What is Batten Disease?

Batten Disease is named after the British pediatrician, Frederick Batten, who first described it in 1903. 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, it has now become the term to include Infantile and Late Infantile forms of NCL.

These forms of NCL are classified by age of onset and have the same basic cause, symptoms and outcome. Over time, affected children suffer mental impairment, seizures, and progressive loss of sight and motor skills. Eventually, children with Batten Disease/NCL become blind, bedridden, and unable to communicate and it is presently always fatal. Batten Disease is not contagious nor preventable.

What are the forms of NCL/Batten Disease?

There are four types of NCL, including two forms that begin earlier in childhood and a very rare form that strikes adults. The symptoms are similar but they become noticeable at different ages and progress at different rates.

• Infantile NCL (Santavuori-Haltia disease): begins between 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. Initial signs of this disorder include delayed psychomotor development with progressive deterioration, other motor disorders, or seizures. The infantile form has the most rapid progression and children live into their mid childhood years.
• Late Infantile NCL (Jansky-Bielschowsky disease): begins between ages 2 and 4. The typical early signs are loss of muscle coordination (ataxia) and seizures along with progressive mental deterioration. This form progresses rapidly and ends in death between ages 8 and 12.
• Juvenile NCL (Batten Disease): begins between the ages of 5 and 8 years of age. The typical early signs are progressive vision loss, seizures, ataxia or clumsiness. This form progresses less rapidly and ends in death in the late teens or early 20s, although some may live into their 30s.
• 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.

NCL/Batten Disease is relatively rare, occurring in an estimated 2 to 4 of every 100,000 births in the United States. The disease has been identified worldwide.

What causes this disease?

Childhood NCLs are autosomal recessive disorders; which means they occur only when a child inherits two copies, one from each parent, of the defective gene. When both parents carry one defective gene, each of their children faces one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting a copy of the defective gene, becoming a carrier.

Symptoms of Batten Disease are linked to a buildup of substances called lipopigments in the body’s tissues. Lipopigments are made up of fats and proteins. Their name comes from the technical word lipo, which means fat, and from the term pigment because lipopigments take on a greenish-yellow color when viewed under an ultraviolet light microscope.

The lipopigments build up in cells of the brain, eye, skin, muscle, and many other tissues. Inside the cells, these pigments form deposits with unique shapes that can be seen under an electron microscope. Some look like half-moons (or comas) and are called curvilinear bodies, others look like fingerprints and are called fingerprint inclusion bodies and still others resemble gravel (or sand) and are called granual osmophilic deposits (grods).

These deposits are what doctors look for when they examine a skin sample to diagnose Batten Disease. The diseases cause death of neurons (specific cells found in the brain, retina and central nervous system). The reason for neuron death is still not known.

Research

The National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institute of health (NIH), is responsible for supporting and conducting research on the central nervous system and brain. The Batten Disease Support and Research Association and the Children’s Brain Diseases Foundation also provide financial assistance for research.

In September 1995, The International Batten Disease Consortium announced the identification of the gene for the juvenile form of Batten Disease. The specific gene, CLN3, located on Chromosome 16, has a deletion or piece missing.

Also, in 1995, scientists in Finland announced the identification of the gene responsible for the infantile form of Batten Disease. The gene, CLN1, is located on Chromosome 1.

In September 1997, scientists at the Robert Woos Johnson Medical School and the Institute for Basic Research, NY, announced the identification of the gene for the Late Infantile form of Batten Disease/NCL. The gene, CLN2, is located on chromosome 11.

It was discovered that the Infantile and Late Infantile diseases are missing key lysosomal enzymes, known as Palmitoyl Protein Thioesterase 1 (PPT1) in Infantile NCL and Tripeptidyl Peptidase 1 (TPP1) in Late Infantile NCL.

Scientists have also identified the gene responsible for Finnish Late Infantile (CLN5), variant Late Infantile (CLN6) and EPMR (CLN8). Research also continues toward identification of the gene for the adult form of Batten Disease/NCL, also known as Kufs Disease.

Identification of the specific genes for Infantile, Late Infantile, Variant Late Infantile and Juvenile Batten Disease/NCL has led to the development of DNA diagnostics, carrier and prenatal tests.

Treatment

Currently there is no treatment or cure that can stop or reverse Batten Disease. There is only a small community of researchers working on this disease as it is considered an orphan disease. There is very little attention to Batten disease because of the few numbers of children it affects. Only $700,000 was given from the government toward research within the past year (2012). This is not acceptable. More needs to be done! That is where we need YOUR help.

Enzyme Replacement Therapy

Enzyme Replacement Therapy is when a patient receives the enzyme that he or she is lacking directly into the brain through injections or intravenously. The exciting news is that Biomarin, a pharmaceutical company based in California, has developed a synthetic enzyme called BMN 190 to administer to patients with Late Infantile Batten disease. BMN-190 is an enzyme replacement therapy designed to restore TPP1 enzyme activity and break down the excess neuronal materials that cause CLN2 or Late infantile Batten disease. BMN-190 must be administered directly to the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord. There is a small device that will be implanted in each patient’s head, much like a medi-port, in order to deliver the enzyme. Animal research has shown that BMN-190 distributes widely in the brain and BMN-190 is able to get into the cells of the brain and break down the storage or garbage materials. Biomarin is currently in Phase1/2 of the trial as it began in September of 2013 in London, England and Hamburg, Germany.
Visit www.bmnr.com for more details

Gene Transfer Therapy

For Late Infantile NCL, there is a gene therapy clinical trial at Weill Medical College of Cornell University in New York sponsored by the National Institute of Health under the direction of Dr. Ronald Crystal. This research team is undertaking a pilot clinical trial determining the impact of putting a working copy of the gene into a virus that can be injected into the brain. Six billion copies of the virus will be injected into the brains for children with Batten Disease in the hopes that they will spread out and infect brain cells, and deliver a working copy of the gene into the cells. These brain cells can then produce the missing enzyme, allowing the brain cells and the children to thrive. If this study can prove that this specific virus and delivery method can deliver the gene to the cells and then cells can incorporate the gene to produce the enzyme, it will be a viable treatment for Batten disease.
To date, 12 children have undergone this procedure without serious side effects. These children will be monitored to determine whether their disease slows, stops or reverses.

Drug Repurposing

There are a few organizations and researchers testing already FDA approved drugs to treat Batten disease. One promising find as of 2013, is the discovery of combining lipid lowering drugs with vitamin A to instigate the production of a child’s own TPP1 enzyme. Although an affected child has very little capability of doing this on their own, these drugs could stimulate the production of this enzyme within their own brain. Hope 4 Bridget is supporting Dr. Pahan at Rush University Medical Center in his research with this investigation.