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 that 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 physically and mentally incapacitated, requiring 24-hour care. Batten disease is often fatal by the late teens or twenties.

It is difficult to imagine a worse fate for a child, but with your support, there is hope. Join us in our mission to find a cure. For many families, this is truly a race against time.

Beyond Batten Disease Foundation is uniquely positioned to accelerate the pace of progress towards developing treatments, and one day, a cure, for Batten disease. Our founders and board members have extensive contacts and relationships in the scientific and medical research communities. As a result, the Foundation is working to build a broad collaborative network of researchers that will bring a fresh and innovative perspective to accelerate the development of successful treatments.

Research for Batten disease is currently ongoing at prominent institutions in the U.S. and abroad. In addition, research is underway in other fields such as neurology and genetics that has applicability to Batten disease. Yet the rarity of the disease means that it receives limited funding. Research dollars from the states and the federal government typically go to those areas where the most people are affected.

There are brilliant researchers dedicating their careers to fighting this disease and others like it; what is in short supply is a consistent, predictable funding stream. To give families hope for a treatment and cure, we must give our scientists the certainty and predictability of financial commitment and continuity.

One of Beyond Batten Disease Foundation’s goals is to create a sustainable funding source through the development of a screening test. In turn, as advances are made, which will have benefits far beyond Batten disease, it becomes more likely that other traditional sources of funding will become available for research into the disease. This will make the fight even more attractive to the brightest scientific minds, and the cycle can continue (i.e., funding → talent → progress → funding → ).

More on Batten Disease

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, or JNCL, some physicians use the term Batten disease to describe all forms of NCL. Other forms are Infantile, Late Infantile, and Adult.

Because Batten disease is so rare, affecting several hundred children in the United States, it is also extremely underfunded. Of the $29 billion awarded by the U.S. Department of Health and Human Services for medical research in 2007, only $1.2 million funded research for Juvenile Batten disease, the most common form. This is not nearly enough.

Research Progress

Progress is being made today, and we plan to share updates on such advances through this Web site. Here are some examples:

• 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 have developed mouse models. Mouse models make it easier for scientists to study the genetics of these diseases and screen potential therapeutic compounds.
• In infantile and late infantile NCL a variety of gene transfer and neural stem cell approaches have been tested in animal models and phase I clinical trials are now underway.1, 2, 3
• Based on research on the neuroimmune response in mouse models with JNCL, it has been suggested that strategies which modify the immune system (immunomodulation) could be therapeutically beneficial in the juvenile form of NCL.4 The University of Rochester has received clearance from the FDA and is preparing to conduct a clinical trial to test this type of treatment in humans, but they are currently lacking some of the necessary funding.
• The blockade of an enzyme receptor using an injected chemical was found to improve motor skills in mice with JNCL.5, 6
• In 2008, Raptor received FDA orphan drug designation for cysteamine formulations, including DR Cysteamine, for the potential treatment of Batten Disease. Raptor plans to execute clinical trials to study DR Cysteamine in Batten Disease.

As you can see, even though Batten disease has been known for decades, most of the progress in research has been made in the last few years. For many families across America and around the world, this is quite literally a race against time. Science provides hope for a cure, but we need to raise additional funds for multi-year research programs and clinical trials in order to turn hope into reality.

Each year, the NCL-Foundation, a nonprofit based in Hamburg, Germany, which is dedicated to developing therapies for Batten disease, hosts an annual scientific meeting at which the world’s leading Batten disease researchers share their latest results and progress. Beyond Batten Disease Foundation will be partnering with the NCL-Foundation as a co-sponsor of the annual meeting in June of 2009. The research abstracts presented at the 2008 meeting can be viewed here: (Research Abstracts). For more information about the NCL-Foundation, please visit: http://www.ncl-stiftung.de/english/

How Many People Have Batten Disease?

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 genes. It is estimated that several hundred children in the United States have Batten disease.

How is Batten Disease Inherited?

Batten disease is an autosomal recessive disorder; that is, it occurs 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 Batten disease. 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.

What Causes Batten Disease?

Symptoms of Batten disease and other NCLs are linked to a buildup of substances called lipofuscins (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 optic nerve 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. Normal human systems regularly dispose of these lipofuscins, something akin to “taking out the trash.” However, these gene mutations and the subsequent impairment of the related proteins prevent the disposition or housekeeping of these lipopigments.

The biochemical defects that underlie several NCLs have been discovered. An enzyme called palmitoyl-protein thioesterase has been shown to be insufficiently active in the infantile form of Batten disease (this condition is now referred to as CLN1). In the late infantile form (CLN2), a deficiency of an acid protease, an enzyme that hydrolyzes proteins, has been found as the cause of this condition.

A mutated gene has been identified in juvenile Batten disease (CLN3), as well as its related protein, also called CLN3. Forty-two mutations have been found in CLN3. One of these mutations in which some of the gene is missing is responsible for 85 percent of the JNCL patients from European descent.

More on Neuronal Ceroid Lipofuscinosis (NCL)

Although Batten Disease is usually regarded as the juvenile form (CLN3) many people use the term to describe all NCL diseases. The NCLs disease group consists of at least nine autosomal recessively inherited disorders, each caused by mutation of a different gene. Most forms of NCL affect children, but the age of onset can range into early adulthood. Although the age of onset varies, NCLs share many common clinical features, including visual deterioration, seizures, and declining cognitive and motor abilities, all leading to premature death. The main subgroups of NCL are listed in the table below.

NCL Type	Age of Onset	Symptoms	Implicated Gene(s)
Infantile (INCL) also called Santavuori-Haltia	6-24 months	Initial symptoms are delayed development, clumsiness, and low muscle tone. As disease progresses the symptoms include seizures, loss of muscle coordination, dementia, and brain tissue atrophy	CLN1
Late Infantile (LINCL) also called Jansky-Bielschowsky	2-4 years	Initial symptoms are seizures and ataxia. As the disease progresses symptoms include, cerebral atrophy and dementia.	CLN2, CLN5, CLN6 and CLN7
Juvenile (JNCL) also called Batten or Spielmeyer-Vogt	5-10 years	Initial symptoms are visual loss or seizures. As the disease progresses symptoms include, loss of muscle control, moderate cerebral atrophy, and dementia.	CLN3
Adult (ANCL) also called Kuf's or Parry's	30 years	Symptoms are milder and progress slowly. Dementia and moderate cerebral and cerebellar atrophy.	CLN4

The biochemical defects that underlie several NCLs have been discovered. An enzyme called palmitoyl-protein thioesterase (PPT1), caused by a defective CLN1 gene, has been shown to be insufficiently active in the infantile form of the disease. A deficiency of an enzyme called tripeptidyl peptidase 1 (TTP1), caused by a defective CLN2 gene, has been found as the cause of the late infantile form. Both of these enzyme deficiencies lend themselves well to gene transfer and neural stem cell treatment approaches.

The most common, juvenile form of the disease is caused by a mutation in the CLN3 gene. The role of the CLN3 protein (also called battenin) has been elusive due to the nature of the protein and the difficulty in determining where in the cell it is found.

How is Batten Disease Diagnosed?

Since Batten disease is so rare, and many physicians are unfamiliar with it, it can be very difficult to get accurately diagnosed. To the frustration of many families, it is often first mis-diagnosed. (Link to the Mitzel’s story.) 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.

With modern genetic testing technology, tests run on a blood sample can confirm the presence of Batten disease. Other diagnostic tests 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. A 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. Another imaging technique that is becoming 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.
• Measurement of enzyme activity. Measurement of the activity of palmitoyl-protein thioesterase involved in CLN1 and the acid protease involved in CLN2 in white blood cells or cultured skin fibroblasts can be used to confirm these diagnoses.
• DNA analysis. In families where the mutation in the gene for CLN3 is known, DNA analysis can be used to confirm the diagnosis or for the prenatal diagnosis of this form of Batten disease. When the mutation is known, DNA analysis can also be used to detect unaffected carriers of this condition for genetic counseling.

Misdiagnosis

Because any one autosomal recessive disorder is rare and often have complex symptoms and laboratory results, timely and accurate diagnoses are difficult. Batten disease is often mis-diagnosed as retinitis pigmentosa. Wilson's disease is another autosomal recessive genetic disorder in which copper accumulates in tissues causing neurological and liver problems. Because the psychiatric problems due to Wilson's disease may include behavioral changes, depression, anxiety and psychosis, it is often mis-diagnosed as schizophrenia. Diagnosis of many of these rare conditions relies on subtle and circumstantial evidence so even the most experienced clinicians may find it difficult to distinguish an autosomal recessive disease from another possibly more common disease that shares some of the same features.

Current State of Recessive Disease Testing

Currently, screening for recessive diseases is cost prohibitive and logistically challenging. For many of these diseases there are only one or two laboratories in the world that can test for a particular disease. A single test for one mutation in one gene costs hundreds of dollars. Multiple mutations and multiple genes may need to be tested leading to thousands of dollars in cost.

Advances in Treatment of Recessive Disorders

Treatment of these disorders requires accurate diagnosis, early intervention, and thorough understanding of the pathogenesis of the disorder. Instructing and educating the patient, using drug intervention and surgical procedures may be used to treat the symptoms. These types of treatments do not correct the genetic defect causing the disease but they may alleviate some of the patient’s symptoms. For example, using anticonvulsants for patients with neurodegenerative genetic disorders like Batten disease.

In 1983 the U.S. Congress passed the Orphan Drug Act to offer incentives for companies to develop drugs (and other medical products) for rare diseases. In the decade prior to the passage of this Act, only 10 orphan drugs were developed without government assistance. Since the Act, more than 200 orphan drugs have been approved by the FDA for marketing in the U.S.

Congress also passed the "Rare Diseases Act of 2002," establishing a role for the Office of Rare Diseases (ORD) at the NIH in encouraging orphan disease research. The ORD provides information on rare diseases, diagnosis, and treatment. Through this office, investigators are linked with research patients and opportunities. It also identifies diseases which may need more support due to lagging research.

There are many treatment strategies that investigators are studying, including:

• Treatment at the metabolite level. This includes dietary changes or medications to help prevent production and buildup of toxins.
• Therapy at the dysfunctional protein level. This includes using vitamins or other medications to enhance the function of a mutant protein and therapies that completely replace a mutant protein with its normal counterpart. Hunter syndrome, Hurler syndrome and Pompe disease are all examples of autosomal recessive disorders in which protein replacement therapy has been developed.
• Organ transplantation and implantation of cells or stem cells. This type of therapy could be considered either protein replacement or gene therapy because a transplanted organ or cell not only brings the ability to make the desired protein but also brings new genetic information. Liver transplantation has been successful for patients with several autosomal recessive diseases including tyrosinemia. Bone marrow transplantation involves the replacement of cells that don’t function correctly with normal cells. This type of treatment has been successful for patients with Hurler syndrome.
• Gene therapy. This is a technique in which a normal gene is inserted in a genome to replace the defective gene in order to correct a deficiency that is causing a disease. Gene therapy has been used in clinical trials to treat Leber’s Congenital Amaurosis (LCA), a rare autosomal recessive eye disease caused by an abnormality in a gene called RPE65.

What is still lacking is the financial backing to enable investigators to continue their research into the mechanisms of these diseases and move potential treatments through clinical trials and on to help the people suffering from these devastating diseases.

Some examples of treatments that have been developed for autosomal recessive disorders are shown in the table below.

Disease	What it is	Treatment
Fabry's	results from a deficient enzyme that is needed to metabolize lipids (fat-like substances). This leads to a buildup of lipids in eyes, kidneys, autonomic nervous system, and cardiovascular system	alpha-galactosidase A as enzyme replacement therapy
Mucopolysaccharidosis (MPS 1)	genetic lysosomal storage disorder caused by the body's inability to produce certain enzymes	Aldurazyme (laronidase) as enzmyme replacement therapy, hematopoietic stem cell transplantation
Tyrosinemia type 1	a pediatric disease causing progressive liver failure and liver cancer	Orfadin (nitisinone) to block a metabolite that occurs in patients with this disease, low tyrosine diet, liver transplantation
Pompe	a disease which disables the heart and muscle tissue and thus, severely reduces muscle and respiratory function	Myozyme as enzyme replacement therapy

Is There Any Treatment?

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.

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. The Batten Disease Support & Research Association is the leading organization that provides support for families of children and young adults with Batten disease. For more information, please visit www.bdsra.org

Information on Batten Disease adapted from the National Institute of Neurological Disorders and Stroke Fact Sheet on Batten Disease.

References

1. Griffey MA, Wozniak D, Wong M et al. CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis. Mol Ther 2006 March;13(3):538-47.
2. Cabrera-Salazar MA, Roskelley EM, Bu J et al. Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease. Mol Ther 2007 October;15(10):1782-8.
3. Passini MA, Dodge JC, Bu J et al. Intracranial delivery of CLN2 reduces brain pathology in a mouse model of classical late infantile neuronal ceroid lipofuscinosis. J Neurosci 2006 February 1;26(5):1334-42.
4. Lim MJ, Alexander N, Benedict JW et al. IgG entry and deposition are components of the neuroimmune response in Batten disease. Neurobiol Dis 2007 February;25(2):239-51.
5. Kovacs AD, Pearce DA. Attenuation of AMPA receptor activity improves motor skills in a mouse model of juvenile Batten disease. Exp Neurol 2008 January;209(1):288-91.
6. Kovacs AD, Weimer JM, Pearce DA. Selectively increased sensitivity of cerebellar granule cells to AMPA receptor-mediated excitotoxicity in a mouse model of Batten disease. Neurobiol Dis 2006 June;22(3):575-85.