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Report on the Rare Diseases and Conditions Research Activities of the National Institutes of Health 1999

National Institute on Neurological Disorders and Stroke

Overview of NINDS Rare Diseases Research Activities

NINDS conducts and supports research on the causes, diagnosis, treatment, and prevention of neurological and neuromuscular disorders. Hundreds of rare diseases attack the nervous system. They kill, disable, or otherwise afflict people of all ages. Among these disorders are some that are well known to the public, such as amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), Duchenne’s muscular dystrophy, and Huntington’s disease, and many others that most people have not heard of until a family member or friend is diagnosed, such as spinal muscular atrophy, spinocerebellar ataxia, or Creutzfeldt-Jakob disease (CJD). In fact, a large percentage of the disorders within the NINDS mission are considered rare. Even the more common neurological diagnoses, such as Parkinson’s disease, Alzheimer’s disease, and epilepsy, include distinct, uncommon variants, so the following is only a sampling of rare diseases-related activities of the Institute.

Rare Diseases Scientific Advances

Duchenne’s Muscular Dystrophy

Duchenne’s muscular dystrophy (DMD) is a progressive degenerative disorder of muscle caused by a mutation in the gene coding for dystrophin, a structural protein of muscle. No treatment is available to halt the degeneration, and patients die of respiratory or cardiac failure by their teens or early twenties. In about 15% of DMD patients, the mutation is a premature stop codon, that is, an incorrect code word in the gene that causes the protein synthesizing machinery of the cell to halt, resulting in the absence of dystrophin. The mdx mouse model of DMD also results from a premature stop codon, so it is an especially good model for these 15% of DMD cases. For several years, scientists have known that certain antibiotics cause misreading of the genetic code and can sometimes suppress premature stop codons by causing the protein synthesizing machinery to misread the stop, insert another amino acid protein building block, and continue.

A team of scientists, supported by NIAMS and NINDS, developed a gentamicin treatment approach for DMD by first using immature muscle cells from mdx mice in cell culture and then in live mice. After treatment with this antibiotic, skeletal muscle cells of the mice expressed dystrophin 10% to 20% of normal levels, and tests showed this was enough to restore muscle strength to the level of normal mice and to protect muscle cells against degeneration. The gentamicin treatment is now in clinical trials to test whether the treatment will work for the 15% of DMD boys whose genetic defect is a premature stop codon. If this therapeutic strategy is effective, it may also apply to several other inherited disorders in which a premature stop codon is involved.


High blood pressure (hypertension) has many possible causes. Rarely, hypertension results from a benign tumor of the adrenal gland that releases potent chemicals such as epinephrine into the bloodstream. Although rare, these tumors, called pheochromocytomas, are important in clinical medicine. Surgical removal of a pheochromocyoma can cure the hypertension, but in response to seemingly mild stress, an untreated pheochromocytoma can secrete chemicals that produce catastrophic consequences such as heart attack and sudden death. Findings such as episodic severe hypertension, sweating, pallor, or headache may suggest to a physician that a pheochromocytoma is present, but blood tests are not sensitive enough to detect pheochromocytomas in all patients. Researchers in the intramural program at NINDS have now developed an effective blood test to detect pheochromocytomas. This should increase the efficiency and decrease the cost of diagnostic evaluation of patients with high blood pressure and findings that suggest a pheochromocytoma.


Narcolepsy is a serious brain disorder that dramatically affects sleep. Usually beginning in adolescence, its symptoms include extreme daytime sleepiness or sleep paralysis—a frightening inability to move shortly after awakening or shortly after dozing off. For many people, the most serious symptom is sudden episodes of muscle weakness called cataplexy. In extreme cases, a person may abruptly collapse to the floor completely paralyzed for several minutes. Cataplexy can occur at any time but is often triggered by strong emotions such as anger, joy, surprise, or laughing. Narcolepsy ruins lives. It impairs job and school performance, predisposes people to have accidents, and can seriously impair social life. An average of 14 years pass before the disorder is properly diagnosed, and, because little is known about what causes narcolepsy, treatment is limited to general nervous system stimulants.

After a decade-long search, a team of scientists has discovered the gene defect that causes an inherited form of narcolepsy in dogs that closely mimics the disease in people. Dogs are one of the few animals that are affected by the disorder. In certain Dobermans and Labradors, narcolepsy is caused by a single gene that must be inherited from both parents, which simplified the search for the gene. The gene provides a crucial clue to the cause of narcolepsy that may lead to more effective treatment. The gene codes for a receptor (i.e., the sensor of the cell) for a chemical messenger called hypocretin. Hypocretin plays an important role in sleep regulation. The same gene exists in humans, and researchers plan to look for defective versions in people with narcolepsy and to test drugs targeting the hypocretin system.

West Nile Encephalitis Virus

In August 1999, health officials in Queens, NY, reported an outbreak of encephalitis accompanied by profound weakness and axonal neuropathy (i.e., involvement of long nerve fibers). Blood analysis for North American viruses yielded results consistent with St. Louis encephalitis virus. Wildlife observers noted increased mortality among birds, including free-ranging crows and exotic birds in the Bronx Zoo; laboratory investigation revealed inflammation affecting the birds’ brains and hearts. Because the St. Louis encephalitis virus does not normally affect birds, efforts to identify other viruses were expanded.

Using molecular analysis techniques, a NINDS grantee, working on samples provided by the New York State Health department, found that four of the five brain samples contained gene sequences consistent with the presence of a Kunjin/West Nile-like virus not previously reported in the Americas. At the same time, investigators at CDC amplified a West Nile-like viral gene sequence. Application of reagents specific for West Nile-like viruses confirmed infection in 50 people and in mosquitoes collected from areas of bird and human infection.

As international trade and travel increase, and wilderness habitats shrink, bringing humans in contact with animal pathogens, infectious diseases from the Third World and other sources are more likely to become a threat in this country. Thus, it is imperative to develop methods and expertise that can be rapidly mobilized to identify and characterize novel infectious agents. NINDS has a long history of supporting research on infections of the nervous system. One example of a rare transmissible disorder that has been a long-term focus of research in the Institute and is now of public health concern is the agent that causes CJD or bovine spongiform encephalopathy (mad cow disease).

Neural Stem Cell Therapies for Rare Neurological Disorders

Stem cells are primitive cells that can multiply and specialize to form many different types of cells. Several experiments in animal models of neurological disorders have demonstrated the potential of stem cells for treating a wide variety of diseases through replacement of lost cells or by serving as a vehicle to deliver needed substances to the brain. In one recent example, an experimental protocol generated precursors of glial cells, the supporting cells that normally form the insulating myelin sheath of nerve fibers. When scientists transplanted those cells into a rat model of the human hereditary disorder Pelizaeus-Merzbacher disease, the transplanted cells efficiently interacted with the host brain and replaced the missing myelin. Other experiments have demonstrated that stem cells can migrate widely in the brain and help counteract enzyme deficiencies in animal models of inherited disorders such as Tay-Sachs disease. Although significant ethical, biological, and technical issues must be resolved, stem cells may be useful for treating many disorders of the nervous system.

Animal Models of Human Genetic Disorders

Many neurological disorders are caused by gene defects. Discovering the specific gene defects that cause a particular disorder is an important step toward understanding and curing a disorder, but the path from gene identification to improving care of patients is a difficult one. One benefit from gene research is the development of genetically engineered animal models of human disease that allow researchers to study disease mechanisms and test treatments. In the last few years, scientists have leveraged gene findings to develop mouse models of several rare neurological disorders including, Canavan disease, neurofibromatosis, Batten disease, ALS, spinal muscular atrophy, Huntington’s disease, and spinocerebellar ataxias. Many of these mice are already crucial research tools. Perhaps surprisingly, many genes and cellular mechanisms in even nonmammalian organisms are quite similar to those in humans. These simpler animals allow efficient experimental manipulations to determine biochemical pathways and other genes that modify the effect of a particular mutation. For this reason, in addition to mouse models, models in simpler organisms such as fruit flies are increasingly becoming useful tools for research, with fly models of leukodystrophies, ataxias, and other forms of neurodegeneration becoming available.

Rare Diseases Research Initiatives


In March 1999, NINDS, in collaboration with NICHD, issued the PA Exploratory Grants in Pediatric Brain Disorders: Integrating the Science (PAS 99 080). The exploratory/developmental (R21) grant mechanism is designed to support creative, novel, or high-risk/high-payoff approaches. This PA targets the many disorders that produce anomalous development of the nervous system, cause neurodegeneration during development, or result from injury, including nervous system injury that is secondary to many types of developmental disorders. The Institutes hope this approach will encourage interaction among scientists, promote new ideas, and allow researchers to attack many disorders about which little is known.

Other recent solicitations relevant to rare diseases include Rett’s Syndrome: Genetics, Pathophysiology, and Biomarkers (PAS-99-0370) and Development of Rapid Assay for Creutzfeldt-Jakob Disease (RFP-99-11).

Rare Disease-Related Program Activities

Workshops and Other Meetings

In FY 1999, NINDS, often in cooperation with other components of NIH and with private organizations, supported workshops relevant to several rare diseases. Among these were meetings focused on Batten disease, Pelizaeus-Merzbacher Disease and the allelic disorder X-linked spastic paraplegia type 2, progressive supranuclear palsy, spinal muscular atrophy, Niemann-Pick disease type C, trigeminal neuralgia, facioscapulohumeral muscular dystrophy, Friedreich’s ataxia, glioma, Sturge-Weber syndrome, restless legs syndrome, periodic limb movement disorder, and narcolepsy.

Meetings planned for FY2000 focus on ataxia telangiectasia, peroxisome biogenesis disorders, hereditary spastic paraplegias, inherited developmental brain disorders, ALS and spinal muscular atrophy, neurofibromatosis, DMD, Hallervorden-Spatz syndrome, brain tumors, channelopathies, and gene therapy in the nervous system.

Other Program Activities

NINDS also supports extensive fundamental research on the normal nervous system that lays the foundation for understanding what goes wrong during disease. The Institute plays a major role in developing new approaches for treatment, such as stem cells and gene therapy, and in improving technologies, such as brain imaging, that have potential applications in the diagnosis and treatment of many disorders. Several continuing program activities are also focused on the problems of particular rare neurological disorders. For example, the Institute is involved in planning and development of outcomes measures for clinical trials to treat Friedreich’s ataxia.

When special scientific opportunities are evident, NINDS actively stimulates research and encourages interest in specific diseases by solicitations and workshops, often working closely with voluntary groups and other components of NIH. However, most research supported by NINDS is investigator initiated, and the Institute relies heavily on the insight of investigators around the country to investigate needs and opportunities for research on rare neurological disorders. Among the many new investigator-initiated grants begun in FY 1999 are research projects focusing on adrenoleukodystrophy (ALD), ALS, Canavan disease, Friedreich’s ataxia, hereditary spastic paraplegia, inclusion body myositis, lissencephaly, myasthenia gravis, narcolepsy, neural tube defects, neuroblastoma, neurofibromatosis, neuronal ceroid lipofuscinosis, Rett’s syndrome, spinal muscular atrophy, spinocerebellar ataxias, torsion dystonia, and Tourette’s syndrome.

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Last Reviewed: January 27, 2005
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