Batten Disease

Batten disease is a fatal, inherited disorder of the nervous system that begins in childhood. Early symptoms of this disorder usually appear between the ages of 5 and 10, when parents or physicians may notice a previously normal child has begun to develop vision problems or seizures. In some cases the early signs are subtle, taking the form of personality and behavior changes, slow learning, clumsiness, or stumbling.

Over time, affected children suffer mental impairment, worsening seizures, and progressive loss of sight and motor skills. Eventually, children with Batten disease become blind, bedridden, and demented. Batten disease is often fatal by the late teens or twenties.

Batten disease is named after the British pediatrician who first described it in 1903. Also known as Spielmeyer-Vogt-Sjogren-Batten disease, it is the most common form of a group of disorders called neuronal ceroid lipofuscinoses (or NCLs). Although Batten disease is usually regarded as the juvenile form of NCL, some physicians use the term Batten disease to describe all forms of NCL.

Batten disease is not contagious or, at this time, preventable.

What are the other forms of NCL?
There are three other main types of NCL, including two forms that begin earlier in childhood and a very rare form that strikes adults. The symptoms of these three types are similar to those caused by Batten disease, but they become apparent at different ages and progress at different rates.

• Infantile NCL (Santavuori-Haltia disease) begins between about 6 months and 2 years of age and progresses rapidly. Affected children fail to thrive and have abnormally small heads (microcephaly). Also typical are short, sharp muscle contractions called myoclonic jerks. Patients usually die before age 5, although some have survived in a vegetative state a few years longer.
• Late infantile NCL (Jansky-Bielschowsky disease) begins between ages 2 and 4. The typical early signs are loss of muscle coordination (ataxia) and seizures that do not respond to drugs. This form progresses rapidly and ends in death between ages 8 and 12.
• Adult NCL (Kufs disease or Parry's disease) generally begins before the age of 40, causes milder symptoms that progress slowly, and does not cause blindness. Although age of death is variable among affected individuals, this form does shorten life expectancy

How many people have these disorders?
Batten disease and other forms of NCL are relatively rare, occurring in an estimated 2 to 4 of every 100,000 live births in the United States. These disorders appear to be more common in Finland, Sweden, other parts of northern Europe, and Newfoundland, Canada. Although NCLs are classified as rare diseases, they often strike more than one person in families that carry the defective gene.

How are NCLs inherited?
Childhood NCLs are autosomal recessive disorders; that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry one defective gene, each of their children faces a one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting just one copy of the defective gene. Individuals who have only one defective gene are known as carriers, meaning they do not develop the disease, but they can pass the gene on to their own children. There is no test yet available to identify carriers of Batten disease or other forms of NCL.

Adult NCL may be inherited as an autosomal recessive or, less often, as an autosomal dominant disorder. In autosomal dominant inheritance, all people who inherit a single copy of the disease gene develop the disease. As a result, there are no unaffected carriers of the gene.

What causes these diseases?
Symptoms of Batten disease and other NCLs are linked to a buildup of substances called lipopigments in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the technical word lipo, which is short for "lipid" or fat, and from the term pigment, used because they take on a greenish-yellow color when viewed under an ultraviolet light microscope. The lipopigments build up in cells of the brain and the eye as well as in skin, muscle, and many other tissues. Inside the cells, these pigments form deposits with distinctive shapes that can be seen under an electron microscope. Some look like half-moons, others like fingerprints. These deposits are what doctors look for when they examine a skin sample to diagnose Batten disease.

The biochemical defects causing NCLs have not been identified. Some scientists suspect these abnormal deposits result from a shortage of enzymes normally responsible for the breakdown of lipopigments. According to this theory, diseased cells produce inadequate amounts of enzymes or manufacture defective enzymes that function poorly. As a result, the cells can not process enough of the lipopigments that occur within them, and the lipopigments accumulate. However, scientists have not pinpointed what specific enzymes are at fault or determined how the stored lipopigments damage nerve cells.

Other scientists believe that abnormal lipopigment buildup may result from a glitch in their production or processing. For example, diseased cells could be producing too much of a normally needed lipoprotein.

How are these disorders diagnosed?
Because vision loss is often an early sign, Batten disease may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of NCL. However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often an eye specialist or other physician who suspects NCL may refer the child to a neurologist, a doctor who specializes in diseases of the brain and nervous system.

In order to diagnose NCL, the neurologist needs the patient's medical history and information from various laboratory tests. Diagnostic tests used for NCLs include:

• blood or urine tests. These tests can detect abnormalities that may indicate Batten disease. For example, elevated levels of a chemical called dolichol are found in the urine of many NCL patients.
• skin or tissue sampling. The doctor can examine a small piece of tissue under an electron microscope. The powerful magnification of the microscope helps the doctor spot typical NCL deposits. These deposits are common in skin cells, especially those from sweat glands.
• electroencephalogram or EEG. An EEG uses special patches placed on the scalp to record electrical currents inside the brain. This helps doctors see telltale patterns in the brain's electrical activity that suggest a patient has seizures.
• electrical studies of the eyes. These tests, which include visual-evoked responses and electroretinograms, can detect various eye problems common in childhood NCLs.
• brain scans. Imaging can help doctors look for changes in the brain's appearance. The most commonly used imaging technique is computed tomography, or CT, which uses x-rays and a computer to create a sophisticated picture of the brain's tissues and structures. A CT scan may reveal brain areas that are decaying in NCL patients. A second imaging technique that is increasingly common is magnetic resonance imaging, or MRI. MRI uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain.

Is there any treatment?
As yet, no specific treatment is known that can halt or reverse the symptoms of Batten disease or other NCLs. However, seizures can sometimes be reduced or controlled with anticonvulsant drugs, and other medical problems can be treated appropriately as they arise. At the same time, physical and occupational therapy may help patients retain function as long as possible.

Some reports have described a slowing of the disease in children with Batten disease who were treated with vitamins C and E and with diets low in vitamin A. However, these treatments did not prevent the fatal outcome of the disease.

Support and encouragement can help patients and families cope with the profound disability and dementia caused by NCLs. Often, support groups enable affected children, adults, and families to share common concerns and experiences.

Meanwhile, scientists pursue medical research that could someday yield an effective treatment.

What research is being done?
Within the Federal Government, the focal point for research on Batten disease and other neurogenetic disorders is the National Institute of Neurological Disorders and Stroke (NINDS). The NINDS, a part of the National Institutes of Health, is responsible for supporting and conducting research on the brain and central nervous system.

Through the work of several scientific teams, the search for the genetic cause of NCLs is gathering speed. Previous research has uncovered a link between juvenile NCL, or Batten disease, and certain markers on chromosome 16. With the help of affected families, NINDS-supported scientists are now conducting research to confirm this link and narrow the search for the culprit gene. Pinpointing the gene will enable physicians to provide patients with earlier and more accurate diagnosis and to identify carriers of the gene. It may also help us understand what body processes go awry in Batten disease and thereby open the door to new treatments.

Some scientists are investigating the theory that children with Batten disease have a shortage of a key body enzyme. Investigators are searching for enzymes that might be scarce, defective, or completely missing. One team of scientists, for example, is testing the theory that a specific enzyme, called phospholipase A1, is deficient in people with Batten disease. Such studies could also prove useful in better diagnosis of patients. In addition, identifying an enzyme at fault might make it possible to treat affected children with natural or synthetic enzymes that would counteract the shortage and clear away stored material. In fact, NINDS scientists have used this approach to successfully treat another storage disorder known as Gaucher's disease.

At the same time, other investigators are working to identify what substances the lipopigments contain. Although scientists know lipopigment deposits contain fats and proteins, the exact identity of the many molecules inside the deposits has been elusive for many years. Recently, however, scientists have unearthed potentially important clues. For example one NINDS-supported scientist, using animal models of NCL, has found that a large portion of this built-up material is a protein called subunit c. This protein is normally found inside the cell's mitochondria, small structures that produce the energy cells need to do their jobs. Scientists are now working to understand what role this protein may play in NCL, including how this protein winds up in the wrong location and accumulates inside diseased cells. Other investigators are also examining deposits to identify the other molecules they contain.

In addition, research scientists are working with NCL animal models to improve understanding and treatment of these disorders. One research team, for example, is testing the usefulness of bone marrow transplantation in a sheep model, while other investigators are working to develop a new mouse model. If successfully developed, mouse models will make it easier for scientists to study the genetics of these diseases, since mice breed quickly and frequently.

Information provided by the
National Institute of Neurological Disorders and Stroke,
National Institutes of Health

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