Start of Main Content
Annual Report on the Rare Diseases and Conditions Research Activities of the National Institutes of Health 1997

Rare Diseases Research Highlights

DNA Repair and Transcription Deficiencies in Premature Aging Syndromes

With the recent cloning of the Werner syndrome (WRN) gene, and with the recent information that this gene, the Cockayne syndrome complementation group B (CS-B) gene, and some Xeroderma pigmentosum (XP) genes are putative helicases, further understanding of the molecular deficiency in these disorders is a high priority for the National Institute on Aging. Cockayne syndrome (Group B), WRN, and other age-related disorders (Bloom syndrome, XP) are characterized by mutations within related genes characterized by conserved motifs of sequence homology. A number of proteins of this family have demonstrated to be DNA-dependent ATPases, a subset of which have also been shown to be helicases. Proteins of this family are involved in various aspects of chromosome metabolism. The molecular defects responsible for the clinical phenotypes of these diseases remain to be determined, but presumably relate to the functional activities of these conserved proteins.

Wegener Granulomatosis

Wegener granulomatosis is a disease of unknown origin characterized by an inflammation of the blood vessels that leads to restricted blood flow to organs and, ultimately, the destruction of tissue. The standard treatment for Wegener granulomatosis is the drug cyclophosphamide, which is not well tolerated by some patients and can have serious long-term side effects. Intramural National Institute of Allergy and Infectious Diseases (NIAID) investigators are conducting clinical studies on the efficacy of the drug methotrexate as an alternative treatment for this disease. Current findings from these studies suggest that methotrexate is effective in treating the disease and, in contrast to cyclophosphamide, causes less severe toxic side effects.

Severe Combined Immunodeficiency

A number of different genetic defects lead to Severe Combined Immunodeficiency (SCID) in humans. All types of SCID are characterized by the absence of B and T lymphocyte function, resulting in severe and often fatal infection early in life. Over the last several years, NIAID-funded researchers have described the genetic defects underlying the various types of SCID. More recently, these investigators determined the genetic frequency, clinical features, and degree of immune system impairment for each type of SCID. These studies will help to further characterize the individual SCID diseases and determine the role of the implicated genes and their protein products in normal immune function.

Multipurpose Arthritis and Musculoskeletal Diseases Center in Juvenile Rheumatoid Arthritis

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) worked closely with a multidisciplinary research group that was able to establish a strong research base in juvenile rheumatoid arthritis. This group has competed successfully in the establishment of a Multipurpose Arthritis and Musculoskeletal Diseases Center, which is undertaking a comprehensive, multidisciplinary approach to pediatric rheumatic diseases, which includes basic studies in animal models as well as studies in children with disease. Studies include a project to determine the usefulness of diagnostic MRI in monitoring the responses of children to various therapies, and another project to assess the effect of calcium supplementation and vitamin D on the bones of patients with juvenile rheumatoid arthritis. Researchers at the center are expected to provide significant laboratory-to-bedside insights into juvenile rheumatoid arthritis.

New Insights into the Causes of Osteogenesis Imperfecta (OI)

Most often, the underlying cause of OI is a defect in the gene that regulates the production of collagen, which is essential for the normal structure of bone. Milder forms of the disease reflect the failure of bone cells to synthesize normal amounts of collagen. More severe forms arise from mutations that alter the structure of the collagen itself, leading to abnormal interactions between the mutant collagen and other components of bone. NIAMS-supported Investigators have now found that certain mutations prevent the synthesis of the mutant collagen. These mutations appear to have their effect during the synthesis of messenger RNA, the first step in protein synthesis. This observation suggests a new approach to the treatment of the severe forms of osteogenesis imperfecta which result from synthesis of abnormal collagens. It may be possible to design chemical agents that will alter the structure of messenger RNAs encoding abnormal collagens in a way that will prevent the synthesis of the disease-causing protein. This could be used to convert a severe form of OI into a milder form.

Genetic Model for Acid Maltase Deficiency (Pompe Syndrome)

Researchers in NIAMS' Intramural Research Program are also studying Glycogen Storage disease Type II (known also as Pompe syndrome or acid maltase deficiency). This is a rare inherited disease mainly affecting muscles. In addition to genetic studies on patients, the group has created a similar disease in mice by knocking out the acid maltase gene and has developed a retroviral vector that can transfer the gene into muscle cells where it can correct the inherited defect. The group collaborates with physicians and scientists in the United States, Europe, and Asia in studies on this disease.

Specialized Center of Research (SCOR) on Scleroderma

NIAMS, along with the NIH Office of Research on Women's Health, recently awarded a grant for the first Specialized Center of Research (SCOR) on Scleroderma, which provides for a coordinated research effort that strongly emphasizes basic research and an interaction between basic and clinical investigations, thus enhancing basic and clinical research in scleroderma.


In order for cancer to metastasize to distant sites, cellular invasion of malignant tumor cells as well as formation of new blood vessels will be required. National Cancer Institute (NCI)-supported investigators have demonstrated that inhibiting the growth of new blood vessels to a tumor can stop its growth and in some cases cause the tumor to regress. One of the most potent inhibitors of angiogenesis is angiostatin. Angiostatin is an internal fragment of the larger endogeneous protein plasminogen. Angiostatin can be produced from plasminogen by an enzyme called metalloelastase (MME) made by tumor infiltrating macrophages. This observation made by a NCI-supported investigator provides an explanation for the presence of large numbers of macrophages at the sites of tumors. Possibly, the macrophages are there to make angiostatin to inhibit the growth of the tumor as well as to interact with T and B lymphocytes to mount an immunological response against the tumor.

Drug Development

The NCI Drug Developmental Program continues screening new synthetic and natural compounds for anti-tumor activity using the automated cancer cell line screen. Approximately 66,000 defined chemical structures have been evaluated since the screen became operational in April 1990. More than 6,100 compounds have demonstrated in vitro anti-tumor activity of which 3,000 agents were selected for in vivo evaluation for assessment of therapeutic activity. It is obvious that there are more compounds to test/develop than current resources would allow. Thus the staff of the Developmental Therapeutics Program had formed a working network of investigators to prioritize compounds for development. Including vaccines and other biologicals as well as chemotherapeutic agents, a total of 38 agents are in Decision Network level 2A (small animal testing), 4 agents are in Decision Network level 2B large animal/primate testing) and 25 are in Decision Network level 3 (ready for human testing subject to obtaining IND). As the agents move through the different levels of the decision process, the level of financial commitment by the NCI increases.


Investigators in the NCI intramural program have begun two new immunotherapy studies in Ewings/PNET and Alveolar Rhabdomyosarcoma. Both studies seek to determine whether the tumor specific fusion proteins that result from the tumor-specific translocations in Ewings and alveolar RMS respectively, can serve as tumor antigens recognized by specific cytotoxic T lymphocytes (CTL). They have already demonstrated in mouse models that antigen presenting cells (APC) pulsed with translocation specific fusion peptides can be used for APC vaccination, which is a crucial step in cell mediated immunity. In addition, they are attempting to determine whether autologous T-cell transfer may increase responses to vaccination. This possibility has already been demonstrated in preclinical models and is now being assessed in clinical studies. To date, 9 patients have been entered onto the current protocol 97-C-0050 and 8 patients are evaluable, 1 is currently on study. One patient had an objective response and another patient demonstrated a proliferative response to the vaccinating peptide. Of further note, only 3 of the 9 patients have had CD4 counts greater than 300 at the start of study due to prior chemotherapy, and the 2 responses seen have been from this subgroup of 3 patients. Another 5 patients have been apheresed and have yet to receive experimental immunotherapy since they are still doing well on chemotherapy alone.

New Treatment for Hypoparathyroidism

Hypoparathyroidism is one of the few remaining hormonal deficiencies for which hormone replacement therapy is not available. Moreover, the existing treatment, vitamin D or its analogs and calcium, lacks the full kidney calcium-retaining action of parathyroid hormone (PTH), and thus, treated patients often exhibit elevated calcium in the urine. To test the hypothesis that treatment with PTH 1-34 can achieve simultaneous normalization of both serum and urine calcium, a randomized, crossover trial of PTH 1-34 compared with calcitrol was conducted in patients with hypoparathyroidism. The study supported by the National Institute of Child Health and Human Development (NICHD) showed daily treatment with PTH 1-34 maintained normal serum and urine calcium. In addition, biochemical markers of bone turnover increased significantly during PTH 1-34 treatment.

Glycerol Kinase Deficiency (GKD) and Complex GKD

Glycerol kinase deficiency (GKD) is an X-linked disorder that is heterogeneous in nature. Clinically, it is recognized in three forms: infantile, juvenile and adult. The infantile form is the most severe and has the most extensive genetic damage associated with it. This form is referred to as complex GKD since the defect in the gene for the enzyme, glycerol kinase, is frequently complexed with defects in one or both of its contiguous genes that are responsible for Duchenne muscular dystrophy and adrenal hypoplasia congenita (AHC). These three genes are in close proximity on the X chromosome and large deletions in this region can leave all three genes damaged. Using a specific genomic scanning approach, the genes for glycerol kinase and DAX1, an adjacent gene responsible for adrenal hypoplasia congenita, were located and sequenced by NICHD supported researchers. The latter gene is also associated with hypogonadotropic hypogonadism and is expressed in the adrenal glands, gonads, pituitary and hypothalamus. Further studies of the genes involved in complex GKD will provide important information on the fundamental relationships between the clinical conditions and corresponding genetic defects in patients with contiguous gene syndromes

Brain and Tissue Banks for Developmental Disorders

NICHD is planning to reissue an RFP to recompete the two existing brain and tissue banks for developmental disorders. The main objective in establishing brain and tissue banks is to develop research resources where biopsied and freshly autopsied tissues from "unaffected" (control) individuals and from patients who had been diagnosed to have various types of developmental disorders could be systematically collected, analyzed, stored and distributed to research investigators. Tissues from several rare diseases are stored in the brain and tissue banks. Examples are galactosemia, citrullinemia, glutaric acidemia, Miller-Dieker syndrome, Prader-Willi syndrome, tuberous sclerosis, Smith-Lemli-Opitz syndrome, and Wiskott-Aldrich syndrome.

Autoimmune Inner Ear Disease

Autoimmune inner ear disease (AIED) is a rare disorder which consists of rapidly progressive (over weeks to months) sensorineural deafness, often associated with vestibular dysfunction (dizziness/ataxia), that affects both ears, usually asymmetrically. Evidence exists indicating that inflammation and altered immunity play a role in the pathogenesis of AIED; accordingly, immunosuppressive drugs (corticosteroids (CS), cyclophosphamide, methotrexate) are the mainstay of current therapy. Important questions exist as to the relative efficacy of the various immunosuppressive agents utilized, how these agents are best used, and whether there are any clinical findings that can be used to predict response to therapy. The NIDCD-funded Otolaryngology Clinical Trials Cooperative Group is conducting a clinical trial investigating: (1) the efficacy of CS in patients with AIED; (2) the feasibility of using methotrexate to maintain hearing gains realized with CS therapy (thereby allowing CS tapering); (3) the relative efficacy of methotrexate, as compared to cyclophosphamide, in CS failures; and (4) the utility of testing for an antibody to a 68 kiloDalton protein (possibly HSP-70, or other protein) which has been noted in patients with AIED, and which may be reflective of disease activity and perhaps predictive of response to CS therapy.

Mitochondrial Genes and Deafness

An area of increasing importance is the link between mitochondrial genes and deafness. Mitochondria are specialized structures within cells which play a crucial role in metabolism and energy production. Mitochondria contain their own genes, which act to replicate the mitochondria during cell division. Most of the mitochondria present in individuals are derived from the mother's egg; thus, diseases which appear to be passed exclusively through the maternal lineage are often linked to defective mitochondrial genes. Another intriguing aspect to mitochondrially linked diseases is that they may exhibit organ specific expression. An NIDCD-supported investigator, who had previously defined an Arab-Israeli family with mitochondrially linked deafness, has now expanded his research efforts to examine maternal patterns of inheritance for aminoglycoside ototoxicity. He now has strong evidence to suggest that a significant amount of aminoglycoside ototoxicity may be linked to mitochondrial gene defects; the precise nature of these defects is under active investigation.

Velocardiofacial Syndrome

Velocardiofacial syndrome (VCFS) is a disorder that has been associated with over 30 different features. The most common occurring features in children with VCF are cleft palate, heart defects, characteristic facial features, minor learning problems and speech and feeding problems. VCFS may also be known as Shprintzen syndrome, DiGeorge syndrome, Cardiofacial syndrome or Conotruncal Anomaly Unusual Face syndrome. These syndromes can have a missing chromosomal segment at 22q11. VCFS is an autosomal dominant disorder. However, VCFS is inherited in only about 10-15 percent of the cases. In most instances, neither of the parents has the syndrome or carries the defective gene and the cause of the deletion in unknown. It is estimated that 130,000 individuals in the United States have this syndrome. This syndrome has often gone undiagnosed or has been diagnosed late. Surgery can repair the cleft palate and can help many of the physical problems; special attention in school may help with learning problems. These children need continued monitoring as there are such a large number of possible problems associated with the syndrome, even if the features were not present at the time the diagnosis was made. The team, supported by NIDCD, at the Children's Hospital of Philadelphia is an ideal model of cooperation between basic and clinical scientists and of cooperation across medical disciplines to begin to ensure better early identification, monitoring and amelioration and treatment for improved quality of life and long-term outcomes for these children.

Tissue Engineering, Biomimetics and Medical Implant

The National Institute of Dental Research (NIDR) co-sponsored with the National Heart, Lung, and Blood Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases a Requests for Application (RFA) for research on Tissue Engineering, Biomimetics and Medical Implant Science. The techniques that are under development and testing in this interdisciplinary field can be applied to the repair and regeneration of tissues that are malformed or missing, as occurs in a number of genetic birth defects affecting the craniofacial complex or that may be destroyed through disease, in the case of oral cancers. In addition, NIDR expects to fund a number of Centers of Discovery--large research and demonstration centers built around a theme or disease topic. Planning grants already awarded reflect interests of investigators in such areas as developmental biology and birth defects and studies of rare chronic pain syndromes.

McCune-Albright Syndrome (MAS)

McCune-Albright syndrome is characterized by precocious puberty, skin pigmentation and weak, deformed bones with marrow replaced by fibrous tissues and sharp needle-like bony deposits (fibrous dysplasia of bone). While mutations leading to the activation of a gene regulating signaling pathways in cells have been identified in patients, the mechanism leading to fibrous dysplasia in bone is not clear. NIDR scientists have shown that the expression of the gene in question is upregulated during maturation of precursor cells to normal bone-forming cells (osteoblasts), and that this pattern of expression is retained in fibrous dysplasia. Characterization of fibrous dysplastic tissues revealed that the fibrotic areas consist of an excess of cells that resemble pre-osteogenic cells, whereas the abnormal bone formed de novo within fibrotic areas represents the output of mature, but abnormal osteoblasts. The abnormal osteoblasts produce a bone matrix enriched in certain anti-adhesion molecules, and poor in certain pro-adhesive molecules found at high levels in normal bone formation. These data indicate that fibrous dysplasia of bone is a disease of cells in the osteogenic lineage, related to the upregulation of gene expression and its effects on bone cell function. They further suggest that a critical, physiological, maturation-related regulation of the gene involved in signaling pathways makes cells in the osteogenic lineage a natural target for the effects of mutations in the gene and may provide a clue as to why bone itself is affected in this painful, crippling disease.

Bartter's and Gitelman Syndromes

Bartter's and Gitelman's syndromes are autosomal recessive disorders characterized by hypokalemic metabolic alkalosis associated with normal or reduced blood pressure. Other clinical features include renal salt wasting of variable severity, hyperreninemic hyperaldosteronism, altered prostaglandin metabolism, and insensitivity to the vasoactive effects of angiotensin II and norepinephrine. Often presenting in infancy, patients with Bartter's syndrome manifest dehydration with low blood pressure, hypercalciuria despite normal calcium serum levels, seizures, tetany, muscular weakness, parathesias, and joint pain due to chondrocalcinosis. Severely affected children may have stunted growth and mental retardation. The phenotype in Gitelman's syndrome is similar, but patients manifest hypocalciuria and hypomagnesemia, and typically present in early adulthood with milder manifestations.

Initial speculation was that Gitelman's syndrome might be an allelic variant of Bartter's syndrome. However the distinctive phenotype, including hypocalciuria and hypomagnesemia, suggested mutation in a different transport protein. Gitelman's syndrome has recently been shown by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-supported researchers to be caused by a loss of function mutations in the thiazide-sensitive Na-Cl- cotransporter, which is expressed in the renal distal convoluted tubule (DCT). These findings establish the molecular basis of these disorders and indicate that the diverse abnormalities seen in affected patients derive from primary defects in these mediators of co-transport function.

Alagille Syndrome

Alagille syndrome is an autosomal dominant disorder characterized by neonatal jaundice and paucity of intrahepatic bile ducts on liver histology. Other accompanying features include heart defects, abnormal vertebrae and other musculoskeletal manifestations. The syndrome has a frequency of 1:70,000 births and is the second most common cause of intrahepatic cholestasis in infancy. Approximately 15 percent of patients will require liver transplantation.

In an analysis of four families with Alagille syndrome, four distinct coding mutations in the Jagged 1 gene have been identified and localized to chromosome 20 by NIDDK-supported scientists. The mutations of the gene, three deletions and one insertion, lie within a conserved region of the gene. Transcription and translation of the defected gene result in frameshifts and gross distortions of the structural protein, which is a ligand for a transmembrane receptor important in cellular differentiation. The cellular ligand and receptor are components of the Notch intracellular signaling pathway. Disruption of his pathway is important to liver ontogeny and differentiation and leads to a multi-system disorder.


The National Institute of Environmental Health Sciences (NIEHS) is working with the Centers for Disease Control and Prevention (CDC), and a number of state and local health officials, to help investigate fish kills (pfiesteria) along the Mid-Atlantic seaboard. Since October 1996, thousands of fish have become infested; most of them later die. In addition, some of the watermen and others exposed to waterways in the Chesapeake Bay region recently became ill or have shown signs of developing skin rashes and memory loss. NIEHS is working to see if there is any association between the toxins and these health effects.

Lead Poisoning

A current NIEHS initiative involves research on lead poisoning. About 1 million children in the US have blood lead levels greater than 10 micrograms/deciliter, and 40,000 have levels above 20. These children have lead-associated developmental delay; it is not known whether treatment prevents or reduces such delay once lead exposure has occurred. To address this critical need the NIEHS is doing a multi-center clinical trial, the Treatment of Lead-exposed Children (TLC) trial, to test whether succimer, a drug that lowers blood lead, prevents or reduces lead-associated developmental delay. An orphan drug, succimer is currently approved for children with blood lead levels greater then 45 micrograms/dl. It has a great advantage over other chelating agents in that it can be given orally instead of intravenously and thus not require costly hospitalization. The Succimer trial recruited its 780 children between August 1994 and January 1997. Recruited children are receiving treatment with succimer or placebo and a vitamin-mineral supplement. TLC cleans all the children's houses to suppress lead dust. Three year follow up of the children's growth and development will be complete in December 1999.

Myelodyplastic Syndrome

Myelodysplastic syndrome is a rare but serious bone marrow disorder that often progresses to acute leukemia. NIEHS has investigated environmental and genetic factors for this condition. Known risk factors include prior chemotherapy, radiation, and exposure to solvents such as benzene. The NIEHS has been investigating the role of enzymes in the body that can detoxify harmful environmental substances and turn them into harmless compounds that can be excreted. The genes that regulate many of these enzymes have been identified and are known to differ between people. The gene for one such enzyme, GSTT1, was four times more likely to be missing in patients diagnosed with myelodysplastic syndrome than in healthy persons. This gene is missing in about 20 percent of the United States' population who may be more susceptible to environmental factors important in the development of this disease.

Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of blinding hereditary retinal degenerative diseases that are characterized by a progressive loss of vision due to the degeneration of photoreceptor cells. The incidence of RP in the United States is about 1 in 3,500 births, and it affects more than 100,000 people. RP patients frequently report night blindness and loss of mid-peripheral vision during adolescence, and are usually legally blind by the age of 40. Photoreceptor cells of the retina, the rods and cones, are responsible for the capture of light and the initiation of an electrical signal to the brain in the process of vision. The study of signaling in the photoreceptor cells, termed the visual phototransduction cascade, has provided a detailed molecular description of this pathway. Current National Eye Institute (NEI)-supported research has now turned to establishing the complete molecular basis of visual signal termination. The availability of animal models, transgenic mice and knockout mice, with mutations in the genes for key components of the visual phototransduction cascade, provides a special opportunity and a very powerful research tool. These animal models are being used to investigate the molecular mechanisms of signal termination. Four of the nine genes that have been identified as causing Retinitis Pigmentosa encode proteins of the phototransduction cascade. Thus, the investigation of these animal models has great potential to provide valuable information on the pathogenesis of Retinitis Pigmentosa.


Retinoblastoma (RB), a sight- and life-threatening intraocular malignant tumor of childhood that arises in the retina, has been found to be associated with loss or alteration of the RB gene. The estimated annual incidence of retinoblastoma is between 1 in 15,000 to 1 in 34,000 people. Scientists have demonstrated that the introduction of a cloned RB gene into cultured retinoblastoma cells significantly inhibited cell growth and suppressed tumorigenesis in mice. In studies of RB gene expression and replacement in other types of tumor cells, scientists supported by NEI have shown that RB gene replacement modifies the neoplastic properties of both osteosarcoma and prostate cancer cells. These studies point to the possible utility of gene therapy in treatment of some types of cancer. Although molecular genetics research has pinpointed the cause of retinoblastoma, a major obstacle has been the lack of an animal model for this disease. NEI-supported scientists have developed a mouse model of retinoblastoma using gene "knockout" or embryonic stem cell homologous recombination technology. This model provides scientists the opportunity to study the process of malignant transformation in RB. It also will assist with developing and testing drugs to treat retinoblastoma.

Hypomelanotic Disorders

Hypomelanotic disorders are characterized by deficiencies of the hormone melanin and results in a loss of ocular and skin pigmentation. These disorders include, but are not limited to, the following rare diseases: Ocular albinism and X chromosome-linked deficiency of pigmentation, limited to the uvea and retinal pigment epithelium. These diseases cause decreased vision, photophobia, nystagmus, diaphanous irides, and light yellow fundi. Chediak-Higashi disease is a rare fatal disease of childhood, identified by generalized decreased pigmentation, with localized hyperpigmentation, peculiar cytoplasmic inclusions of the leukocytes, hepatosplenomegaly, and a predisposition to malignant lymphomas. The ocular manifestations are albinism of the eye, photophobia, increased lacrimation, and nystagmus. Tyrosinase-positive oculotaneous albinism and hemorrhagic diathesis, caused by defective platlets and accumulation of ceroid-like material in the reticuloendothelial system, oral muscosa, and urine characterize Hermansky-Pudlak syndrome. Also, nystagmus, photophobia, and decreased vision may occur.

NEI-supported researchers are investigating mutations in specific genetic loci that are known to control pigmentation. These scientists are planning to study the eyes and skin of inbred mice with various mutations that affect pigmentation.

Human Genetic Mutant Cell Repository

The National Institue of General Medical Sciences (NIGMS) Human Genetic Mutant Cell Repository provides a valuable resource for investigators studying genetic disorders. The Repository, located at the Coriell Institute for Medical Research in Camden, NJ, collects, characterizes, maintains, and distributes cell lines from patients and families with a wide variety of genetic disorders and from normal persons whose tissues serve as controls. More than 6600 cell lines, representing more than 500 different diseases, are available to qualified investigators. The Repository stimulates research on rare diseases by providing access to cell lines, and DNA samples derived from these cell lines, that otherwise are not readily available. Among the cell lines requested most frequently in the last year are those from patients with rare diseases, such as ataxia-telangiectasia, xeroderma pigmentosum, fragile X-linked mental retardation, Bloom syndrome, and Huntington disease.

Recent acquisitions to the collection include samples from patients with the following rare disorders: ectodermal dysplasia, ataxia-telangiectasia, glycogen storage disease type II, Leopard syndrome, and hemochromatosis. These cell lines, as well as those previously acquired, are used for biochemical, cellular, and molecular studies to help elucidate the causes of genetic defects. The Repository has a growing collection of cell lines in which the mutation has been characterized at the molecular level. These include samples with characterized trinucleotide expansions from patients with Huntington disease, dentatorubral-pallidoluysian atrophy, myotonic dystrophy, and fragile X.

In addition, the Repository supplies DNA isolated from two complete panels of well-characterized human-rodent somatic cell hybrids and from a growing number of chromosome-specific somatic cell hybrid panels. The hybrids are a valuable resource to investigators interested in mapping the location of disease-related genes, frequently the first step in characterizing the etiology of the disease.

Malignant Hyperthermia

Malignant hyperthermia, a potentially fatal pharmacogenetic disorder, occurs when an individual is exposed to certain volatile anesthetic agents, such as halothane, in combination with surgical muscle relaxants, such as succinylcholine. The aerobic and anaerobic metabolism rates increase significantly and are accompanied by an intense production of heat, carbon dioxide, and lactic acid producing a prolonged, rigid contracture of skeletal muscles. The NIGMS supports research targeting the molecular mechanism involved in the development of malignant hyperthermia and into diagnostic procedures designed to predict an individual's susceptibility and the population genetics of this disorder.

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a set of inherited cardiac diseases, with a prevalence of two per thousand population, characterized by increased ventricular wall mass in the absence of other causes of hypertrophy. It is associated with disabling symptoms, heart arrhythmias, and sudden death. The National Heart, Lung, and Blood Institute's (NHLBI) intramural Cardiology Branch has developed a transgenic mouse expressing a mutant myosin light chain. Studies of the mechanical properties of hearts from these animals, before the development of HCM, have shown the existence of a novel property of cardiac contraction that leads to cardiac failure. In addition, the Branch has recently identified two new genes that cause a specific heart muscle abnormality and has established the role of pacing as an alternative to heart surgery with obstructive HCM.


Lymphangioleiomyomatosis (LAM) is a rare lung disease that affects women, usually during their reproductive years. Symptoms develop as the result of the proliferation of atypical, non-malignant smooth muscle cells in the lungs. Diagnosis is usually made by lung biopsy. Common symptoms include shortness of breath, coughing, and sometimes coughing up blood. Patients often develop spontaneous pneumothorax or chylous pleural effusion (collapse of the lung or collection of milky looking fluid around the lung). The clinical course of LAM is quite variable, but is usually slowly progressive, eventually resulting in death from respiratory failure. No treatment has proven effective. Some patients with Tuberous Sclerosis Complex (TSC), a genetically transmitted disease, develop lung lesions identical to those seen in LAM. In some cases, the clinical distinction between TSC and LAM may be difficult.

Fanconi Anemia

Fanconi anemia (FA) is an autosomal recessive bone marrow failure syndrome characterized by pancytopenia, developmental defects, DNA cross-linking agent hypersensitivity, and cancer susceptibility. Many FA patients can be identified at birth because of congenital anomalies, although approximately 25 percent do not have birth defects. FA is a clinically heterogeneous disorder and until recently had been divided into at least five different complementation groups designated A through E. Two FA genes, A and C, which account for an estimated 75 percent of all FA patients world wide, have been cloned by NHLBI investigators. In 1997, three additional complementation groups were reported, suggesting that at least eight genes are involved in the manifestations of FA. In addition, the NHLBI Hematology Branch has initiated a trial of gene therapy for Fanconi's anemia in which a normal gene has been introduced into the bone marrow cells of three patients. The cells have been safely implanted and each patient has had evidence of gene transfer to blood cells.

Electronic Gene Map

Gene discovery has been aided by a "gene map" ( compiled by more than 100 scientists from government, university, and commercial laboratories around the world. Constructed largely by scientists at the National Human Genome Research Institute (NHGRI)-supported research centers and the National Library of Medicine, the map represents the Human Genome Project's most extensive effort so far to locate and identify the 80,000 genes in the human genome. In 1997, the map contained about 16,000 gene tags. As more genes are precisely mapped, it will become almost routine for disease gene hunters to find an already characterized gene waiting for them when they arrive at the neighborhood they know is involved in a disease. An electronic version of the gene map organizes the details into a readily accessible Internet site with extensive links to supporting data about the DNA structure of the genes and the proteins they encode.

Immunodeficiency Diseases - Severe Combined Immunodeficiency (SCID)

NHGRI scientists are using immunology, genetics, molecular biology, and gene therapy to study and treat inherited and acquired immunodeficiency diseases. Areas of emphasis include adenosine deaminase SCID, X-linked SCID, the most common of the several genetic defects causing the SCID syndrome, Wiskott-Aldrich syndrome and JAK3 deficiency. NHGRI intramural research scientists also are studying a specific genetic alteration that results in SCID, treating fetuses known to have SCID in the womb with immune cells taken from their fathers. These children were born healthy, with functional immune cells, and are now more than two years old. DIR scientists also develop gene therapy for IL-2 receptor gamma chain deficient X-linked SCID (IL2RG SCID). Immature cells from the umbilical cord are genetically engineered to produce the missing protein. These cells may then be introduced back into the patient without fear of immune rejection. This strategy is being tested in mice and dogs with SCID. On humans, researchers have collected immature cells at birth from newborns with IL2RG SCID, and are testing them to see if they can be genetically altered and expanded in a laboratory setting.

Developmental Disorders and Disorders of Early Childhood - Achondroplasia, Human Skeletal Dysplasias

NHGRI investigators are working to identify genes causing a variety of human skeletal dysplasias, including pycnodysostosis, Ellis van Creveld syndrome (EvC), Brachydactyly type C, and the type II collagen disorders. NHGRI intramural research scientists are now performing clinical and molecular studies of achondroplasia to identify and characterize the causes of illness and death. They seek to understand the correlation between symptoms and gene alterations that cause this and related disorders. They also carry out molecular genetic studies designed to identify alterations in this gene that result in disorders other than achondroplasia. Another lab focuses on issues surrounding prenatal genetic testing for achondroplasia. Before prenatal tests become widely available, researchers hope to learn more about the lives of affected individuals and their families, and the education and counseling needs of these communities.


Autism is a severe disorder, characterized by a profound preoccupation with subjective trends of thought or behavior that occurs in children and adults. A major focus of the National Institute of Mental Health (NIMH)-sponsored research on autism is to identify the genes that confer susceptibility, paving the way for improvements in diagnosis, treatment and, ultimately, prevention. Evidence strongly suggests that multiple susceptibility genes are involved and over the last year, a number of promising leads have emerged to help locate some of these genes in the human genome. Analysis of data from 38 multiplex families with autism led to the exclusion of linkage across the entire X chromosome for a disease susceptibility locus. A pedigree has recently been described, in which two autistic siblings and their unaffected mother had a duplication of the 15q11-q13 chromosomal region. This led to the hypothesis that a maternally imprinted gene in this region may contribute to susceptibility. Another study has reported linkage evidence using chromosome 15 markers. In addition, an association between autism and an allele at the HRAS gene on 11p has been reported in two small population-based association studies. Yet another association was found between autism and the serotonin transporter gene on 17q in a family-based association study. While not yet confirmed, these results provide exciting leads to pursue in ongoing NIH-supported projects.

Infantile Autism

Infantile autism is a severe disorder of communication and behavior, which usually begins at birth but invariably is present by age three. The disease severely disrupts the development of social knowledge and many types of higher cognitive, affective and communicative functions, including well-described abnormalities in attention. Earlier, NIMH researchers proposed that the cerebellum played a role in attention and cognitive processing and predicted that it would be a common site of maldevelopment in autism. Now, two cerebellum sites have been identified with anatomical abnormality in an autistic patient: the posterior cerebellum (vermis and hemispheres) and the parietal lobes of the cerebral cortex.

Researchers are now using functional magnetic resonance imaging (fMRI) to determine which neuroanatomic regions of the cerebellum show abnormal patterns of activation in autistic subjects. Preliminary results show that posterior cerebellar attention activation is abnormal while motor activation in the anterior cerebellum remains within normal limits.

Anorexia Nervosa

Anorexia nervosa, a syndrome of extreme, and often life-threatening, weight loss associated with a distorted body image and a pathological fear of gaining weight, is estimated to have a life-time prevalence among women of about 0.5 percent, with most cases occurring in adolescent and young adult women; the prevalence among men is about one tenth that among women. A variety of treatment approaches are effective in the acute phase of weight restoration for anorexia nervosa; however, follow-up studies indicate that in spite of initial progress during the acute weight-gain phase of inpatient care, approximately 30-50 percent of individuals relapse to the extent that they require repeated hospitalizations. Moreover, even in cases not requiring rehospitalizations, follow-up studies suggest that the majority of patients continue to report serious emotional and functional impairment. Clearly, more effective treatments are needed.

To understand the course and outcomes of eating disorders better, NIMH is supporting a longitudinal study of anorexia and bulimia nervosa that is now in its ninth year. A large group of women with these disorders are being interviewed at six-month intervals. Most of the women had other mental disorders along with the eating disorders; the majority had current major depression and at least one anxiety disorder. The women participated in a variety of treatments - primarily individual therapy - but also group therapy, family therapy, pharmacotherapy, and nutritional counseling. At this point in the study, indications are providing valuable knowledge of the comorbidity and outcomes in anorexia and bulimia nervosa that not only helps us to unravel the largely unknown origins and nature of these disorders but also has practical clinical applications for treatment. This knowledge is also urgently needed as a base to develop appropriate educational efforts. A recent effort by independent educators to disseminate information about eating disorders demonstrated this need for knowledge. Their educational efforts went awry when the target audience of young women perceived the celebrities speaking of their own experiences with eating disorders as glamorous and began adopting eating-disordered behaviors.

Facioscapulohumeral (FSH) Muscular Dystrophy

FSH muscular dystrophy is an autosomal dominant form of muscular dystrophy that initially affects muscles of the face (facio), scapula (scapulo) and upper arms (humeral). A progressive skeletal muscle weakness usually develops in other areas of the body as well; often the weakness is asymmetrical. Nearly all cases are associated with a large deletion at the end of chromosome 4. There appears to be a correlation between the size of the deletion and severity of symptoms. The deletion, however, does not appear to disrupt a transcribed gene but is thought to interfere with the expression or regulation of a gene or genes located proximal to the deletion. Researchers supported by the National Institute of Neurological Disorders and Stroke (NINDS) are continuing the sequencing of the entire region involved in the deletion and investigating possible bases for the hypothesized position effect.

Multiple Sclerosis (MS)

MS is characterized by patches in the brain and spinal cord causing some degree of paralysis, tremor, nystagmus, and disturbances of speech. Researchers supported by the National Institute of Nursing Research (NINR) are refining and confirming an explanatory model that can guide development of health-related interventions for promoting quality of life in individuals with MS. The focus of this first phase is to extend understanding of the key model concepts of quality of life, health-promoting behaviors, search for possible additional concepts, and to determine that the measurement instruments to be used in the subsequent phases are valid representations of the concepts as viewed from the frame of reference of the person with MS. In Phase II, data collected from a large sample of individuals with MS (N=500) will be used to statistically test variable relationships and overall fit to the theoretical model refined in Phase I. Antecedents and modifying factors identified in Phase II will provide the basis for future tests of the utility of the statistically confirmed model in proposing specific nursing interventions for individuals with MS.

Complete DiGeorge Syndrome

"Complete DiGeorge Syndrome" is an immunodeficiency disease in which children are born without a functioning thymus gland and without functioning T cells. Functioning T cells are essential for a normal immune system. Researchers at the General Clinical Research Center (GCRC) at Duke University transplanted cultured postnatal human thymic tissue into a 3-month old patient with Complete DiGeorge Syndrome. Prior to this transplantation, the infant had no detectable T cell function. Three months after transplantation, the transplanted thymus showed normal T cell development. By nine months after the transplant, functioning T cells were restored throughout the body. It appears that the transplanted thymic tissue was responsible for the re-establishment of normal T-cell immunity.

GenBank, Online Mendelian Inheritance in Man, and the Human Genome Map

The National Center for Biotechnology Information (NCBI) at the National Library of Medicine also produces and distributes GenBank, the NIH collection of all known DNA sequences. Among the 1.1 million human DNA sequences are several hundred involved in genetic disease. NCBI also hosts the Web version of Online Mendelian Inheritance in Man (OMIM), a database created and maintained by Dr. Victor McKusick of Johns Hopkins School of Medicine. OMIM contains up-to-date descriptions of over 3,000 inherited disorders. For diseases which have associated genetic mapping data, NCBI has the Human Gene Map available on the Web. Researchers as well as the general public can find graphics and descriptions on hundreds of genetic disorders. Each day NCBI handles several hundred thousand queries of its molecular genetics databases over the Web.


The muco polysaccharidoses (MPS) are a group of severe inborn errors of metabolism in which there is failure of the lysosomes to degrade a class of compounds called the glycosaminoglycans (GAGS). These compounds form an important component of connective tissues and are present in most organs of the body. When specific lysosomal enzymes are deficient due to genetic defects in the genes which code for them, a storage of undergraded GAGS occurs and, depending upon the tissues involved, affected individuals have severe defects in growth and development involving variously the bones and joints, the heart, brain, eye, and other organs. Most forms of MPS are severely disabling, may result in mental retardation and other neurological problems, and are lethal in childhood or early adulthood. Transplantation of genetically altered bone marrow has been minimally effective treating children with these disorders, but animal model research is needed to advance this field. An NCRR grantee, Dr. Donald F. Patterson, and colleagues at the University of Pennsylvania School of Veterinary Medicine (UPSVM) in collaboration with Dr. John Fyfe of the Veterinary College at Michigan State University have recently identified a model of MPS VII in the cat. This disorder is caused by mutations in the gene coding for the lysosomal enzyme, beta-glucuronidase. As in humans, the disorder is characterized by deficiency of this enzymatic activity and severe defects of the bones and joints, facial dysmorphia, corneal clouding, and liver and spleen enlargement. The investigators of UPSVM have established a colony of cats with this mutation and will make it available for gene therapy studies.


In the more recent designation of buprenorphine (1994), FDA appeared to be taking a more restrictive view via application of their more recently promulgated regulations. Although the issue was not definitively answered in the case of buprenorphine, FDA expressed the view that orphan designation where the population in question exceeded 200,000 would be difficult unless there was a medical/biological reason why the product could not be utilized by 200,000. In other words, treatment capacity or the number of persons seeking treatment might not suffice for orphan designation.

In the case of buprenorphine, this did not prove to be an insurmountable burden because that product's sponsor could prove to the FDA that based on historic, current, and projected expenditures, it would not recoup its investment during 7 years of exclusive marketing in the United States. Thus, a unique situation exists where the preclinical efforts are completed, NIDA is supporting clinical trials, and the sponsor has the expertise to manufacture new formulations. Buprenorphine became the first product to receive an orphan designation based on an economic, rather than a population, rationale. This route was selected by the sponsor since there was less certainty that the FDA would continue to allow orphan designation based on the capacity of the treatment system as opposed to the actual incidence and prevalence of opiate dependence.

The Office of Rare Diseases

The Office of Rare Diseases (ORD) continues to maintain the Rare Diseases Clinical Research Database to link patients and health care providers with research investigators. Over 900 research projects are provided in the database for searching by the public.

The Office supports scientific workshops and symposia to stimulate research with rare diseases and conditions. During the past four years, the Office served as co-sponsor with NIH research Institutes and Centers for 96 workshops and symposia related to rare diseases. It is the hope of ORD that these workshops will stimulate research related to rare diseases. Support for 24 scientific workshops and symposia was provided this year.


National Institute of Allergy and Infectious Diseases

o Workshop on Pediatric Scleroderma

o Gene Therapy for Inherited Phagocyte Disorders

o Workshop on Developing Chimeric Virus Systems to Safely Study Ebola and

Other Biohazardous Viruses in Low-Containment Laboratories

o Workshop on Improved Laboratory Methods for the Diagnosis of Human Borreliosis

National Institute of Arthritis and Musculoskeletal and Skin Diseases

o Conference on Emerging Opportunities in Scleroderma Research

National Cancer Institute

o Workshop on Phacomatoses Revisited

o neurofibromatosis 1 and 2

o tuberous sclerosis 1 and 2

o von Hippel-Lindau syndrome

o Gorlin syndrome

o Cowden's disease

o familial adenomatous polyposis

o Natural Killer Cell Workshop

National Institute of Child Health and Human Development

o Workshop for Strategies for Drug Development and Trials in Children and includes:

o early infantile autism

o Rett syndrome

o adrenoleukodystrophy

o Lesch-Nyhan disease

o attention deficit-hyperactivity disorder

o schizo-affective disorders in children

o urea cycle enzymopathies such as ornithine transcarbamylase deficiency

and ariginino-succinicaciduria

o organic acidurias

o Williams syndrome

National Institute of Deafness and Other Communication Disorders

o Symposium on Cochlear Implants in Children

o Symposium on Advances in Brain Imaging and Electrophysiological

Measurement of Human Olfactory Function in Health and Disease

National Institute of Diabetes and Digestive and Kidney Diseases

o Workshop on Cyclic Vomiting Syndrome

o Workshop on Update of Gene Therapy of Genetic Diseases

o Workshop on Acute Liver Failure

National Institute of Environmental Health Sciences

o Linking Environmental Agents and Autoimmune Disease: Models and Mechanisms

National Heart, Lung, and Blood Institute

o Therapeutic Interventions in Idiopathic Pulmonary Fibrosis

National Human Genome Research Institute

o Microdeletion Syndrome Workshop

National Institute of Mental Health

o NIMH and NHGRI Collaborative Workshop on Carbohydrate Deficient Glycoprotein


o International Research Workshop on Factitious Disorder by Proxy (Munchausen syndrome by proxy)

o Assessment of Heavy Metal Effects on Attention and Cognition in Children

National Institute of Neurological Disorders and Stroke

o Conference on Multiple System Atrophy

o International Workshop on Neurodegeneration in Ataxia-Telangiectasia

o Workshop on Histopathologic Basis of Imaging Abnormalities in Normal

Appearing White Matter

National Institute of Nursing Research

o Interdisciplinary Workgroup to Target Long-term Transplantation Survivors'

Quality of Life Ten to Twenty Years Following Transplantation

National Center for Research Resources

o National Gene Vector Laboratory Symposium Addressing Issues of

Relevance to the Initiation of Gene Therapy Trials

Office of Rare Diseases

o Fish Malodor Syndrome

Combined Health Information Database (CHID) Subfile on Medical Genetics and Rare Disorders

The Office of Rare Diseases with the National Human Genome Research Institute continues to expand the Combined Health Information Database (CHID) Subfile of Medical Genetics and Rare Disorders. The National Organization for Rare Disorders provided assistance to the Office to gather information from approximately 1,000 voluntary rare disease support organizations. Information devoted to acquired or inherited rare diseases and conditions in this database will focus on audiovisual and printed materials available from over 1,000 voluntary health organizations representing patients with rare genetic and acquired disorders. Three thousand bibliographic resource materials have been acquired according to specified guidelines, formats, and technical specifications.

Home Page of the Office of Rare Diseases

The Home Page developed by the ORD is currently being upgraded to become more user friendly. The Home Page acts as a gateway to information about rare diseases, ongoing research, and services and information available from voluntary patient support groups. The information is directed to patients and their caregivers, health care providers, and research investigators. Links are provided to other Institutes and Centers of the NIH with information of interest to the rare diseases community. The Home Page may be located at the following URL:

Previous Contents Next

Last Reviewed: January 25, 2005
Back to Top
Back to Top