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Report on Research on Rare Diseases in Children: FY 2000 to FY 2005

National Heart, Lung, and Blood Institute (NHLBI)

Overview of NLBI Rare Diseases in Children Research Activities, FY 2000–FY 2005

NHLBI provides leadership for a national program in the causes, diagnosis, treatment, and prevention of diseases of the heart, blood vessels, lungs, and blood, and in the uses of blood, and the management of blood resources. NHLBI's mission also includes investigation and treatment of sleep disorders. While the major part of the research supported by NHLBI addresses common conditions such as hypertension, coronary heart disease, and chronic obstructive pulmonary disease, a significant amount of research is devoted to rare diseases in children and adults.

Recent Scientific Advances in Rare Diseases in Children Research

NHLBI activities related to rare disease research in children in FY 2000 are described below.

Heart and Vascular Diseases Program


Abetalipoproteinemia is a rare congenital disorder that prevents the body from producing low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and chylomicrons. Individuals with this condition are unable to digest fats properly. In FY 2000, NHLBI-supported studies directed at understanding abnormal synthesis of apolipoprotein B (apoB), the major protein in LDL, found that the amount of microsomal triglyceride transfer protein (MTP) may determine apoB levels.

Antiphospholipid Syndrome (APS)

Patients with APS have circulating autoantibodies to certain phospholipids (lipids containing phosphorus), chiefly cardiolipin, as well as the lupus anticoagulant. Recent findings provide strong support for the involvement of antiphospholipid antibodies in atherogenesis. Autoreactive antibodies were found to form against phospholipid components of dead or dying (apoptotic) cells and then were found to cross-react with normal vascular constituents that are produced in response to environmental stimuli, including bacteria. In other studies, small differences in a common lipid carrier protein appeared to be genetically linked to APS as well as to atherosclerosis.

Arrhythmogenic Right Ventricular Dysplasia (ARVD)

ARVD is a family of rare cardiomyopathies that result in sudden cardiac death and malignant heart rhythm disturbances, including fibrillation. NHLBI investigators have reported on the localization of a mutation to chromosome 10p12-14 in one family with a common congenital form of ARVD.

Bartter's Syndrome

Bartter's syndrome, a rare autosomal recessive disease, typically manifests itself through salt imbalance and low blood pressure. A NHLBI-supported investigator has found that the disease is genetically heterogeneous. In addition to the mutation on the Na-K-Cl co-transporter, mutations on potassium and chloride channels have been discovered, and there are indications that additional Bartter's genes remain to be found. The hypotensive state of Bartter's syndrome suggests that these mutated genes protect against the development of high blood pressure.


ß-sitosterolemia is a rare genetic disease characterized by increased absorption of dietary cholesterol and plant and shellfish sterols that entails an increased risk of premature cardiovascular disease. In FY 2000, NHLBI intramural scientists established the genetic defect in ß-sitosterolemia as a defect in either the ABCG5 or ABCG8 transporters present in the enterocyte and liver.

Brugada's Syndrome

Brugada's syndrome is a rare inherited disorder characterized by cardiac electrophysiological abnormalities, specifically right bundle branch block and ST elevation in the precordial leads, and is associated with a high occurrence of sudden cardiac death. One group of NHLBI-supported investigators has identified a second site on chromosome 3 associated with Brugada's syndrome and has extensively characterized cardiac electrical abnormalities in families with this mutation.

Congenital Heart Disease

Congenital heart disease affects approximately 8 in 1,000 live-born infants, or approximatley 32,000 per year in the United States, making it the most common birth defect and an important cause of infant mortality, pediatric and adult morbidity, and shortened adult life expectancy. In 2001, two NHLBI-supported researchers reported discovery of a genetic abnormality associated with congenital heart defects in mice. Other researchers have been able to develop high-resolution ultrasound imaging for the characterization of hemodynamic function in the developing mouse embryo and have shown that mutations in a single human gene, Nkx2.5, are responsible for a variety of structural congenital cardiovascular malformations, some of which are also associated with arrhythmias.

DiGeorge Syndrome

DiGeorge syndrome is characterized by many abnormalities, including cardiac outflow tract anomalies, hypoplasia of the thymus and parathyroid glands, cleft palate, and facial dysmorphogenesis. Recent studies in mice implicate the transcription factor Tbx1 as a key candidate gene for the cardiac outflow tract defects seen in DiGeorge syndrome.

Doxorubicin Cardiomyopathy

Doxorubicin cardiomyopathy is a serious side effect of using the potent, broad-spectrum antitumor agent doxorubicin (brand name: Adriamycin) in treating a variety of cancers, including solid tumors and leukemia. NHLBI-supported investigators have demonstrated that doxorubicin selectively deregulates the expression of cardiac-specific or cardiac-restricted genes by depleting the levels of tissue-specific transcription factors and co-factors, resulting in disruption of normal cardiomyocyte function. Another investigator found that mitochondrial changes seem to contribute to the progressive inability of cardiac tissue to tolerate metabolic stress, particularly when associated with induction of the membrane permeability transition pore by doxorubicin.


Dysbetalipoproteinemia is a rare disorder with a strong heritable component characterized by the presence of beta-migrating VLDL. The disorder leads to formation of characteristic yellow skin plaque (xanthomas) and predisposes to early ischemic heart disease and peripheral vascular disease. A mutant form of the protein apoprotein E (apoE2) has been identified as the primary molecular defect. In FY 2000, NHLBI-supported investigators demonstrated that apoE2 has a significantly higher half-life (an indicator of the time the protein spends in the cell) than apoE3 and apoE4.

Familial Hypertrophic Cardiomyopathy (FHC)

FHC is associated with myofibrillar disarray in the heart muscle, which leads to hypertrophy (enlargement of the heart). Using a genetically engineered animal model for FHC, one NHLBI-supported investigator has decreased hypertrophy and fibrous tissue by using Losartan, an angiotensin II blocker. The same investigator has successfully used Doppler myocardial tissue imaging on the transgenic rabbit model of human hypertrophic cardiomyopathy (HCM) to detect those afflicted with FHC before hypertrophy develops. A second investigator has produced two genetically engineered mouse models of FHC. Each model has a single-site mutation comparable to mutations observed in humans with FHC.

Familial Hypobetalipoproteinemia (FHBL)

FHBL is an apparently autosomal dominant disorder of lipid metabolism characterized by very low levels of apoprotein B-containing lipoprotein cholesterol. A newly identified genetic susceptibility for FHBL has been identified on chromosome 3 (p21.1-22), which has been narrowed down to an area containing three potential candidate genes.

Infectious Myocarditis

Infectious myocarditis, which affects both children and adults, is an inflammation of the heart muscle that sometimes leads to progressive heart failure and the need for heart transplantation. Using a primate model infected with simian immunodeficiency virus (SIV), a virus similar to HIV, a NHLBI-supported investigator has made a critical discovery regarding the pathogenesis of AIDS-related cardiac dysfunction, namely that cardiac myocytes are not the target for SIV. Instead, the virus may be infecting cardiac dendritic cells or monocytes, both of which bear the CD4 receptor required for viral infection. Another investigator studying the effects of a soluble viral regulatory factor called Tat has found that Tat-mediated changes may create a pro-inflammatory stimulus, thereby increasing the morbidity of HIV infections.

Liddle's Syndrome

Liddle's syndrome is a rare autosomal dominant disorder of severe hypertension. A diagnostic test for Liddle's syndrome has been developed by one of the NHLBI Specialized Center of Research (SCOR) programs on Molecular Genetics of Hypertension. In order to study the responsible mechanism, the same SCOR has developed a mouse model that develops high blood pressure, metabolic alkalosis, and hypokalemia accompanied by cardiac and renal hypertrophy, very similar to a human form of salt-sensitive hypertension. This mouse model exhibits both sodium channel and renin locus dependency for blood pressure control, as recently described in the normal healthy human, and thus represents the first potential digenic (reproduced in alternate generations) model for hypertension.

Long QT Syndrome (LQTS)

LQTS is characterized clinically by a prolonged QT segment on the cardiac electrocardiograph that is associated with syncope, ventricular arrhythmias, and, frequently, sudden cardiac death. This family of conditions is thought to be caused by alterations in the cardiac cell action potential induced by mutations in at least six cardiac ion channel genes. NHLBI investigators recently summarized the functional and clinical consequences of the various ion channel deficiencies that have been discovered. Their report includes suggestions that mutations in calcium, sodium, and potassium channels may all cause similar cardiac electrical abnormalities, and that sodium channel inhibitors may be useful in treating patients with one form of the disease. Studies of clinical symptoms and their respective mutations are producing data that may be useful in identifying and treating patients with different forms of the disease. Pharmacogenetic studies on mutations involved in acquired LQTS have also provided information important in identifying, and removing from the U.S. drug market, a number of prescription and over-the-counter drugs that increase susceptibility to sudden death by these same mechanisms.

Niemann-Pick Type C (NPC) Disease

NPC disease is an autosomal recessive lipid-storage disorder usually characterized by hepatosplenomegaly (enlargement of the liver and spleen) and severe progressive neurological dysfunction. In 2001, a putative cholesterol sensor in the plasma membrane that affects cholesterol trafficking into and out of cells was further characterized.

Smith-Lemli-Opitz (SLO) Syndrome

SLO syndrome is an inherited disorder caused by a defect in the enzyme involved in cholesterol biosynthesis. NHLBI-supported investigators this year improved the commonly used diagnostic and screening tests for SLO by improving the separation of accumulated unsynthesized cholesterol and thus achieved a more accurate determination of its concentrations in blood and other biological fluids such as amniotic fluid.

Tangier Disease

Tangier disease is a rare syndrome characterized by a deficiency of high-density lipoprotein (HDL), mild hypertriglyceridemia, neurologic abnormalities, and massive cholesterol ester deposits in various tissues such as the tonsils. Recently, efforts by an NHLBI-supported investigator to understand the role of the ABCA1 transporter protein in intracellular cholesterol trafficking led to the finding that its cellular location was in areas distinct from the lipid-rich plasma membrane domains called rafts. Furthermore, the cholesterol transported out of the cell by ABCA1 does not appear to be from these lipid-rich rafts.

Williams Syndrome (WMS)

WMS is a rare genetic disorder characterized by a constellation of features, including mental retardation, aberrant cranial shape, unusually gregarious personality, premature wrinkling of the skin, dysmorphic facial features, and supravalvular aortic stenosis (SVAS; a congenital narrowing of the ascending aorta).

A NHLBI-supported study has established the elastin gene (ELN) as the locus for SVAS in both inherited and sporadic cases.

Lung Diseases Program

Advance Sleep Phase Syndrome (ASPS)

ASPS is a genetically based sleep disorder characterized by early evening onset of sleep and spontaneous early awakening with normal sleep duration. ASPS was linked to a variant of the biological clock gene, hPer2 (HL59596) using linkage analysis of a single family in which many related individuals exhibited a large 4-hour advance of sleep, temperature, and melatonin rhythms. Genetic studies identified a single base mutation that alters the ability of hPer2 to interact with other components of the biological clock. The hPer2 mutation linked to ASPS is hypothesized to advance the biological clock by accelerating the accumulation of other gene products composing the biological clock.

Bronchopulmonary Dysplasia (BPD)

BPD is a chronic lung disease characterized by disordered lung growth, with changes in cell size and shape and a reduction in the number of alveolar structures available for gas exchange. Recent progress by the NHLBI Collaborative Program for Research in BPD includes identification of a new marker (bombesin peptide) that is predictive for the development of BPD and will enable infants at particular risk for the disorder to be identified. Other results indicate that early delivery of a recombinant antioxidant enzyme to human infants at high risk for BPD may reduce lung injury. Delivery of a synthetic antioxidant has also been found to be prophylactic against the development of BPD.

Cystic Fibrosis (CF)

CF is a multi-system disease characterized by defective transport of chloride and sodium across the cell membrane. Pseudomonas aeruginosa is the main cause of chronic lung infection leading to lung failure in individuals with CF. NHLBI-supported studies are providing insight into how Pseudomonas endures for long periods in the lung and how it can be controlled. The bacteria were recently shown to form, through a process called quorum-sensing, a protective outer layer, or biofilm, on the lungs of CF patients, serving to protect the bacteria from conventional antibiotics and the body's natural immune responses. The biofilm allows the bacteria to remain in the CF lungs, causing life-long Pseudomonas infections. Recently, NHLBI-supported research found that xylitol, a non-ionic osmolyte that lowers salt concentrations without providing an energy source for bacteria, may provide an important new therapeutic to prevent or slow the onset of bacterial infection in CF.

Lymphangioleiomyomatosis (LAM)

LAM is a rare lung disease that affects girls and women from puberty through menopause. Symptoms develop as the result of proliferation of atypical, non-malignant smooth muscle cells in the lungs. A prospective study within the NHLBI Intramural Program discovered that mutations in the tuberous sclerosis complex gene TSC2 can cause pulmonary LAM. In another scientific advance, an immunohistochemical analysis suggests that the production of proteins that inhibit cell death in LAM cells may be controlled by estrogen and progesterone. NHLBI ORWH support a national LAM Patient Registry that by the end of FY 2000 had enrolled more than 200 LAM patients.

Persistent Pulmonary Hypertension of the Newborn (PPHN)

In PPHN, inappropriate muscularization of fetal pulmonary vessels prevents the lung arteries of affected newborns from dilating after birth and thus interferes with normal blood flow to the lung. A NHLBI SCOR on the Pathobiology of Lung Development has demonstrated that treatment of neonatal rats with the synthetic adrenocortical steroid dexamethasone causes lung hypoplasia, decreases alveolization, and results in an increase in the development of subsequent pulmonary hypertension. The results demonstrate the importance of temporospatial relationships in the coordination of vascularization and cardiopulmonary development and the limits of our understanding of those relationships.

Primary Ciliary Dyskinesia (PCD)

PCD, also known as Kartegener's syndrome or immobile ciliary syndrome, is an inherited disease characterized by defects in the cilia lining the respiratory tract. A NHLBI-supported study characterizing HFH-4, a regulatory protein expressed specifically in ciliated epithelial cells, suggests that the protein has a role in the regulation of the early development of cilia (ciliogenesis) and that cilia function may be critical in left-right body axis symmetry.

Primary Pulmonary Hypertension (PPH)

PPH is a rare, progressive lung disorder characterized by a sustained elevation of the pulmonary artery pressure. Recently, two research groups independently identified germ line mutations in the bone morphogenetic protein receptor II (BMPR2) gene in patients with the disease. Another recent study reported that endothelial cells (ECs) from the lung tissue of sporadic PPH patients acquire somatic mutations from other genes involved in EC growth and apoptosis.


Sarcoidosis is a chronic multi-system disease of unknown cause in which affected organs, especially the lungs, are invaded by different types of inflammatory cells that become organized into clusters of cells called granulomas. In recent studies, histologic and clinical similarities between tuberculosis and sarcoidosis have suggested a shared underlying pathophysiology related to the NRAMP1 human protein. Contrary to previous findings in tuberculosis patients, the less common gene variations were found more often in control subjects than in sarcoidosis patients, and one variation was actually found to have a protective effect.

Blood Diseases and Resources Programs

Acute Graft versus Host Disease (GvHD)

Acute GvHD is a condition that typically occurs within three months after allogeneic hematopoietic stem cell transplantation when donor T cells react against "foreign" tissue antigens in the recipient. Combining data from their respective registries, the International Bone Marrow Transplant Registry and the Eurocord-Cord Blood Transplant Group compared results of sibling umbilical cord blood (UCB) and bone marrow (BM) transplantation for a group of patients younger than 15 years. Their study found that although engraftment (the time for new white blood cells and platelets to grow in the recipient) was longer in the UCB recipients, the incidence of GvHD was lower, and the overall survival was the same.

The results suggest that unrelated umbilical cord blood transplants might compare favorably with unrelated donor marrow transplants.

Aplastic Anemia (AA) and Paroxysmal Nocturnal Hemoglobinuria (PNH)

AA is a form of bone marrow failure in which hematopoietic cells are replaced by fat, resulting in low blood counts. In PNH, a clone derived from a single hematopoietic stem cell expands, leading to marrow failure, red blood cell destruction, and venous thrombosis. Using sensitive flow cytometry, NHLBI intramural scientists have established that an expanded PNH clone is present in a large proportion of patients with aplastic anemia. In a randomized trial to compare conventional antithymocyte globulin immunosuppression to high-dose cyclophosphamide, the researchers established that the latter treatment is excessively toxic and leads to a high rate of severe fungal infections and increased mortality.

Cooley's Anemia

Cooley's anemia (also called beta-thalassemia, thalassemia major, or Mediterranean anemia) is a genetic blood disease that results in an inadequate production of hemoglobin. In FY 2000, NHLBI grantees used a beta-globin gene/beta-locus control region retroviral vector to optimize gene transfer and expression in a mouse transplant model. New methods of transfusion therapy were developed; less toxic methods of stem cell transplantation that provide potential utility for patients with thalassemia were developed; new iron chelators were evaluated; a new clinical research network designed protocols that will provide clinically useful information in the areas of hepatitis and osteoporosis management as well as insights into the potential utility of fetal hemoglobin (hemoglobin F) induction as a function of genotype; and several compounds that increase hemoglobin F values were described.

Fanconi Anemia (FA)

FA is an autosomal recessive bone marrow failure syndrome characterized by a decrease in blood cells and platelets (pancytopenia), developmental defects, and cancer susceptibility. A number of studies over the past year have further defined the FA complex of proteins and provided insight into their potential function. Developments include cellular localization of the functional complex and determination of the role of the complex in DNA repair and prevention of mutagenesis. Recent transplantation protocols using Fludarabine have provided new hope that stem cell transplantation may become a therapeutic option for patients with FA.


Hemophilia is a hereditary bleeding disorder that results from a deficiency in either blood coagulation factor VIII or factor IX. Gene therapy studies by NHLBI-supported scientists have shown sustained expression of factor IX in mice and hemophilic dogs after muscle injection or intraportal administration of AAV vector containing factor IX. Preliminary results of the first phase I clinical study for AAV-mediated muscle directed gene transfer of factor IX indicate that the procedure is well-tolerated and show evidence of protein expression. On the basis of pre-clinical safety and efficacy data, a clinical study for intrahepatic delivery of AAV vector-expressing factor IX has been proposed.

Hereditary Hemorrhagic Telangiectasia (HHT)

HHT, or Osler-Weber-Rendu disease, is a bleeding disorder that is due to weakness of the vascular support structure. Progress has been made in determining the underlying molecular basis of HHT, which appears to be a mutation in the genes of two TGF beta receptor family members on the endothelial cell. Eight mutations in endoglin leading to HHT have been identified, and a database on genetic mutations related to HHT has been established.

Immune Thrombocytopenic Purpura (ITP)

ITP is an autoimmune disease resulting in rapid clearance or destruction of the platelets (thrombocytopenia) and clinically significant bleeding. In FY 2000, it was shown that the transcription factor GATA-1 is necessary for megakaryocyte maturation and platelet production. Subtractive hybridization experiments between megakaryocytes lacking GATA-1 and controls show that the 4-Ptase I enzyme is essential for this process. A transgenic mouse model has been developed.

Sickle Cell Disease (SCD)

SCD occurs when an infant inherits the gene for sickle hemoglobin from both parents (sickle cell anemia) or the gene for sickle hemoglobin from one parent and the gene for another abnormal hemoglobin from the other parent (sickle cell disease types Hb SC, Hb S-Beta thalassemia, etc.). Research published in the past year confirmed that adhesive interactions between individual blood components and between blood components and cells that line blood vessels (endothelium) are likely to be important initiators of sickle cell vaso-occlusive crises. In addition, investigators have been able to induce inflammatory responses in sickle mice but not normal mice by removing and then providing oxygen. This observation was correlated in the sickle mice with oxidant production by vascular endothelial cells and was found to be completely prevented by prior infusion into mice of an antibody directed toward the P-selectin molecule expressed on vascular endothelium.

Systemic Lupus Erythematosus (SLE or Lupus)

SLE is an autoimmune disorder in which the body produces antibodies that harm its own cells and tissues. Recent NHLBI-supported studies have found that some lupus antibodies have catalytic properties and can specifically convert prothrombin to thrombin, thereby creating a hypercoagulable condition that may explain the high incidence of thrombosis in patients with SLE.

Ongoing, New, and Planned Research Initiatives in Rare Diseases in Children

NHLBI-initiated programs in rare diseases in children totaled $119.7 million in FY 2000 and are estimated to increase by approximately 10 percent per year over the next five fiscal years.

Ongoing Initiatives

  • Clinical Research on Cooley's Anemia (FY 1998-FY 2002)

  • Comprehensive Sickle Cell Centers (FY 1998-FY 2002)

  • Immunogenetics of Inhibitor Formation in Hemophilia (FY 1998-FY 2001)

  • Mitochondrial DNA Mutations in Heart, Lung, and Blood Diseases (FY 1997-FY 2000)

  • Specialized Centers of Research (SCOR) in Neurobiology of Sleep and Sleep Apnea, Airway Biology and Pathogenesis of Cystic Fibrosis, and Acute Lung Injury (FY 1997-FY 2001)

  • Specialized Centers of Research (SCORs) in Pathobiology of Fibrotic Lung Disease, Pathobiology of Lung Development, and Cellular and Molecular Mechanisms of Asthma (FY 1997-FY 2001)

  • Stem Cell Transplantation to Establish Allochimerism (FY 1999-FY 2002) Strategies to Augment Alveolization (FY 1999-FY 2002)

  • T Cell Depletion of Marrow for Unrelated Bone Marrow Transplantation: Clinical Trial to Ascertain Risk-Benefit Ratio (FY 1994-FY 2001)

  • Thrombocytopenia: Pathogenesis and Treatment (FY 1998-FY 2002)

Initiatives Begun in FY 2000

  • Cellular and Molecular Mechanisms of Primary Pulmonary Hypertension (PPH) (FY 2000-FY 2002)

  • Programs of Excellence in Gene Therapy (PEGT) (FY 2000-FY 2004) Specialized Centers of Research (SCOR) in Hematopoietic Stem Cell Biology (FY 2000-FY 2004)

Initiatives Planned for the Future

  • Blood and Marrow Transplant Clinical Research Network (FY 2001-FY 2005)

  • Genetic Modifiers of Single Gene Defect Diseases (FY 2001-FY 2005)

  • Pathogenesis and Treatment of Lymphedema (FY 2001-FY 2004)

  • Pediatric Heart Disease Clinical Research Network (FY 2001-FY 2005)

  • Comprehensive Sickle Cell Centers (FY 2003-FY 2007)

Rare Diseases in Children-Related Program Activities

  • A "Workshop on Bronchopulmonary Dysplasia" was organized by NICHD, NHLBI, and ORD, to review the definition of BPD and lung injury in very pre-term infants, to identify gaps in knowledge of lung development, to select the best indicators of outcome for infants with BPD, and to prioritize areas for future research.

  • A "Working Group on Stem Cell Plasticity" met in March 2000 and developed RFA-HL-01-007, Hematopoietic Stem Cell Plasticity, issued in November 2000.

  • The NHLBI Hematology Branch participated in the "Symposium on Fanconi Anemia" at the Annual Scientific Meeting of the International Society for Experimental Hematology in Tampa Florida, and in the Annual International Fanconi Anemia Scientific Symposium, held in Amsterdam, The Netherlands.

  • A "Forum on Allogeneic Unrelated Cord Blood Banking and Transplantation," co-sponsored by FDA, met in August 2000. Leaders in cord blood banking and transplantation from around the world discussed requirements for collecting, processing, storing, and transplanting unrelated allogeneic umbilical cord blood. The recommended practices included infectious disease screening and testing, determining the number of viable cells post-processing, collecting donor family histories, and maintaining a sample attached to the frozen cord blood unit for follow-up testing.

  • NHLBI and the LAM Foundation co-sponsored the "International LAM Symposium" held at Columbia University in November 1999.

  • A May 2000 meeting on "Conquering Lymphatic Disease: Setting the Research Agenda," cosponsored with the Lymphatic Research Foundation, ORD, and four other NIH Institutes resulted in a Program Announcement, PA-01-035, Pathogenesis and Treatment of Lymphedema, released in December 2000.

  • NHLBI and the Pulmonary Hypertension Association (PHA) have agreed to joint sponsorship of a program to train clinicians to perform biomedical research related to pulmonary hypertension. The training will be supported by the Mentored Clinical Scientist Development Award (K08) mechanism.

  • At a "Workshop on Nitric Oxide as a Potential Therapeutic Agent for Sickle Cell Disease and Other Vascular Diseases" in September 2000, a discussion was held on the promise of nitric oxide (NO) as a possible therapy for sickle cell disease associated acute chest syndrome, respiratory distress in premature infants, and other severe vascular problems.

    A "Workshop on Central Nervous System Disease in Children with Sickle Cell Disease" was held in September 2000 at NHLBI to discuss current understanding of the effects of SCD on the central nervous system (CNS), contemporary methods of evaluation of the CNS, prophylactic and therapeutic interventions that may alleviate brain damage, and future directions for research.

  • After 20 years and more than 40 publications, the Cooperative Study of Sickle Cell Disease has ended. In September 2000, the investigators met to discuss manuscripts still to be written based on the database and the stored genetic and sera samples.

  • At the STOP Trial Steering Committee Meeting in September 2000, the STOP investigators met to discuss the STOP II Trial protocol to be submitted for review by the Data and Safety Monitoring Board. The STOP II Trial will attempt to ascertain if it is safe to stop transfusing children for stroke prevention after 30 months.

  • At the "MSH Patients' Follow-up Steering Committee Meeting" in September 2000, the investigators met to discuss follow-up of the study cohort for the next five years. A paper summarizing survival over the past eight years is planned. Data from the study suggest that survival is improved if fetal hemoglobin levels are elevated by continuing hydroxyurea therapy.

  • At the first "BABY HUG Steering Committee Meeting" in September 2000, investigators discussed plans for protocol development and recruitment. The objective of the clinical trial is to determine if hydroxyurea therapy is effective in preventing chronic end-organ damage in young pediatric patients with sickle cell anemia.

  • At a "Workshop on von Willebrand Factor and Thrombotic Thrombocytopenic Purpura" held in July 2000, investigators in the area of TTP gained a clearer understanding of worldwide efforts to address the disorder and laid the groundwork to develop new collaborations.

Problem Areas Related to Rare Diseases in Children

Aplastic Anemia (AA) and Paroxysmal Nocturnal Hemoglobinuria (PNH)

The viral agent in post-hepatitis aplastic anemia, which is probably the same agent that is responsible for seronegative acute hepatitis and fulminant hepatitis of childhood, needs to be identified using samples of blood, liver, and stool from patients with acute hepatitis. Better immunosuppressive treatment of aplastic anemia requires large clinical trials, and patients must be recruited to specified research centers rather than treated haphazardly in private practice. To elucidate the relationship between an autoimmune disease (AA) and clonal expansion of mutated cells (PNH), large numbers of patients must be available for study.

Arrhythmogenic Right Ventricular Dysplasia (ARVD)

A concerted multi-laboratory program, combining basic, clinical, and genetic approaches, is needed to identify the causes of this highly lethal form of cardiomyopathy so that a rational search for therapies can begin. Additional clinical centers, and perhaps a national registry, would be useful to investigators who are already studying its origins and potential treatments.

Creutzfeldt-Jakob Disease (CJD)

Standardized reference materials to validate assay systems to detect transmissible spongiform encephalopathies (TSE) such as CJD are urgently needed. In April 1999, the World Health Organization (WHO) recommended the establishment of international reference materials for TSE diagnosis. Standards proposed would include human brain tissue, human blood, animal tissues, and animal blood. These materials would be used to calibrate the in-house reference materials of individual laboratories to the same single, international standard. The need for blind panel validation of all assays, (i.e., the validation of the sensitivity, reproducibility, and predictive abilities of any given candidate assay) is emphasized. Without standardized reference materials, it is not possible to evaluate the relative merits of any assay developed, or even to know for sure whether or not they are more sensitive than existing Western blots or ELISAs.

Fanconi Anemia (FA)

The eight distinct complementation groups represent a high degree of locus heterogeneity, which complicates molecular diagnosis of FA and may make screening cumbersome. However, certain complementation groups prevail in specific populations (FA-C in Ashkenazi Jews, FA-A in Afrikaansspeaking people and Italians), which helps to set priorities for mutation screens. The FA-A and FA-C proteins have no sequence homologs in the current databases, although structural homologs may exist. Thus, resolution of difficulties in FA protein purification and pursuit of the X-ray crystallographic structure of FA proteins is considered a high priority.

Graft Versus Host Disease (GvHD)

The nature of the responding cells in GvHD and reliable methods to predict and ameliorate the problem remain elusive. A challenge remains in fostering graft versus leukemia or graft versus tumor effect while avoiding GvHD. In addition, the basic immunology, biology, and tissue specificities of the response require further definition.

Infectious Myocarditis

A non-invasive test for infectious myocarditis having appropriate sensitivity and specificity is needed. At present, the endomyocardial biopsy, which is invasive and has limited specificity and sensitivity, is the gold standard for diagnosis.

Lymphangioleiomyomatosis (LAM)

Scarcity of data and LAM tissue has hindered learning about the etiology and pathogenesis of LAM. The small number of patients makes it difficult to learn about important aspects of the disease such as its prevalence, prognosis, and clinical course, or the effects of various treatments. A lack of animal models makes it necessary to obtain human cells or tissue to do LAM research. The LAM Foundation continues to facilitate collection of LAM tissue at the time of lung transplantation. Progress in LAM research has increased demand for this scarce resource. A NHLBI LAM Tissue committee is establishing procedures and guidelines for LAM tissue collection and distribution.

Long QT Syndrome (LQTS)

Access and identification of sufficient numbers of new patients for studies remain a constant problem. Identification of mutant gene carriers would be greatly facilitated by accurate means of screening individuals in afflicted families for specific founder mutations. Improved means of identifying new mutations in the various genes involved would also be helpful.


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Last Reviewed: February 1, 2005
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