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

National Center for Research Resources (NCRR)

Overview of NCRR Rare Diseases Research Activities

NCRR develops and supports critical research technologies that underpin health-related research to maintain and improve the health of our Nation's citizens. NCRR supports shared resources, sophisticated instrumentation and technology, animal models for study of human disease, clinical research, and research capacity building for underrepresented groups.

Through its support of multidisciplinary research, NCRR is uniquely positioned to provide either primary research support or resource support in partnership with other ICs to address emerging clinical and basic research needs, such as the study of rare diseases. Expansion of NCRR's efforts in new technologies and instrumentation, development of animal models, and clinical research will foster interdisciplinary collaborations and advance NIH's efforts to study rare diseases.

Recent Scientific Advances in Rare Diseases Research

Clinical Research

Severe Combined Immunodeficiency

Investigators using NCRR resources at Duke University summarized their experience with 89 consecutive patients treated for inborn errors of the immune system classified as severe combined immunodeficiency (SCID). Patients were treated with bone marrow transplantations and were surveyed 3 months to 16.5 years posttransplantation. Investigators were particularly interested in the relative outcomes of patients receiving bone marrow from immunologically identical versus half-identical donors. Some patients had a sibling with a complete histocompatibility match (HLA identical), whereas others did not and had to rely on a donation from a parent who was only half-matched (HLA haploidentical). The exactness of the match is important because, although the patient has no immune system and cannot reject the donated marrow, once the marrow reconstitutes the immune system, it can recognize the recipient's body as foreign and cause a serious condition known as GVHD.

The hope is to maximize the chance for rebuilding the immune system while minimizing the chance of rejection. It was theorized that, if the donor bone marrow was depleted of T cells (cells associated with GVHD) before transplantation, both conditions would be satisfied. In reviewing the data, there was an overall 81% survival rate, and the 12 patients having transplantations with immunologically identical donors were all alive. Sixty of 77 (78%) of those who received half-identical donations were alive. The latter group included two of three who received placental blood as a source of stem cells, in addition to the bone marrow. Other factors favoring survival were gender, ethnicity, and age at transplant. All of the transplanted girls survived, whites had a better survival than African Americans or Hispanics, and 95% versus 76% of children transplanted before the age of 3.5 months survived. There were no deaths attributed to GVHD, although one recipient (of a half-matched donation plus placental blood) is on continuous cyclosporine for chronic GVHD.

Congenital Lipodystrophy

NCRR investigators at the University of Texas in Dallas are doing genetics studies on patients with a rare disease known as congenital lipodystrophy (CGL), which is characterized by nearly total lack of body fat and marked muscularity from birth. In addition to the distinctive physical appearance, these patients have a series of metabolic derangements including marked insulin resistance, severe hyperinsulinemia, hypertriglyceridemia, and low levels of HDL cholesterol. Abnormal glucose tolerance and diabetes mellitus usually appear during or after puberty. Fatty infiltration of the liver occurs early and may lead to cirrhosis and its complications.

The observation that the depletion of body fat is from selective areas of the body, with normal fat distribution in other areas such as the orbits, palms, soles, and scalp, has led to the hypothesis that the gene defect in CGL interferes with growth and differentiation of metabolically active adipose tissue and could result from either failure to form fat cells, failure of precursors of fat cells to differentiate into mature fat cells (adipocytes), or failure of mature adipocytes to synthesize and/or store triglycerides. Consequently, a search for genes that are active in adipocyte differentiation was undertaken. Previous studies, using a candidate gene approach, excluded several genes involved in insulin action, lipid metabolism, and adipocyte biology; however, many other candidate genes were not studied.

With the development of a mouse model (transgenic mouse) exhibiting many features of CGL, the altered expression of certain transcription factors became a focus of investigation, and a new approach was used to localize the gene(s) altered in CGL. Seventeen family members with a relative with CGL were recruited. The new genetic approach was applied to the genetic material of affected individuals and their family members, and one gene, known as RXR, emerged as strong a candidate as the defective one in this disease. If confirmed in further studies, knowledge about the genetic defect in this disease may lead to treatment or cure.

Huntington's Disease

Huntington's disease is a devastating neurological illness that afflicts men and women in their 30s and 40s. It affects approximately 30,000 individuals in the United States, and, because it is an autosomal dominant disorder, another 150,000 people are at risk for developing the disease.

Cytosine, adenosine, guanine (CAG) is the genetic code for glutamine, an organic compound derived from ammonia. When multiples of CAG are strung together in the nuclear material, a toxic polymer of glutamine, known as the Huntington protein, is synthesized. When this genetic abnormality is found in that part of human genetic material known as chromosome 4, the affected individual develops the motor, cognitive, and behavioral dysfunctions of Huntington's disease.

A compound known as Riluzole is an antiglutamatergic agent that has been shown to improve symptoms of Huntington's disease in baboons. Based on these promising animal data, NCRR investigators at the Massachusetts General Hospital administered 50 mg of Riluzole twice daily for 6 weeks to eight humans afflicted with this illness. The writhing movements associated with Huntington's disease decreased by 35% during treatment but worsened on discontinuation of the drug. The disordered tone and decreased total functional capacity scores associated with Huntington's disease were unchanged throughout the course of therapy, and no significant drug toxicity was noted. The investigators believe that additional studies to determine the neuroprotective potential of this agent are warranted. Any agent that ameliorates the symptoms or, perhaps, has the potential for preventing the antecedent neurological damage would be of enormous benefit to patients and families who have or know that they will contract this illness.

Minority Health

Systemic Lupus Erythematosus

Scientists at institutions receiving support from NCRR are providing information that could be crucial for understanding SLE. SLE is an autoimmune disease in which the body's own immune system turns against itself and attacks its own healthy cells and tissues, causing inflammation of the joints, skin, kidneys, heart, lungs, blood vessels, and brain.

Researchers want to know why some individuals are predisposed to SLE. It is more common in women than men; moreover, some racial and ethnic groups are disproportionately affected. SLE is three times more common in African-American women than in white women, and it is also more common in women of Hispanic, Asian, and Native American descent. Disease outcome also differs according to ethnic groups (African-American patients, for example, have kidney and CNS involvement more often than do white patients).

In seeking answers to these questions, NCRR investigators at the University of Hawaii at Manoa collected data from individuals with one type of lupus from Hawaiian medical facilities and a patient support group. They found that the disease was not only more prevalent among non-Caucasian groups such as Japanese, Filipinos, and Chinese, but that mortality rates were three times higher for non-Caucasians than for Caucasians. Reasons for these disparities are being sought.

NCRR-supported scientists at the Universidad Central del Caribe School of Medicine in Bayamón, Puerto Rico, are gaining a better understanding of SLE by studying this population of mixed (mainly Spanish, African, and native aborigine) ancestry. Puerto Rican patients studied were more likely to suffer from sensitivity to light and facial rash than from arthritis, inflammation of tissues around the heart and lungs, kidney involvement, seizures, psychoses, and other major organ damage. The study concluded that genetic factors are probably most important in explaining these differences and pointed the way for current studies of genetic associations in different ethnic populations. Understanding what attenuates the symptoms of SLE in Puerto Ricans may lead to improved care and management of this disease and contributes to the growing knowledge base.

Animal Models

Krabbe's Disease

Krabbe's disease is a rare, degenerative inherited condition that is usually fatal by age 2. Scientists have found that a defective gene that attacks the nervous system causes the disease and that the basis of Krabbe's disease lies in the myelin sheath that protects the nerve cells. Diseases associated with this problem are known as leukodystrophies. Like most body substances, myelin is regularly manufactured and broken down as part of the life cycle, but as a result of the genetic defect, people with Krabbe's disease do not have enough of the enzyme that breaks down two myelin components. This deficiency causes problems with the sheath that leads to poor communication throughout the nervous system followed by deficits in breathing, body temperature, and digestion. The Tulane Regional Primate Research Center has the only breeding group of rhesus monkeys carrying this genetic disease. Availability of this animal model, along with a talented team of investigators at a new facility for gene therapy research, offers an unprecedented opportunity to develop genetic therapy for Krabbe's disease and other leukodystrophies.


Autism is a neurodevelopmental disease characterized by profound impairment of the affected individual's ability to relate to other people. Scientists from the University of California Davis have developed the hypothesis that a part of the brain known as the amygdala may be a critical player in the development of autism. The amygdala is a region of the brain that is composed of at least 13 nuclei and cortical areas. The region is involved in a wide array of brain activities, from lower order ones such as regulating respiration and cardiovascular function to higher order ones such as cognition and emotion.

Because the nonhuman primate is an ideal research model for such disorders, scientists from the University of California-Davis, in collaboration with the investigators at the NCRR-supported California Regional Primate Research Center, are using nonhuman primates for both the study of control of normal social behavior and the understanding of certain neurodevelopmental disorders that impair social interactions.

Using sophisticated neurosurgical techniques guided by MRI, the research team delicately threads a minute cannula through the brain into the amygdaloid complex, where a neurotoxic substance is painlessly injected to ablate a section of the complex. The animals are observed while they interact with one or more control animals whose amygdalas are intact. The primary goal is to use new strategies to investigate the specific role of the amygdala in social behavior in both the mature and the developing animals.

The goal is to understand how the amygdala is involved in allowing normal social behavior to emerge and to determine whether, if damaged, social interactions are disrupted in a manner similar to autistic behavior. Determining the brain regions targeted by autism will be a major step toward prevention and, hopefully, treatment of this condition.

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Last Reviewed: January 27, 2005
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