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 always fatal, often 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.
Passion is our driver. Strategy is our compass. With your support, Beyond Batten Disease Foundation (BBDF) has developed a dynamic plan to diagnose and prevent juvenile Batten disease while at the same time investing in the most promising research to treat children and families living with the disease. Since the foundation’s inception in August 2008, we have made exciting progress. With help from donors, we have 1) developed an easy and inexpensive test to prevent Batten and hundreds of other rare and devastating diseases, and 2) invested in research projects and strategies that are accelerating progress toward a cure.
Our very first goal of creating a test to diagnose and prevent Batten and over 600 other rare devastating conditions is complete, making Time magazine’s list of Top Ten Medical Discoveries in 2012. Prior to the development of our test, screening for hundreds of rare and devastating diseases was hindered by a lack of availability and the cost of testing for gene defects one-by-one. While most states do screen for 30-50 genetic diseases, this is done as part of newborn screening initiatives, well past the point of prevention. Our multiplex platforms are four times more comprehensive than its nearest commercially available neighbor, absolutely accurate and will cost less than $2 per disease. The test has been beta launched as a diagnostic tool at Kansas Children’s Mercy Hospital, where it is helping families avoid the painful diagnostic odyssey experienced by so many of those affected with Batten and other rare diseases.
To reach our second goal of investing in research that will lead to a cure for juvenile Batten disease, we created a strategy for success modeled after and advised by the most successful medical research foundations and government programs, incorporating a business model used by pharmaceutical research and biotechnology companies. This multifaceted approach includes determining what goes wrong on a cellular level to identify drug targets, screening thousands of drugs for their ability to fix cellular mishaps, speeding things up by creating and disseminating new research tools, and preparing for clinical trials. This approach acknowledges that we cannot wait for the next breakthrough to begin recruiting patients and identifying reliable biomarkers for measuring treatment effects. We know that lab-tested treatments are coming. We need to be ready. See a copy of our video for more information: http://beyondbatten.org/videos/research-strategy/
Understanding the progression of the disease on a molecular level is vital to any successful therapy, as researchers must identify the cellular structures and processes that would make appropriate targets for potential drug treatments. Our researchers at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital (TCH), the University of Iowa, King’s College London in the United Kingdom, the University of Medicine and Dentistry in New Jersey, Weizmann Institute of Science in Israel, and the New York Consortium of Membrane Protein Structure (NYCOMPS) are all exploring the underlying causes of juvenile Batten disease, with an intense focus on lysosomes, the cell’s recycling centers that are damaged in patients with the disease.
Drs. Sardiello, Ballabio, and their colleagues joined the Neurological Research Institute of TCH to determine whether activation of master gene TFEB, a molecular “switch” that regulates the activity of around 40 genes related to lysosome functioning, induces the production of more lysosomes, to improve the cell’s overall ability to degrade accumulated material and inhibit disease progression. The fundamental lysosome problem in juvenile Batten disease is that they work at a reduced capacity and thus get overwhelmed and eventually die, so increasing the number and efficiency of lysosomes in each cell could compensate for this dysfunction. The beauty of TFEB is that it could prompt the cell to fix the problem itself.
Another important project conducted by Drs. Cooper and Williams of King’s College London is to investigate whether glial cells, support cells that act as a sort of pit crew for neurons, are malfunctioning and causing damage to neurons. If true, this work will open up a new line of glial drug targets, which may be easier to reach than neurons themselves.
To explore present-day treatment possibilities, we are fueling the Combined Central Nervous System Screening Initiative (CCSI), a simple, cost-effective way to test more drugs in juvenile Batten disease by sharing promising compounds between drug discovery centers and across diseases. Led by the Harvard NeuroDiscovery Center’s Laboratory for Drug Discovery in Neurodegeneration at Brigham and Women’s Hospital, the CCSI will also serve as a platform for sharing ideas, research tools, and theories about juvenile Batten disease, other neurodegenerative diseases and their common cellular defects. By pooling resources and ideas, the CCSI has the potential to accelerate the evaluation of more than 1 million compounds for their potential to treat juvenile Batten and other neurodegenerative diseases by several years while saving millions spent on current programs. This initiative is representative of BBDF’s larger strategy, one that pushes against the traditional model of academic research, which typically encourages self-sufficiency, limits collaboration outside of the academic community, and actually fails to reward translating discoveries into medicines.
The CCSI is one of the steps being taken to combat the sequestration of disease-specific resources among different research groups, which has been shown to hinder progress. An additional effort BBDF is taking is creating and distributing critical research tools that can give researchers a technological “leg up” in their quest for a cure. One of our initiatives is funding the development of hard-to-make CLN3 antibodies, which scientists will use to understand how the elusive juvenile Batten disease protein functions normally and during disease. BBDF also supports the development of animal models that provide important information about lysosome functioning and brain activity incentivizing researchers to place their unique resources in the commercial sector. BBDF successfully applied for inclusion in the National Institutes of Health (NIH)-funded New York Consortium on Membrane Protein Structure (NYCOMPS) to use advanced bioinformatics and structure analysis to better understand CLN3. The information gathered from these efforts will go a long way to informing our drug development and treatment research.
Research is an expensive venture: $1 million is the amount considered by many to be necessary to make a meaningful difference. But according to a June 2011 issue of Time, over 90% of 225,000 medical research nonprofits in the US never reach this mark. This is not the case for BBDF. Our very first grant to the Jan and Dan Duncan Neurological Research Institute at TCH in Houston Texas exceeded $2.5 million. Plus, the Will Herndon Fund of BBDF reached its annual $1 million mark in less than 3 years. In just 4 short years, the investments made at TCH have attracted additional funders such as the European Commission, the NIH and the March of Dimes, resulting in $3.7 million in new projects. The ripple effect of BBDF funding is vast: Transcription Factor EB (TFEB), the flagship discovery of [this group], is now being studied in 20 more laboratories around the globe.
BBDF is also outperforming industry standards in the realm of research publications. Over 40% of scientific discoveries never receive attention beyond a single publication, but BBDF researchers publish in the top 1% of 11,000 medical research journals with the highest circulation. The true influence of a publication is often measured in citations, which gives an indication just how important a discovery is by seeing who mentions the discovery when publishing their own work. BBDF-funded investigators are often-cited and in high-demand.
We are not waiting for accidental victory. Recent developments our understanding of the lysosome, how neurons communicate, and the effects glia may have on neurons along with the increasing availability of previously-unavailable promising compounds to treat disease are resulting in clinical trials for several lysosomal storage diseases like juvenile Batten disease. We believe our turn is next and recognize that a well-designed registry is critical to the success of any trial. Therefore, together with Batten Disease Support and Research Association (BDSRA), Biomarin Pharmaceutical, LLC, Noah’s Hope, Blake’s Purpose and Our Promise to Nicholas, we are expanding a European Commission-funded, online Batten disease patient registry in Germany, Finland, Italy, India and the United Kingdom into the United States, Brazil, Argentina, Turkey, France, Norway and Denmark. Project teams from each country will work together to collect the world’s largest, clinically and genetically best characterized set of Batten disease patients.
For us, there will be only one clear measure of success: providing treatments and a cure for juvenile Batten disease. With your help, we will continue to be groundbreakers. Because of the generosity of our donors and the passion of affected families, we are empowered with funding that drives us in promising directions and provides us with reason to be optimistic, hopeful, and energized to close the gap between here and a cure. Thank you and congratulations on these accomplishments; without your support, they wouldn’t have been possible. Please continue to bolster our efforts to find a cure.
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.
<tr >NCL TypeAge of OnsetSymptomsImplicated 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. (Watch the Mitzel Family 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.
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.
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- 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.
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