For a child to be born with an autosomal recessive disease, of which Batten Disease is one of hundreds, both parents must carry the same gene mutation. Because these diseases are so rare, and testing is currently so expensive, few doctors talk to their patients about testing for these gene mutations.
One of the goals of the Beyond Batten Disease Foundation is to develop one easy and inexpensive blood test to detect the gene mutations for hundreds of rare diseases. To accomplish this goal the Foundation partnered with Dr. Stephen Kingsmore and the National Center for Genome Resources (NCGR), one of the world’s top genetic screening laboratories, to create a low-cost, comprehensive screening test for hundreds of genetic diseases, like Batten disease. Dr. Stephen Kingsmore continues to lead the project and is now Director of the Center for Pediatric Genomic Medicine at Children’s Mercy Hospital in Kansas City, Mo.
In January 2011, Dr. Kingsmore’s team published the results of the first phase of test development in Science Translational Medicine (Sci Transl Med 2011;3:65ra4). The study included 448 autosomal recessive diseases that cause severe childhood illness or death. The researchers found that, on average, each subject carried approximately three disease-causing gene mutations. In addition, they found that many disease mutations were mis-annotated in the scientific literature. They are now working to expand the test panel to around 600 diseases and preparing it for public launch in early 2012.
More on Autosomal Recessive Conditions
Autosomal recessive conditions 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 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.
More on X-Linked Recessive Conditions:
With X-linked recessive diseases, if a women who carries a gene mutation has children with an unaffected male, their male children have a 50% chance of having the disease, and their female children have a 50% of being carriers.
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 serious 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|
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.