National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Overview of NIDDK Rare Diseases Research Activities NIDDK supports research on many rare diseases. Although diseases such as type 1 diabetes and type 2 diabetes are not rare, there are rare single-gene defects that cause diabetes such as maturity-onset diabetes of the young (MODY) and lipodystrophy. Many of the genes causing these disorders were recently identified. NIDDK also supports research on kidney and liver diseases. Each year 20,000 babies are born with kidney problems, 2,000; of these children will die, and 1,000 will begin treatment for renal failure. The most common childhood renal problems are genetic renal diseases, kidney and urinary tract malformations, focal segmental glomerulosclerosis (FSGS), and primary glomerulonephritis. NIDDK also supports research on genetic metabolic and hematologic diseases such as cystic fibrosis (CF), lysosomal storage diseases (LSDs), congenital disorders of glycosylation, Cooley's anemia, and sickle cell disease (SCD). Recent Scientific Advances in Rare Diseases Research Lipodystrophies Lipodystrophies are a group of conditions caused by abnormal lipid metabolism resulting in the reduction or absence of fatty (adipose) tissue. The lipodystrophies may be acquired or inherited, and both the anatomic location and degree of fat loss vary among the different disorders. These conditions are often accompanied by insulin resistance and/or diabetes, elevated levels of blood lipids, and vascular disease. There is a congenital form of the disorder in which the patients have no subcutaneous fat. This year the gene for this form of lipodystrophy was localized to 9q. At puberty, patients with familial partial lipodystrophy (FPLD), Dunnigan variety, lose subcutaneous fat from the extremities, trunk, and gluteal regions of the body, but excess fat becomes deposited in the face, neck, and back. Last year, investigators found that mutations in the lamin A/C gene, which was known to cause a form of muscular dystrophy, also causes FPLD. The lamin A/C protein is a component of the cell's nuclear envelope. NIDDK-supported researchers detected four independent mutations in this gene in members of 14 families. All of the alterations resulting in FPLD occur within a particular region of the lamin A/C protein. Mice with a targeted deletion of this gene not only develop a form of muscular dystrophy, but also lack distinguishable white fat, which serves as a valuable source of energy. Collectively, these data imply that mutations within this region of the lamin A/C protein are involved in one or more activities required by fat cells in specific tissue beds. It has been hypothesized that in FPLD, loss of fat cells affects insulin sensitivity through reduced levels of "adipocyte-derived circulating factors," such as leptin, a hormone produced by fat cells that regulates food intake and energy metabolism. A clinical trial has been initiated to determine if the symptoms of lipoatrophy improve with leptin treatment. Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) NIDDK supports several studies aimed at understanding the etiology and mechanism of PHHI. Mutations in several different genes have been shown to cause this disorder. Children with PHHI can have a defect in SUR1 , the high-affinity sulfonylurea receptor, or the potassium pore ( KIR6.2 ), which together form the potassium channel in the pancreatic beta cell. A mutation in glucokinase, the primary "glucose sensor" of the pancreatic beta cell that lowers its affinity for glucose, can also result in PHHI, as can mutations in glutamate dehydrogenase. Another mechanism described for congenital hyperinsulinism is focal adenomatous lesions of the pancreas, which involves loss of heterozygosity with retention of a SUR1 or KIR6.2 mutation. It was recently shown that patients with defects in the potassium channel can be identified by loss of an insulin response to tolbutamide. This test could identify patients that have PHHI due to mutations in SUR1 or KIR6.2 . Many of these patients respond to surgical interventions. Polycystic Kidney Disease (PKD) PKD is a genetic disorder characterized by the progressive development and subsequent growth of numerous cysts in the kidneys. It can be inherited as autosomal dominant (ADPKD) or as autosomal recessive (ARPKD) types. In humans, ADPKD has a later onset and slower development than ARPKD, which usually affects newborns and young children. Most affected children who survive the neonatal period die from renal insufficiency associated with ARPKD. NIDDK supports a comprehensive research portfolio on PKD, which includes investigator-initiated research programs, more complex Program Project Grants, Specialized Centers of Research (SCORs) in PKD, and a new research program (CRISP Study) that includes a consortium established with the purpose of developing and testing new or improved radio-imaging techniques to ascertain renal disease progression in patients affected with PKD. IgA Nephropathy IgA nephropathy is one of the most common primary forms of glomerulonephritis in children worldwide. IgA nephropathy was initially considered a benign condition, but in the light of more recent studies and extended follow-up of patients, the overall prognosis remains unclear. Most adult patients continue to have hematuria, and 20% to 30% have been found to progress to end-stage renal failure one or two decades after the initial diagnosis. Four research projects currently receive support, the focus being on determinants of the autoimmune process and studies of mechanisms of fibrosis leading to progression to end-stage renal disease (ESRD). An ongoing clinical trial comparing different treatment approaches to halt progression in children and young adults affected with IgA nephropathy should reach completion within the next 12 to 18 months. Focal Segmental Glomerulosclerosis (FSGS) FSGS is a common irreversible glomerular process with steroid-resistant nephritic syndrome. Complications including frequently relapsing nephrotic syndrome, generalized edema, cardiovascular problems, thromboembolisms, and progression to ESRD are commonly found and make disease management difficult, especially in pediatric patients. The risk of disease progression is even greater in African American children. FSGS is one of the most common recurrent renal diseases in children, resulting in new injury to the transplanted kidneys in 20% to 30% of cases, and in graft loss in 40% to 50% of transplant cases. Three projects supported under the Pediatric Nephrology program are studying the molecular genetic mechanisms of nephritic syndrome in FSGS. Cystic Fibrosis (CF) CF is the most common fatal genetic disease in Caucasians, affecting approximately 1 in 2,500 newborns. Patients are diagnosed in early childhood due to symptoms of the disease such as failure to thrive. With management of the nutritional problems and infections, the life expectance for CF patients has been increased to 30 years. Since the cloning of the CF gene and identification of its protein product, CFTR, as a cAMP-regulated chloride channel, there has been impressive progress in the molecular understanding of this disorder. NIDDK supports a research portfolio directed at further defining the molecular mechanisms underlying CF and translating information about the molecular basis of the disease into new treatments. This year NIDDK-supported researchers defined new interactions between CFTR and other cellular proteins. CFTR has been shown to interact with a membrane-bound protein, syntaxin 1A, which binds to the amino-terminal of CFTR and regulates the ability of the tail of CFTR to interact with the regulatory domain to control channel activity. CFTR has also been shown to interact with other membrane proteins such as ezrin and EBP50 through its PDZ domain. These adaptor molecules may control the phosphorylation of CFTR. In addition, CAP70 may enhance dimerization of CFTR by bridging two CFTR molecules. These molecular interactions may also explain how CFTR regulates the activity of the epithelial Na+ channel (ENaC). In sweat glands, ENaC cannot be activated when CFTR is defective. This new understanding of the interactions of CFTR with other cellular proteins should help to explain the complex pathophysiology of cystic fibrosis. Niemann-Pick Type C (NP-C) Disease NP-C, a lysosomal storage disease, is an autosomal recessive lipid storage disorder characterized by progressive deterioration of the central nervous system resulting in death in early childhood. Biochemical characterization of cells from NP-C patients reveals that they accumulate large amounts of unesterified cholesterol resulting in downstream effects on cholesterol homeostasis. The frequency of the disease is estimated at about 1 in 100,000 live births. Defects in the gene for NP-C1 account for about 95% of the cases of NP-C, while defects in the gene for NP-C2 account for the remaining cases. NIDDK-funded researchers have made two important findings in the past year. First, they have established that NP-C1 can function to transport fatty acids, but not cholesterol, out of endosomes and lysosomes. Second, they found that the protein defective in NP-C2 is a widely expressed lysosomal protein that binds cholesterol. These results provide new avenues for investigating the functions of NP-C1 and NP-C2 in cholesterol transport and homeostasis, which are greatly impaired in children with NP-C. Congenital Disorders of Glycosylation (CDGs) Defects in the modification of proteins by carbohydrates cause a syndrome of mental and psychomotor retardation, dysmorphism, and blood coagulation defects. Defects in the numerous enzymes that are in the pathway for N-glycosylation have been shown to cause this group of disorders. Last year, a new form of this disorder was described. These patients have a defect in DPM1 , the gene coding for the catalytic subunit of dolichol-phosphate-mannose synthetase. Supplementation with mannose has been shown to be successful in treating some CDG patients with defects in phosphomannose isomerase. Patients with the newly identified DPM1 mutations are being supplemented with mannose to see if this therapy will be effective in these patients. Cooley's Anemia Patients with Cooley™s anemia (also known as beta-thalassemia) continue to suffer from the sequelae of transfusion-induced iron overload due to the inadequacies of current iron-chelation therapy. Most of the patients are children and young adults. Compliance with the use of subcutaneous desferrioxamine (DFO) continues to be a major problem despite convincing evidence that it markedly reduces morbidity and prolongs life. The full potential of iron-chelation therapy will not be realized until a more effective and more easily administered drug is available. NIDDK is supporting two new clinical studies: one examining tissue damage potentially arising from free iron appearing in the blood immediately after chelator treatment, and a second assessing oral and subcutaneous iron chelation in combination, which is proving to be a more effective therapy than use of individual chelating drugs alone. Based on recommendations from a 1998 NIDDK workshop on "Iron: From Current Biochemistry to New Chelator Development Strategies," a Request for Grant Applications was issued to improve the control of iron transport and metabolism, develop a better understanding of the biological consequences of iron overload, and improve therapy. As a result, several new projects were funded that will increase our understanding of how chelating drugs act, and how to use them more effectively. NIDDK currently is conducting preclinical testing of a new iron-chelating drug that will go into clinical studies late in 2001, sponsored by a pharmaceutical company. Alpha-1-Antitrypsin (AAT) Deficiency AAT deficiency causes an inherited form of lung and liver disease. In this disease, an abnormal alpha-1-antitrypsin molecule (alpha-1-ATZ) is produced in patients, and as a result of its accumulation in hepatocytes, creates liver damage leading to cirrhosis and in some cases to cancer. This year chemical chaperones were shown to increase the amount of alpha-1-ATZ that can be correctly folded and exported into the circulation. In particular, 4-phenylbutyrate was able to increase alpha-1-antitrypsin levels in transgenic mice with the Z mutation to between 20% to 50% of normal. Because phenylbutyrate has been used in humans to treat other disorders, these studies may lead to a pharmacological intervention for this disorder. Biliary Atresia (BA) NIDDK supports a clinical study designed to determine the basis of poor growth for children with BA, a neonatal liver disorder, and to ascertain if these patients are likely to benefit from the anabolic and growth-promoting effects of supplemental growth hormone and/or supplemental nutrition. Although surgical approaches have attempted to correct the anatomic problem, these children typically fail to grow adequately. Ultimately, 70% of affected children require liver transplantation, with the most common indication for transplantation being poor growth. BA patients have a disturbance of the growth hormone-insulin-like growth factor (GH-IGF) axis. They have increased insulin, increased growth hormone, increased IGFBP-1, depressed IGF-I, and depressed IGFBP-3. This pattern of disturbance can be seen with either malnutrition or growth hormone (GH) resistance. An interventional study will determine if treatment of children with biliary atresia with either recombinant human growth hormone (rhGH) or supplemental nutrition early in the course of the liver disease will correct the alterations of the GH-IGF axis and improve outcome measures. Rare Diseases Research Initiatives Last year NIDDK and NHLBI issued RFA DK-99-009, "Biology of Iron Overload, and New Approaches to Therapy." Twelve grants were awarded from this RFA in FY 2000. These grants studied iron transport and chelation in rare diseases such as hemochromatosis and beta-thalassemia. NIDDK issued RFA DK-00-013 for a Cystic Fibrosis Core Center. Applications were received in FY 2000, and one Center will be funded in 2001. NIDDK has joined the National Heart, Lung, and Blood Institute (NHLBI) in an initiative titled, "Genetic Modifiers of Single Gene Defect Diseases," issued August 25, 2000. This initiative will fund studies to identify and characterize the modifier genes responsible for variation in clinical progression and outcome of heart, lung, and blood disease due to single-gene defects. It is anticipated that 18 applications will be funded in FY 2001. This year NIDDK issued two Program Announcements to study rare diseases. PA-00-055, "Hemochromatosis and Diabetes Mellitus," was issued on February 9, 2000. This announcement solicits grant applications studying the molecular mechanisms underlying the pathogenesis of diabetes mellitus in hemochromatosis and other forms of iron overload. PA-00-091, "Research Studies on the Hereditary Calcium Oxalate Stone Diseases," was issued on April 27, 2000. This announcement solicits grant applications to study primary hyperoxaluria and other genetic causes of oxalate stone disease. Current active PAs on rare diseases include PA-99-040, "Molecular and Genetic Mechanisms in Pancreatitis";PA-94-036, "Characterization and Treatment of Genetic Metabolic Diseases"; and PA-98-002, "Polycystic Kidney Disease." Rare Diseases-Related Program Activities Conferences on Rare Diseases NIDDK and ORD supported the "First Annual Shwachmann-Diamond Syndrome International Meeting" held April 4, 2000 in Boston, Massachusetts. This meeting provided a forum for clinical and basic researchers to present their most recent data on Schwachmann-Diamond syndrome. The meeting brought together gastroenterologists, hematologists, geneticists, and patients for their perspectives on this disease. NIDDK, NHLBI, and ORD organized a workshop titled, "Design Issues for Clinical Trials in Acute Renal Failure," held September 10-12, 2000. The workshop focused on designing clinical trials to prevent acute renal failure, to treat the condition using drugs and dialysis, and to prevent acute renal failure after transplantation. NIDDK will use the advice from this meeting to plan a multicenter Acute Renal Failure Trial Network. NIDDK and ORD supported a workshop titled, "Congenital Disorders of Glycosylation," held on November 8, 2000. This satellite meeting was held in conjunction with the Society for Glycobiology to raise awareness for this group of disorders. It brought together researchers studying this group of newly discovered genetic diseases to present their findings. NIDDK and the Oxalosis and Hyperoxaluria Foundation organized a workshop on "Oxalosis and Calcium Oxalate Stone Disease," held November 16-17, 2000. This workshop brought together experts in the field, introduced new investigators to the field, and discussed the development of a network of investigators to facilitate sharing of data.

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Last Reviewed: January 27, 2005