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Examples of Rare Heart, Lung, and Blood Diseases
The NHLBI is interested in rare diseases and conditions that affect the blood, lung, and cardiovascular system. Examples are first grouped by discipline (heart, lung, and blood) and listed alphabetically under these headings. Short paragraphs with more detailed descriptions are provided for a few selected diseases. These are examples only, other rare heart, lung, and blood diseases may also be appropriate for this RFA.
Examples of rare cardiovascular diseases:
Examples of rare lung diseases:
Examples of rare blood diseases:
Research examples for rare cardiovascular diseases:
Marfan Syndrome is a rare, multi-system connective tissue disorder that affects individuals of all ages. The genetic mutation is known, but the pathogenesis has just started to be elucidated. A recent NHLBI Working Group on Research in Marfan Syndrome recommended collaborative research to identify genetic modifiers of disease severity and outcome, and to study cardiovascular and pulmonary complications in affected adults and children.
Peripartum Cardiomyopathy is a rare syndrome of acute heart failure of unknown cause that occurs in the latter stages of pregnancy and the first 6 months postpartum. It is challenging to diagnose, and difficult to treat effectively because the cause is not known. A network effort to obtain more epidemiological information, as well as help to identify causes and effective therapies, would be a big plus for women's health.
Inherited channelopathies and other rhythm disorders such as Long-QT Syndrome and Brugada Syndrome.
Disorders of the lymphatic vasculature: The lymphatic vasculature is essential to interstitial fluid and protein transport. It is involved in immune response and immune cell trafficking, and in cancer metastasis. Recent investigations suggest a potential link between lymphatic malfunction and obesity. However, lymphatic biology is poorly understood. A recent NIH Working Group recommended research in lymphatic biology to better understand the role of lymphatic vasculature in immune response, cancer metastasis and obesity, and to identify treatment strategies for congenital lymphedema and prevention strategies for acquired lymphedema.
Hereditary Hemorrhagic Telangectasia (HHT): HHT also referred to as Osler-Weber-Rendu (OWR) syndrome is a genetic disorder in which there are no capillaries between the arterial and venous vessels. In those areas lacking capillaries, blood entering the venous side is under high pressure and causes hemorrhaging in skin, mucous membrane and in a number of internal organs. If large vessels are involved, the lesion is referred to as an aterio-venous malformation.
Supravalvular Aortic Stenosis (SVAS) is a vascular proliferative obstructive disease believed to be caused by a mutation in the gene for elastin, an extracellular matrix protein accounting for about 50 percent of the dry weight of the vascular wall. It affects the aorta, coronary, carotid and peripheral arteries, and its incidence is thought to be less than five percent of all congenital heart defects. Unlike Marfan's, it is a vascular proliferative disease leads to blockage of the arteries.
Klippel-Trenaunay-Weber Syndrome (KTWS) is a very rare, vascular deformation disease involving capillary, lymphatic, and venous channels whose incidence is unknown. It usually manifests itself as three symptoms present together: cutaneous port-wine capillary malformations, varicose veins, and enlargement of soft tissues and bone in one limb. KTWS symptoms are usually present at birth, with 75 percent of patients having symptoms before the age of ten.
Research examples for rare lung diseases:
Lymphangioleiomyomatosis (LAM) is a rare, progressive and often fatal lung disease that affects almost exclusively, women, usually becoming symptomatic during the childbearing bearing years. LAM occurs sporadically and in women who have tuberous sclerosis complex (TSC). The underlying defect in the TSC genes promotes uncontrolled growth of the smooth-muscle-like LAM cells and the enables them to metastasize. Basic studies of the pathways controlled by the TSC genes identified sirolimus (rapamycin) as a potential treatment, which is now under investigation in the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. However, it is likely that multiple drug therapy will be needed to control the disease since sirolimus slows growth, but does not kill LAM cells and LAM cells from different individuals vary in their sensitivity the drug. Other potential treatment strategies need to be identified and tested.
Idiopathic (IPAH) and Familial Pulmonary Arterial Hypertension (FPAH) formerly known as Primary Pulmonary Hypertension (PPH) is a rare, disabling and lethal lung disease which threatens thousands of lives. It is clinically and pathologically identical whether it appears to be familial (FPAH) or not (IPAH) and it affects women disproportionately, with a mean survival of only three years. Clinical networks could help in obtaining the genetic, phenotypic, and environmental data needed to understand the underlying mechanisms, identify promising treatment targets, and test promising therapies.
Alpha-1-antitrypsin deficiency (A1AT) is a rare clinically under-recognized genetic disorder affecting the lung and other organs. In the lung, severe deficiency of A1AT predisposes to chronic obstructive pulmonary disease, especially panacinar emphysema. Early onset emphysema associated with A1AT is exacerbated by smoking cigarettes. More than 100 alleles of AAT have been identified, but the most common deficient allele associated with emphysema is the Z allele, carried by two to three percent of the Caucasian population in the United States. Emphysema is thought to result from an imbalance between neutrophil elastase in the lung, which destroys elastin, and the protective elastase inhibitor A1AT. A network system could facilitate efforts to improve, phenotyping, and study diagnostic and treatment options.
Primary ciliary dyskinesia (PCD), also called the immotile-cilia syndrome, is a rare condition inherited as an autosomal recessive that affects approximately 1 in 10,000 to 1/30,000 individuals. Mutations associated with disease are being identified. The clinical phenotypes are highly variable and better diagnostic tests are being sought. “Typical” findings in PCD include chronic cough, chronic rhinitis, chronic sinusitis, and chronic otitis media. Respiratory failure is frequently present in the newborn period and obstructive lung disease with bronchiectatis is often present later in life. Immotile sperm are cause high infertility rates in affected males and females with PCD may also have decreased fertility. Lack of functional nodal cilia in the embryo, permits random rotation of the heart and visceral organs. This can result in situs inversus or heterotaxy, which is associated with congenital heart abnormalities. Studies to understand the course of the disease, improve diagnostic testing, and identify disease causing mutations could be aided by a well integrated clinical network system.
Research examples for rare blood diseases:
Hemophilia is a hereditary bleeding disorder that results form a functional deficiency in either blood coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). The severity of the disease is related to the levels of circulating functional clotting protein. Infusion of plasma derived or recombinant coagulation factor is the current treatment that is used to control bleeding episodes or to prevent bleeds. About 25% of individuals with severe hemophilia develop neutralizing antibodies requiring higher doses or alternative therapy. There are a number of research directions that may provide novel treatment options for hemophilia patients, such as modified factor VIII or IX molecules with improved stability or reduced immunogenicity, gene and cell therapy approaches, and adjunct therapy to induce immune tolerance.
Thrombotic thrombocytopenic purpura (TTP, or Moschcowitz disease) is a rare blood disorder that affects coagulation system. It has been demonstrated that deficiency or inhibition of the enzyme ADAMTS13, which is responsible for cleaving large multimers of von Willebrand factor plays important ethiological role in the development of this rare disease. ADAMTS13 is a Zn2+- and Ca2+-requiring 190,000 dalton glycosylated protein that is encoded on chromosome 9q34 and produced predominantly in the liver. Current medicine has difficulty in diagnosing TTP, its treatment, and prevention of the relapses. Even successful treatment with plasma exchange and immunosuppressive therapy may reveal unexpected long-term sequelae that require further studies.
Hereditary hemorrhagic telangiectasia (HHT, or Rendu-Osler-Weber disease) is a rare autosomal dominant disorder and has two variants, HHT1 and HHT2, associated with mutations in the ENG and ALK-1 genes, respectively. The disorder has serious effects, the most common being severe hemorrhaging of the telangiectasias in the nose and gut. However, arteriovenous malformations may also affect lungs, brain, and liver. HHT is a chronic disease, with telangiectasias and arteriovenous malformations increasing in size and frequency with age. The disease is very diverse and although most serious complications occur later in life, death from the disorder can take place in newborns and juveniles. Researchers explore multiple directions from the practical implementation of new procedures for bleeding prevention to understanding the ethyology of the disease. Additional research is needed to provide effective specific treatment for patients with HHT.
Creutzfeldt-Jakob disease (CJD) is a very rare and incurable degenerative neurological disorder (brain disease) that is ultimately fatal. This transmissible spongiform encephalopathy is caused by prion that promotes refolding of native proteins into the diseased state. CJD most commonly affects people between the ages of 60–65, however, the more recently-recognised 'variant' CJD (vCJD) occurs in younger people. Currently scientists are looking into the dynamic of the disease progression that may take up to 50 years to develop into clinically evident state, and also into possible genetic variations that may have predisposition for CJD. It has been shown that in the hereditary form of CJD, a mutation occurs in the gene for PrP, PRNP. RNA interference has been investigated to slow the progression of the disease in animal models. The RNA blocks production of the protein that the CJD process transforms into prions. However there is no effective treatment available for human use at this moment.
The antiphospholipid syndrome is a rare autoimmune disorder that is characterized by abnormal clotting of blood and the presence of antiphospholipid antibodies (cardiolipin or lupus anticoagulant antibodies) in the blood. During pregnancy it leads to premature miscarriages, unexplained fetal death, or premature birth. Patients with antiphospholipid syndrome have developed abnormal symptoms while having antiphospholipid antibodies that are detectable with blood testing. A very rare form of APS is the Catastrophic Antiphospholipid Syndrome (cAPS). cAPS is characterized by multiple and rapid organ thrombosis/dysfunction that leads to high mortality rate. Aspirin and anticoagulants are the most used treatment at the moment. There is evident need to develop and optimize the specific treatment options for APS patients.
Cooley's anemia (beta thalassemia major) is a rare disease that results from the deletion of both beta chain genes and causes the most severe type of beta thalassemia. Thalassemia major patients need frequent blood transfusions and may have decreased lifespan. During the first 1 - 2 years of life they can be pale, fussy, have a poor appetite, and have many infections. Without treatment, the spleen, liver, and heart become enlarged, and bones can become thin and brittle. A major problem is the accumulation of iron in the heart and other organs that results in heart failure for some patients in their teens or early twenties. Symptomatic therapy, splenectomy, iron chelating measures, and bone marrow transplantation currently employed for beta thalassemia major patients. Better understanding of the pathophysiology and molecular mechanisms of this disease may provide with novel clinical approaches.
Last update: October 31, 2007