to be delivered to cells at specific sites. Scientists hope the replacement gene will take over for or restore the production of the protein in the cell. Other researchers are using a novel adeno-associated virus to understand the gene mutation in juvenile-onset NCL disease and how it contributes to nerve cell loss. Researchers hope the results will determine if the virus will be effective in treating the disease in humans.
Scientists are combining gene therapy with bone marrow transplantation to treat infantile Batten disease. Using a mouse model of the disease, they found some effectiveness in using stand-alone gene therapy but no detectable increase in palmitoyl-protein thioesterate-1 (PPT1) activity in the brain using bone marrow transplants alone. The combined therapy was shown to extend life span with improved motor function. Researchers now hope to determine the effectiveness of novel combinations of small molecule drugs, gene therapy, and bone marrow transplantation in this model of the disease. None of these studies have been done in children suffering from CLN1 disease.
NIH researchers have identified a potential new drug—the NtBuHA molecule—to treat CLN1 disease. The scientists tested the NtBuHA molecule in a mouse model of disease and found that the compound greatly reduced the waxy buildup, protected neurons in the brain, slowed the deterioration in motor coordination, and extended the animals’ lifespans. Another molecular project is studying lanthionine ketamine, a natural compound found in the brain that activates a cell’s ability to recycle its contents (a process called autophagy). The compound and its derivative, lanthionine ketamine ethyl ester, have been shown to have neuroprotective properties and may lead to research into the development of new molecules capable of treating a variety of neurological disorders in which the cellular recycling process has been disrupted.
CLN2 Disease. Several studies seek to assess the natural history of Batten disease and find ways to treat it. One NINDS-funded project is studying the genetic and observable characteristics of how the disease progresses in children of all ages who have been diagnosed with late-infantile Batten disease. The study is running parallel with an NIH-supported study that is evaluating the effectiveness of a new drug for the disorder that will be delivered by gene therapy. Another study will refine and validate the Unified Batten Disease Rating Scale as a clinical rating instrument for Batten disease. Currently there have been no systematic clinical studies of Batten disease using a standardized rating instrument.
CLN3 Disease. The amino acid glutamate—a chemical involved in the way cells speak with each other—is constantly recycled by neurons and supportive cells. Excessive glutamate can damage or kill nerve cells, and elevated glutamate levels have been found in the brains of children with the CLN3 gene mutation. NINDS-funded researchers are using a mouse model to investigate the metabolic recycling pathways responsible for the regulation of glutamate levels in the brain. By studying a compound that might improve the ability of support cells to recycle glutamate and prevent glutamate toxicity within neurons, researchers hope to develop a potential therapy for children with juvenile Batten disease.
It is likely that multiple medications/approaches or a combination of multiple drugs with activity against ceroid along with gene therapy may be required as treatment against the different NCLs.
NINDS helps fund the Lysosomal Diseases Network, a combined network of research centers, clinical investigators, patient advocacy groups, and other interested parties that advocate for research on diagnosing, managing, and treating lysosomal and related diseases, including Batten disease. Research emphasis includes quantitative analysis of the central nervous system structure and function, the development of biomarkers (biological measures that may indicate the presence or accurately predict the rate of disease progression in a person, or the effectiveness of a therapy), and longitudinal studies of the natural history and treatment of the disease.
For additional information about clinical research on Batten disease and NCL disorders, visit ClinicalTrials.gov, a registry and results database of clinical studies of human participants conducted around the world. More information about research on NCL disorders supported by NINDS and other NIH Institutes and Centers can be found using NIH RePORTER, a searchable database of current and past research projects.
How can I help research?
NINDS supports the NIH NeuroBioBank, a collaborative effort involving several brain banks across the United States that supply investigators with tissue from people with neurological and other disorders. Tissue from individuals with Batten disease is needed to allow scientists to study this disorder more intensely. The goal is to increase the availability of, and access to, high quality specimens for research to understand the neurological basis of the disease. Prospective donors can begin the enrollment process by visiting https://neurobiobank.nih.gov/donors-why/.
Where can I find more information?
P.O. Box 5801
Bethesda, MD 20824
Information also is available from the following organizations:
Batten Disease Support and Research Association
1175 Dublin Road
Columbus, OH 43215
Children's Brain Disease Foundation [A Batten Disease Resource]
Parnassus Heights Medical Building, Suite 900
San Francisco, CA 94117
Nathan's Battle Foundation [For Batten Disease Research]
459 State Road 135 South
Greenwood, IN 46142
Hide and Seek Foundation for Lysosomal Storage Disease Research
6475 East Pacific Coast Highway
Long Beach, CA 90803
"Batten Disease Fact Sheet", NINDS, Publication date June 2018. NIH Publication No. 18-NS-2790
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