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

National Institute of Environmental Health Sciences (NIEHS)

Rare Diseases Research Initiatives

Mitochondrial Diseases

Between 1,000 and 4,000 children are born each year with mitochondrial diseases with mortalities ranging from 10% to 50% per year, depending on the specific disease. Leigh syndrome, for example, is one of the more lethal mitochondrial diseases in which 50% of the children die in the first year after diagnosis. Such diseases are caused by mutations of or depletion of mitochondrial DNA. NIEHS scientists are studying the cause of these mutations by understanding the role of DNA replication and repair in mitochondrial DNA mutagenesis.

Autoimmune Disease

NIEHS scientists are examining the potential for increased incidence and/or exacerbation of autoimmune disease in MRL/lpr autoimmune-prone mice exposed prenatally to environmental agents. MRL/lpr mice exhibit severe renal necrosis (glomerulonephritis), similar to that observed in human SLE patients, with females normally presenting circulating autoantibodies against nucleoprotein particles and subsequent renal complement-antibody immune complexes at approximately 14 to 16 weeks of age versus males at 20 to 22 weeks. Severity of autoimmunity is evaluated via quantitation of serum autoantibodies to single-stranded DNA, urinary protein levels, and renal histopathology in both sexes to determine whether differential chemical-induced effects occur. Preliminary results suggest that developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin, and possibly other endocrine-disrupting environmental contaminants, may accelerate the onset of SLE in both male and female autoimmune-prone mice.

DNA Triplet Repeat-Based Diseases

There are more than 14 rare neurological and neuromuscular diseases, including Haw River syndrome that affects a small group of African-American families in North Carolina, that result from the expansion of triplet repeat DNA sequences. NIEHS scientists are investigating the underlying systems responsible for triplet repeat expansion and have proposed a molecular model in which triplet expansion is due to a deficiency of 5 -flap cleavage during DNA replication. In particular, the interactions of the human enzyme responsible for 5 -flap cleavage (FEN1) with other components of DNA metabolism, such as proliferating cell nuclear antigen (PCNA) and DNA polymerases and , are being addressed genetically. This work will provide further understanding of how the disease might arise and possible consequences of variations in the relevant DNA metabolic proteins.

Nijmegen Breakage Syndrome (NBS)

Nijmegen breakage syndrome (NBS) is a rare, autosomal recessive disorder characterized by increased sensitivity to ionizing radiation, defective cell cycle checkpoint responses, and elevated cancer incidence. Both NBS and a related ataxia-telangiectasia-like disorder (A-TLD) are caused by mutations in the chromosomal DNA repair genes hNBS1 and hMRE11, respectively. Functional homologs of the human genes, referred to as XRS2 and MRE11, are present in the genetically tractable budding yeast Saccharomyces cerevisiae. NIEHS scientists and others have demonstrated that these genes perform similar functions in both yeast and human cells, with the view that the MRE11 and XRS2 proteins are components of a complex with DNA exonuclease and endonuclease activities. Recently, the nuclease function was found to be critical in the repair of broken chromosomal DNA by homologous recombination but not for recombination-independent mechanisms of repair performed by the complex.

The Treatment of Lead-Exposed Children Trial

The Treatment of Lead-Exposed Children trial (TLC) is a four-center, double-blind study of oral chelation with succimer to treat lead-associated disorders of growth, development, and behavior in toddlers with blood lead levels of 20 to 44 µg/dl. TLC randomized 780 children between 1994 and 1997 and followed them for 3 years after treatment with tests of behavior, cognition, and neuropsychiatric function. About 900,000 U.S. children have elevated blood lead levels (above 10 µg/dl). Perhaps 40,000 to 400,000 of them, mostly African-American children in deteriorated inner-city housing, would be eligible for this trial on blood lead criteria. Results are due soon on the first round of testing; followup on the cohort is continuing.

Growth Control and Cancer

NIEHS scientists are investigating molecular mechanisms of cell cycle control, focusing on critical control points in cell cycle transitions. Specifically, studies are under way to investigate the molecular mechanisms involved in cell cycle checkpoint responses to exposures to ionizing radiation (IR) and other environmental agents in normal human fibroblasts and in fibroblasts that lack normal function of p53 (including cells from individuals with Li-Fraumeni syndrome), pRB, or the ataxia telangiectasia (AT) cancer susceptibility gene products. In addition to aiding understanding of the process of carcinogenesis, these studies hold great potential for providing insight into the mechanism of action of environmental toxins, particularly those that have been classified as nongenotoxic carcinogens.

Environment-Infection-Gene Interactions in Autoimmune Disease

Approximately 80 separate autoimmune diseases, including Graves' disease, Hashimoto's thyroiditis, rheumatoid arthritis, type 1 diabetes mellitus, multiple sclerosis, SLE, inflammatory bowel disease, psoriasis, uveitis, Sjögren's syndrome, autoimmune inner ear disease, and scleroderma, affect more than 9 million Americans (1 in 31). Autoimmune mechanisms may also underlie rapidly progressive sensorineural hearing loss, with or without vertigo, and certain childhood neuropsychiatric disorders such as obsessive-compulsive disorder and Tourette's syndrome. Women and some minorities are disproportionately affected by many autoimmune diseases. All of these diseases result from an attack of the immune system on the body's own tissues. Environmental and infectious agents and/or their products have been implicated in the pathogenesis of autoimmune diseases. Several environmental chemicals have been associated with autoimmune diseases, including silica dust and lupus; vinyl chloride and organic solvents in scleroderma; mercury, gold, or perchloroethylene in autoimmune kidney disease; and polybrominated biphenyls in autoimmune thyroid disease.

An RFA, issued in 1999 and supported by NIEHS and 10 other Institutes plus the Office of Research on Women's Health, was designed to support innovative basic, epidemiological, and preclinical research to understand the role of and mechanisms by which environmental and infectious agents influence the development and exacerbation of autoimmune diseases and to understand the role of genes and hormones in modulating the immune response to environmental and infectious agents. The RFA resulted in 23 awards, 7 of which are NIEHS grants. The NIEHS-supported researchers are studying SLE, thyroiditis, and the environmentally induced disruptions of the immune system.

Pfiesteria Toxins

An estuarine dinoflagellate, Pfiesteria piscicida, has been implicated in occasional fish kills along the southeastern United States. The toxins produced by this dinoflagellate are suspected of affecting not only fish but also fishermen and other people working on contaminated waterways. Human effects of exposure to Pfiesteria toxin include neurotoxicity and skin lesions. Toxin isolation and purification is the major bottleneck in conducting well-controlled toxicologic and monitoring studies of Pfiesteria's health effects. Two NIEHS Marine and Freshwater Biomedical Sciences (MFBS) Centers are active in this research area. Scientists at the University of Miami MFBS Center, working with samples provided by researchers at North Carolina State University (NCSU) since 1993, have isolated a lipid-soluble fraction that is dermonecrotic (i.e., damaging to the skin) and a water-soluble fraction that is neurotoxic (i.e., damaging to the nervous system). The dermonecrotic factor is being isolated and purified and will soon be available to multiple research groups for study. To enhance the timeliness of this work, NIEHS has given a supplement to this Center that will allow its researchers to aggressively pursue the purification and chemical characterization of the two known Pfiesteria toxins, to study their oral toxicities in a mouse model, and to study their respiratory toxicities in a sheep asthma model. Researchers also plan to collect preliminary information on risk factors and critical exposure levels for health effects associated with human environmental exposure to Pfiesteria and on the duration of symptoms associated with human exposure. A correlation of PET brain scan results from environmentally exposed humans and experimentally exposed sheep will be carried out.

NIEHS has recently combined with NINDS to issue the RFA The Role of the Environment in Parkinson's Disease (PD). The objective of this initiative is to stimulate research on the relative roles of environmental, endogenous, neurochemical, and modifying genetic factors in the cause of PD. Recent evidence from twin studies has shown that genetics plays less of a role and environmental factors a potentially greater role than previously thought in the development of late-onset PD. In response to this finding, NIEHS and NINDS invited scientists to submit grant applications for research aimed at elucidating the role of the environment in the development of PD. The results of these investigations will help to clarify the role environmental factors play in the etiology of the disease. Fifty-one applications were received in response to the RFA. Awards will be made during the summer of 2000.

Recent Scientific Advances in Rare Diseases Research

Systemic Lupus Erythematosus

SLE is an understudied autoimmune disease that particularly affects women and minority populations, severely damaging the kidneys, joints, and other tissues. The Carolina Lupus Study focuses on measures of endogenous and exogenous estrogen exposure, occupational exposures (e.g., silica dust), and medical history-related factors including infectious diseases, allergies, and transfusions. This is a population-based case-control study of recently diagnosed patients living in eastern North Carolina and South Carolina, consisting of 265 cases and 355 control subjects frequency matched by age, gender, and State enrolled; 90% of the cases are female, and 61% are AfricanAmerican. Cases are identified through community- and university-based rheumatology practices, public health clinics, and patient support groups.

Preliminary analysis of medical-related risk factors has been conducted on 159 cases and 201 control subjects. This analysis was limited to conditions that occurred before the age at diagnosis (or reference age for control subjects) and were adjusted for age, gender, and race. The risk of developing SLE increased with a history of hives and was somewhat increased with herpes zoster. Also, SLE patients were more frequently allergic to sulfa drugs and codeine but not to penicillin. No association was found between SLE risk and history of eczema, asthma, hay fever, urinary tract infection, or allergy to foods or insect stings. Patients were somewhat more likely than control subjects to report they had received a transfusion; transfusions relating to anemia or platelet disorders were excluded from analysis. A history of stroke, blood clot, or pulmonary embolism was also more common in SLE patients. These results raise questions about the role of specific inflammatory, infectious, and allergic conditions, and possibly of transfusion-related microchimerism or infections, in the development of SLE.

Friedreich's Ataxia

Friedreich's ataxia (FRDA) is the most common cause of recessive ataxia and occurs at an incidence of 1 in 30,000 Caucasians. The yeast homolog of the FRDA gene, YFH1, which codes for the protein frataxin, is responsible for regulating the amount of iron in the mitochondria. The absence of frataxin leads to iron accumulation and the production of radicals. NIEHS scientists have established that frataxin limitation leads to nuclear and mitochondrial DNA damage. This novel finding has implications for the pathological symptoms associated with the disease and potential treatment strategies. It also has many implications for possible origins of aging and cancer.

Lung Hemorrhage in Cleveland Infants

Over the past 5 years, a relatively rare disorder, acute pulmonary hemosiderosis, or hemorrhage, has been found in many infants in inner-city Cleveland, OH. Thirty-seven cases in a limited area of Cleveland resulted in 12 deaths, including 7 originally thought to be sudden infant death syndrome. The environmental mold Stachybotrus chartarum has been identified as the causative agent, with the young child's developing lung being particularly vulnerable. NIEHS is supporting a pilot study that will allow a local physician to further define the environmental components for a condition that has a 30% mortality rate and is disproportionately affecting inner-city children. The researchers have identified environmental tobacco smoke as a possible trigger for the acute bleeding. Additionally, this researcher has developed a home remediation program that completely eliminates the mold spores from contaminated homes.

Previous Contents Next

Last Reviewed: January 27, 2005
Back to Top
Back to Top