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

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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

NIDDK supports research on many diseases affecting children. Although diseases such as type 1 diabetes, which primarily affects children, and type 2 diabetes, which has become more prevalent in children, 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 have recently been identified.

NIDDK also supports research on kidney and liver diseases in children. Approximately 5,000 children are being treated with dialysis or have a transplanted kidney because of end-stage renal disease (ESRD) and kidney failure; about 60% are 12 years old or younger. Every year, 20,000 babies are born with kidney problems, 2,000 of whom will die, and 1,000 of whom will begin treatment for renal failure. The most common childhood renal problems are genetic renal diseases, kidney and urinary tract malformations, focal segmental glomerulosclerosis, and primary glomerulonephritis.

NIDDK also supports research on genetic metabolic and hematologic diseases such as cystic fibrosis, lysosomal storage diseases, peroxisomal biogenesis disorders, Cooley's anemia, and sickle cell disease. Many of these diseases are rare diseases primarily affecting children.

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

Activities Supported in FY 2000


Lipodystrophy refers to a group of conditions caused by abnormal lipid metabolism and resulting in the reduction or absence of adipose (fatty) 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 has been localized to 9q.

At puberty, patients with Dunnigan variety familial partial lipodystrophy (FPLD) lose subcutaneous fat from the extremities, trunk, and gluteal regions of the body, while excess fat becomes deposited in the face, neck, and back. In 2000, investigators found that mutations in the lamin A/C gene, which was known to cause a form of muscular dystrophy, also caused FPLD. The lamin A/C protein is a component of the cell's nuclear envelope. NIDDK-supported researchers detected 4 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. The clinical trial is planned to continue until 2003.

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 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 in PKD, and a new research program (the CRISP Study), which includes a consortium established to develop and test new or improved radio-imaging techniques to ascertain renal diseases progression in PKD patients. (FY 2000 through FY 2004)

Alport Syndrome

Alport syndrome is an inherited renal disorder characterized by familial occurrence in successive generations of progressive hematuric nephritis, changes in the glomerular basement membrane, and hearing loss. Ocular defects are also commonly associated with Alport syndrome. Male patients have a more severe course. In the autosomal recessive form, the nephritis progresses to early-onset ESRD. In the autosomal dominant type, renal prognosis is better than in the X-linked form, with median renal survival of 51 versus 25 years. Four research programs currently supported under the Pediatric Nephrology Program are looking into the molecular genetic aspects of renal disease progression and the urogenital development of Alport syndrome. (FY 2000 though FY 2005)

IgA Nephropathy

IgA nephropathy is one of the most common primary forms of glomerulonephritis in children worldwide. It 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 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 12-18 months. (FY 2000 through FY 2004)

Focal Segmental Glomerulosclerosis (FSGS)

FSGS is a common, irreversible glomerular process, with steroid-resistant nephritic syndrome. Complications such as frequently relapsing nephrotic syndrome, generalized edema, cardiovascular problems, thromboembolisms, and progression to ESRD are commonly found and make 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 the transplanted children. Three projects are currently supported under the Pediatric Nephrology program, studying the molecular genetic mechanisms of nephritic syndrome in FSGS. (FY 2000 through FY 2005)

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, often due to symptoms such as failure to thrive. With management of nutritional problems and infections, the life expectancy for CF 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. NIDDK also supports several clinical studies investigating ways to improve treatment for CF patients. Two of these studies investigate whether behavioral interventions such as improving eating in children with CF leads to increased weight gain and an improved clinical prognosis.

A pilot newborn screening program was initiated in Wisconsin to identify infants with CF and intervene before the appearance of symptoms. This study is in its 13th year of following these patients. Patients who received treated from birth had increased weight, height, and head circumferences. This study is continuing to follow these patients to determine if early intervention results in improved lung function. Another clinical trial is under way to test whether the prophylactic use of inhaled tobramycin to prevent infections in infants with CF will improve long-term lung function. (FY 2000 through FY 2005)

Lysosomal Storage Diseases (LSDs)

LSDs are a group of disorders that are caused by a missing enzyme, resulting in the accumulation of undegraded material in the lysosome. These disorders are relatively rare but as a group have been estimated to occur in 1 in 5,000 newborns. This group of disorders includes the mucopolysaccharidoses, Batten disease, Krabbe disease, Tay-Sachs disease, and Niemann-Pick disease, all of which are fatal in childhood. NIDDK supports research into several methods of treating these largely untreatable disorders. These methods include:

  • Enzyme replacement therapy.

  • Substrate deprivation.

  • Bone marrow transplantation.

  • Gene therapy to replace the defective gene.

Enzyme replacement therapy has effectively treated the adult form of Gaucher disease, which does not involve the brain. The juvenile form of Gaucher disease, like many of the LSDs, however, involves storage of material in the brain that is not corrected because the enzyme cannot penetrate the blood-brain barrier.

Niemann-Pick disease type C (NPC), 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 NPC patients reveals that patients accumulate large amounts of unesterified cholesterol, resulting in downstream effects on cholesterol homeostasis. The frequency of the disease is estimated at approximately 1 in 105 live births. Defects in the gene for NPC1 account for approximately 95% of the cases of NPC disease, while defects in the gene for NPC2 account for the remaining cases. Researchers funded by NIDDK have made two important findings in the past year. First, they established that NPC1 can function to transport fatty acids (but not cholesterol) out of endosomes and lysosomes. Second, they found that the protein defective in NPC2 is a widely expressed lysosomal protein that binds cholesterol. These results provide new avenues for investigating the functions of NPC1 and NPC2 in cholesterol transport and homeostasis, which are greatly impaired in children with NPC. (FY 2000 through FY 2005)

Peroxisomal Biogenesis Disorders (PBDs)

Peroxisomes are organelles present in almost all eukaryotic cells that participate in important metabolic processes. In humans, these processes include beta-oxidation of fatty acids; synthesis of bile acids, cholesterol, and plasmalogens; and catalysis of a variety of hydrogen peroxide-producing oxidation reactions. The enzymes responsible for these functions are synthesized in the cytoplasm and are post-translationally imported into the peroxisome where they function. PBDs are a genetically heterogeneous group of rare human diseases caused by an inability to import peroxisomal proteins. The PBDs include Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondrodysplasia punctata. These diseases often result in neurological, hepatic, and renal abnormalities; mental retardation; and death in childhood. Since the peroxisomal import process has been conserved from yeast to humans, investigators have used genetic screens and selection in yeast to identify more than 16 proteins required for peroxisome biogenesis and normal peroxisome import. NIDDK investigators are actively trying to elucidate how these proteins are involved in recognition, targeting, and translocation of proteins into peroxisomes, with the ultimate goal of creating therapeutics to alter the progression of the disease processes in PBDs. (FY 2000 through FY 2005)

Cooley's Anemia

Patients with beta-thalassemia (Cooley's anemia) 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 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.

On the basis of recommendations from the 1998 NIDDK workshop, "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 is currently conducting preclinical testing of a new iron-chelating drug that will go into clinical studies late in 2001, sponsored by a pharmaceutical company. (FY 2000 through FY 2005)

Hereditary Liver Disease

Research is under way to identify and characterize the molecular bases for two forms of inherited liver disease: cholestasis-lymphedema syndrome (CLS) and familial hyperbileacidemia (FHB). The study will contribute to an overall understanding of the genes and proteins critical for normal liver function. It is also possible that these genes contribute to prevalent adult diseases involving the biliary system such as gallstones. Another study investigates a different inherited form of liver disease, alpha-1-antitrypsin deficiency. In this disease, an abnormal alpha-1-antitrypsin molecule (alpha-1-ATZ) is produced and, as a result of its accumulation in hepatocytes, creates liver damage, leading to cirrhosis and in some cases, cancer. These studies will ultimately allow the investigators to predict susceptibility among alpha-1-antitrypsin-deficient patients and target susceptible hosts for specific pharmacologic interventions. (FY 2000 through FY 2005)

Alagille Syndrome (AGS)

AGS (syndromic bile duct paucity) is a dominant genetic disorder affecting the liver, heart, eyes, vertebrae, and facial structures. Expressivity is highly variable and penetrance is incomplete, making accurate diagnosis and genetic counseling difficult. A number of projects support research in the etiology, pathogenesis, diagnosis, and treatment of this condition, including the study of growth and nutrition in children with this syndrome. (FY 2000 through FY 2005)

Biliary Atresia (BA)

BA is a neonatal liver disorder. NIDDK supports a clinical study seeking to determine the basis of poor growth for children with BA and to ascertain if these patients are likely to benefit from the anabolic and growth-promoting effects of supplemental growth hormone (GH)and/or supplemental nutrition. Although surgical approaches have attempted to correct the anatomic problem, these children typically fail to grow adequately. Ultimately, 70% of these children require liver transplantation, and the most common indication for transplantation is poor growth. Patients have a disturbance of the growth hormone insulin-like growth factor (GH-IGF) axis, along with increased insulin, increased GH, increased IGFBP-1, depressed IGF-I, and depressed IGFBP-3. This pattern of disturbance can be seen with either malnutrition or GH resistance. An interventional study will determine if treatment of children with BA with either recombinant human growth hormone or supplemental nutrition early in the course of the liver disease will correct the alterations of the GH-IGF axis and improve outcomes. (FY 2000 through FY 2004)

Activities Planned for FY 2001–FY 2005


Congenital Disorders of Glycosylation - November 2000
Lipoatrophic Diabetes and Other Syndromes of Lipodystrophy - March 2001
Workshop on Noninvasive Measurements of Iron for Cooley's Anemia - April 2001
Strategies for Therapy of MPS and Related Diseases - June 2001
Society for Inherited Metabolic Diseases - March 2001
Workshop on PKD - 2002

Research Initiatives

Genetic Modifiers of Single-Gene Defect Diseases

NIDDK has joined NHLBI in this initiative to 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. NIDDK may reissue this initiative in 2002 and expand it to cover diabetes and metabolic, liver, and kidney diseases.

Polycystic Kidney Disease (PKD) Pilot Clinical Projects

An RFA was recently issued to initiate pilot clinical projects followed with a full-scale clinical trial to improve the management and outcome of disease progression in PKD patients.

Cystic Fibrosis (CF) Specialized Center of Research

This initiative will recompete funding for one CF SCOR. NIDDK plans to fund the successful Center in 2002 through 2007.

Clinical Centers in Focal Segmental Glomerulosclerosis (FSGS)

The goal of this initiative is to establish a consortium of clinical centers and a data coordinating center, in order to participate with NIH in developing and testing treatment interventions to prevent progression of renal disease in FSGS in children and young adults. (Planned for FY 2002 through FY 2007)

Pediatric Clinical Research Centers in Biliary Atresia (BA) and Neonatal Hepatitis

This initiative aims to establish a database of clinical information and serum/tissue samples to expand research into the pathogenesis of these disorders. (Planned for FY 2002)

Database and Registry for Genetic Renal and Genitourinary Patients

The goal of this initiative is to create a registry of well-characterized pediatric urology and nephrology patients with single-gene disorders for basic and clinical studies. (Planned for FY 2002)

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Last Reviewed: May 15, 2003
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