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

National Human Genome Research Institute (NHGRI)

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

The mission of NHGRI is to understand the structure and function of the human genome and the role it plays in human health and disease. To that end, NHGRI supports the Human Genome Project (HGP), an international research effort to sequence the human genome and determine the function of the genes contained within the genome. The publication of the initial sequence and analysis of the human genome in February 2001 was an historic scientific achievement. The sequence information from the HGP has been continuously, immediately, and freely released to the world, with no restrictions on its use or redistribution.

This information is a major resource for all the areas of basic and applied biomedical and behavioral research in the 21st century. The HGP is producing research tools and information that are leading to improved detection and diagnosis of genetic disorders by intramural scientists and scientists in the broader biomedical research community.

Using the information and tools produced by the HGP, scientists in NHGRI's intramural research program are developing techniques to study the fundamental mechanisms of genetic disorders and genetic factors involved in common and rare diseases. These cutting-edge approaches are yielding new knowledge about human genetic diseases and their diagnosis, prevention, and treatment.

Recent Scientific Advances in Rare Diseases in Children Research

NHGRI's FY 2000 activities related to rare diseases and conditions research in children are described below.

Tools for Gene Discovery

Human DNA Sequencing

In March 1999, the HGP international consortium launched the full-scale effort to sequence the estimated 3 billion base pairs that make up the human genetic instruction book. In the following months, production of human genome sequence skyrocketed and the HGP produced 1,000 bases per second of raw sequence 7 days a week, 24 hours a day. June 26, 2000, marked an historic milestone when leaders of the public HGP and Celera Genomics Corporation announced that both had successfully completed the production of a "working draft" of the human genome.

In March 2001, public and private research teams published their data, including an initial analysis of the main features of the sequence. The intense phase of analyzing the sequence for gene content and a host of other biological features is now under way. A list of links to a number of important Web sites that contain information about the human genome sequence, other genome sequences, and other relevant genomic information can be found at:

"DNA Chip" Microarrays

The newfound abundance of genomic information is propelling scientists out of the pattern of studying genes individually. Scientists are now able to monitor thousands of genes at a time. For such large-scale analyses, miniaturized "DNA chip" technologies, also called microarrays, can be rapid, efficient, and economical. Microarrays are being used to compare gene activity in people with or without a disorder. This technology will benefit rare disease research because it can identify altered patterns of gene expression.

"Tissue Chip" Microarrays

In order to determine the importance of any gene in a more physiological setting, a second kind of array, called the tissue microarray, can confirm the importance of each gene that emerges as a candidate. NHGRI researchers have developed a way of arranging some 1,000 tiny cylindrical tissue biopsies in a small paraffin block. Tissue arrays permit researchers to examine the molecular details of many different healthy tissue types or in different stages of disease. NHGRI researchers combined cDNA and tissue microarray technologies to make rapid diagnoses of rare disorders and to better predict how a given patient will respond to available treatments and medications.

Genetics of Human Disease

Severe Combined Immunodeficiency (SCID)

SCID, also known as Bubble Boy Disease, is a rare but devastating complete lack of T cell and B cell immunity. The gene for the most common form of SCID was discovered by NHGRI scientists to be the IL2RG gene, which encodes the common gamma chain of receptors for several lymphocyte growth factors or cytokines. When this gene is defective, lymphocytes cannot develop normally, and affected infants therefore have frequent, severe infections that are ultimately fatal unless the immune system can be restored. Scientists are analyzing the expression and function of the common gamma chain protein.

Carrier testing and genetic counseling can then be provided, can prenatal diagnosis, which makes affected infants eligible for improved early treatments. In addition, scientists have developed and tested methods for correcting the genetic defect in X-linked SCID by gene transfer. Clinical trials of human gene transfer are planned to treat patients with X-linked SCID who were not helped by bone marrow transplant.

Hyper IgE Syndrome (Job's Syndrome)

Hyper IgE syndrome is an enigmatic, rare condition characterized by recurrent skin abscesses, recurrent pneumonia with development of lung cysts, and extreme elevations of serum IgE. The specific immune defect has not been discovered; however, NHGRI scientists have found that the syndrome can be inherited as an autosomal dominant disorder, and therefore genetic studies may help find the cause. NHGRI and National Institute of Allergy and Infectious Diseases (NIAID) scientists have arrived at a new clinical understanding of the condition as a multi-system disorder with immune, dental, and skeletal abnormalities. It has variable expressivity and penetrance. Genome-wide linkage studies show at least three loci in the human genome that may be associated with hyper-IgE syndrome. Scientists are currently investigating the genetic regions and hope to identify disease genes for this condition.

Autoimmune Lymphoproliferative Syndrome (ALPS)

ALPS is a newly discovered syndrome in which patients have large lymph nodes and spleens, autoimmune disease, increased numbers of a rare type of lymphocyte called CD4-/CD8-T cells, and defects in programmed cell death of their lymphocytes. NIH research has shown that people with ALPS have a high risk of lymphoma. NHGRI and NIAID scientists have discovered that most patients with this condition have inherited defects in the apoptosis mediator Fas. The position of mutations within the Fas gene influences the severity of the case of ALPS and whether family members with the same mutation are likely to have symptoms. Mouse models for ALPS combined with studies of family members can show how varying genetic background influences the disease manifestations.

Hirschsprung Disease

Animals heterozygous for dominant megacolon (Dom/+) exhibit multiple defects in neural crest development, including reduced numbers of melanocytes in the skin and an absence of myenteric ganglion in the colon. A human congenital disorder, Hirschsprung disease also exhibits rectocolic aganglionosis and can be associated with hypopigmentation. Thus, Dom/+ mice, as well as the piebald and lethal spotting mutants, serve as mouse models for this disease. Investigation of the involvement of Dom in Hirschsprung disease will be explored.

Congenital Disorders of Glycosylation (CDGs)

CDGs are a group of metabolic disorders characterized by a wide range of phenotypic presentations, from severe developmental delay and systemic manifestations to only gastrointestinal symptoms and normal development. CDGs result from defective N-linked oligosaccharide synthesis, a pathway with approximately 200 steps, with different types of CDG resulting from a disruption in any individual step. NHGRI scientists are identifying new patients with CDG and conducting studies to determine the pathogenic basis for novel cases of CDG and to define the relationship between genotype and phenotype in CDG patients. As an outcome of the proposed investigations, NHGRI scientists expect to elucidate the correlation between the phenotype, the glycobiology, and the genes involved.

Smith-Magenis Syndrome (SMS)

SMS, due to deletion on the short arm of chromosome 17, is associated with a distinct phenotype of physical features, developmental delay, speech delay with or without associated hearing loss, clinical signs of peripheral neuropathy, and neurobehavioral problems including sleep disturbance, outbursts, and self-injurious behaviors. More than 200 individuals representing a diversity of ethnic backgrounds have been identified with the syndrome worldwide. Utilizing existing physical maps and comprehensive clinical analysis of the physical, cognitive, and neurobehavioral aspects of SMS, the SMS Research Team seeks to define the natural history and pathophysiology of SMS across the life span and identify genes in the chromosome 17p11.2 region that contribute to physiologic and functional aspects of human cognition, speech/language development, and behavior.

Holoprosencephaly (HPE)

NHGRI researchers are studying HPE, the most common structural disorder of the developing human forebrain. HPE is associated with varying degrees of developmental disability and mental retardation. Scientists have located four genes that cause HPE in humans. These findings suggest that the following genes play an important role in the brain's separating into left and right hemispheres: Sonic Hedgehog (SHH), ZIC2, SIX3, and TG-interacting factor (TGIF). Maternal diabetes, low maternal cholesterol, and other environmental factors have been associated with abnormal brain development. Analysis of regulation, interaction, and physiological role of these genes and factors will help our understanding of normal and abnormal formation of the central nervous system.

Batten Disease

Juvenile neuronal ceroid lipofuscinosis (NCL type III), known as Batten disease, is a degenerative neurological disease resulting from a lysosomal storage disorder. The Batten gene, CLN3, encodes a protein with an as yet incompletely understood function. Scientists at NHGRI have created a mouse carrying a deletion of the CLN3 gene that encodes a transmembrane lysosomal protein of unknown function. The mouse has the same biochemical abnormalities seen in human patients with Batten disease. Work in yeast performed at the University of Rochester has revealed that the yeast ortholog of CLN3 is a vacuolar protein which, when deficient, abnormally lowers the vacuolar pH. NHGRI scientists hypothesized that humans (and mice) deficient in CLN3 might store lipofuscin in their lysosomes because of abnormal depression of lysosomal pH that interferes with degradative enzyme function. Scientists have started a treatment protocol of mice with chloroquine, an alkaline base that accumulates in the lysosome, to see if they can correct the biochemical abnormalities seen in Batten disease with this widely used and characterized drug.

Lowe Syndrome

Lowe syndrome is a rare X-linked disorder characterized by congenital cataracts, developmental delay, and Fanconi syndrome of the renal tubules. The defect is a deficiency in an enzyme, a phosphatidylinositol 4,5 bisphosphate 5-phosphatase localized in the Golgi complex, particularly the trans-Golgi network. NHGRI scientists are investigating the relationship between this enzyme deficiency and the clinical phenotype through cellular and animal models.

Idiopathic Scoliosis (IS)

IS is a structural lateral curvature of the spine present in the late juvenile or adolescent period in otherwise normal individuals. Previous studies from a number of populations have suggested autosomal dominant, X-linked, and/or multifactorial modes of inheritance. As part of a large collaborative study of familial IS, 200 families (1,200 individuals) with at least 2 individuals with scoliosis have been ascertained and clinically characterized. A genome-wide screen for 1,200 individuals was performed at the Center for Inherited Disease Research (CIDR). Preliminary analysis for linkage has been completed for all 1,200 individuals. Several candidate regions have been identified, and flanking markers are being typed to corroborate the findings from the genomic screen.

Camptodactyly-arthropay-coxa vara-pericarditis (CACP) Syndrome

Scientists have identified mutations in a gene previously known as megakaryocyte growth and stimulating factor, which causes CACP syndrome. This is an autosomal recessive disease with synovial hyperplasia as the basic underlying defect, which leads to several clinical phenotypes (mainly loss of proper joint growth and function). Scientists have made a mouse knockout construct and are currently studying these animals to see whether they can replicate the human phenotype in mice. This will allow better understanding of joint development and the identification of the basic molecular components responsible for CACP.

Achondroplasia and Other Fibroblast Growth Factor Receptor 3 (FGFR3) Disorders

The achondroplasia family of skeletal dysplasias includes three previously recognized diagnoses and one that has been defined under this project. The three well-established conditions are achondroplasia, hypochondroplasia, and thanatophoric dysplasia (TD). Work published over the last year has described a new syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). All four disorders in this family of conditions are caused by mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3). Work during FY 2000 has focused on the creation and characterization of two mouse models for FGFR3 disorders.

Marfan Syndrome and Related Conditions

NHGRI scientists are studying patients with Marfan syndrome and related conditions (Ehlers-Danlos syndrome [EDS] and Stickler's syndrome). Studies have documented newly recognized gastrointestinal complications of these disorders and shown that chronic musculoskeletal pain is a significant complication of both EDS and Stickler's syndrome. Studies have also documented an increased risk of femoral head failure in children with Stickler's syndrome. Scientists have proposed diagnostic criteria for Stickler's syndrome based on clinical and molecular studies in this population, and have identified a previously undescribed connective tissue disorder with features resembling Marfan syndrome, Stickler's syndrome, and EDS. Chronic musculoskeletal pain is a serious complication of many of the hereditary disorders of connective tissue. During FY 2000, scientists performed a pilot study of the Mindfulness-Based Stress Reduction Program to examine its efficacy in the relief of chronic pain in this population.

Alagille Syndrome (AGS)

Scientists at NHGRI have shown that mutations in the Jagged1 (JAG1) gene are responsible for AGS, a developmental disorder affecting multiple organ systems including the liver, heart, eyes, face, and vertebrae. In order to understand the role of Jaggeds in vertebrate development and to understand how alterations in their function lead to AGS in humans, scientists have isolated and characterized three homologous genes termed Jagged 1, 2, and 3 from zebrafish. Expression of dominant negative forms of the Jaggeds and blocking their expression with antisense oligonucleotides are being carried out to evaluate the function of the Jagged proteins.

Cleft Lip and Palate

NHGRI collaborates on a study of the genetics of oral clefts (cleft lip, cleft palate, or both) with investigators in Syria. Several hundred persons have been studied in Syria, and genotyping and linkage analysis of the first set of families has been completed for a genome-wide set of markers. Regions with suggestive evidence of linkage are currently being studied with fine-mapping techniques in the original set of families and in a new set of recently collected families. These analyses and the collaborative data collection in Syria will continue into FY 2001.

Pallister-Hall Syndrome, Greig Cephalo Polysyndactyly Syndrome (GCPS), Polydactyly

This research study encompasses a range of phenotypes that include Pallister-Hall syndrome, the allelic disorder Greig cephalo polysyndactyly syndrome (GCPS), and disorders with overlapping phenotypic manifestations. These overlapping disorders include the McKusick-Kaufman syndrome, Bardet-Biedl syndrome, the oral-facial-digital syndromes, and the short-rib-polydactyly syndromes. The clinical manifestations of these disorders include polydactyly, central nervous system malformations (with or without mental retardation and seizures), craniofacial malformations, and visceral malformations such as renal malformations or congenital heart defects. Scientists are using positional cloning strategies, biochemical approaches, and cell biologic studies to understand the genomic alterations, predict consequences to the proteins, and integrate these at the cellular or embryologic level. These data are then used to develop additional hypotheses that can be investigated at the clinical or molecular level.

McKusick-Kaufman Syndrome (MKS) and Bardet-Biedl Syndrome (BBS)

Scientists at NHGRI have identified an altered gene responsible for a rare developmental syndrome found predominantly among the Old Order Amish population. MKS is the first human disorder to be attributed to a mutation in a gene affecting a type of molecule called a chaperonin. Chaperonins, sometimes called "protein cages," protect cells by capturing and refolding misshapen proteins that could otherwise interfere with normal cellular functions. Females with MKS are affected by hydrometrocolpos (accumulation of fluids in the uterus and vagina). Both males and females have a form of polydactyly (the presence of extra fingers or toes) and congenital heart disease. The disorder is most serious in female infants in whom the hydrometrocolpos can cause death due to lung compression complications. Further research has shown that this gene is also mutated in some persons with BBS, an inherited form of blindness, mental retardation, and obesity. These results suggest that therapies directed at chaperonin function may ameliorate these symptoms.

Amish Nemaline Myopathy

Amish nemaline myopathy is a progressive muscle disease that has so far only been identified in the Old Order Amish of Pennsylvania. It causes muscle wasting that results in death before five years of age. NHGRI scientists isolated the disease-causing mutation in this disorder in FY 2000. This alteration is in the Troponin T1 gene, known to play a role in the muscle, but not previously known to cause any human disease. A collaborative group of scientists and physicians are working to translate these results into a potential treatment for this disease.

Lenz Microphthalmia Syndrome

Lenz microphthalmia syndrome causes small or absent eyes, mental retardation, and other anomalies. Its rarity is matched by its variability, and there is a significant confusion and controversy about the range of the phenotype and its overlap with other disorders that cause microphthalmia. NHGRI scientists, in collaboration with doctors at Children's National Medical Center, have teamed up to analyze a large family with multiple members affected with this disorder. The results of this research should allow development of accurate diagnostic tests.

Cataract and Craniofacial Anomalies Syndrome

A new, rare syndrome involving congenital cataracts and craniofacial anomalies in an inbred Saudi Arabian family has been identified. The most prominent feature is a failure of closure of the fontanels and sutures; at birth, the anterior fontanel is large due to open sagittal and metopic sutures. The second major feature is posterior Y-shaped structural cataracts that are congenital or develop over time. Chromosomal and biochemical studies were normal. A genome-wide screen was performed using 387 markers at the CIDR on 21 DNA samples, and efforts to fine-map the gene are currently under way.

Rieger Syndrome

A continuing area of interest of this group involves the homeodomain family of proteins, which play a fundamental role in the specification of body plan, pattern formation, and the determination of cell fate. Recent work has focused on two genetic disorders caused by defects in Pitx2, which codes for a homeodomain protein. Mutations in the human Pitx2 gene in 4q25-q26 lead to two eye-related disorders, Rieger syndrome and iridogoniodysgenesis. Sequelae include iris hypoplasia and the eventual development of glaucoma. In the past, biochemical observations explaining these diseases were documented simply as "loss-of-function"; this is the first time that a concrete, structural underpinning for the development of these disorders has been proposed. Continuing work in this area involves another homeodomain protein called FOXC1 that has also been implicated in Rieger syndrome and iridogoniodysgenesis.

Left-Right (L-R) Axis Malformations

A study of the complex genetics of L-R axis malformations has been undertaken with an emphasis on those genes that are associated with common phenotypes of L-R disorders, including situs inversus, heterotaxia, and organ isomerism. L-R defects can result from either environmental or genetic causes. It is the aim of these investigations to determine the genes responsible for both normal and abnormal L-R axis formation through the study of patients with these disorders. Mutations in genes such as ZIC3, LEFTY A, and ACVR2B have been shown to be responsible for several familial and sporadic cases of heterotaxia. It is anticipated that many additional genes important for L-R development will be identified in the search for genetic causes of laterality disorders. NHGRI scientists have recently identified the human CFC1 gene as causing laterality defects and are studying this and other genes in individuals with cardiac anomalies.

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

Planned FY 2001 Scientific Meetings and Workshops

Congenital Disorders of Glycosylation (CDGs) -Type 1A

NHGRI is planning a workshop entitled, "Exploration of Therapeutic Interventions for Congenital Disorders of Glycosylation-Type 1A," for summer 2001. CDGs are a group of rare metabolic disorders with a multisystemic clinical presentation. CDG-Type 1A is the most common of the CDG types, with approximately 200 cases worldwide. The clinical presentation includes severe developmental delay, coagulopathy, cerebellar hypoplasia, failure to thrive, seizures, liver disease, and stroke-like episodes. The metabolic basis of CDG-type 1A is a deficiency of phosphomannomutase with mutations defined in its gene, PMM2. This reflects defective synthesis of N-linked oligosaccharides, with clinical manifestations a direct result of the role of N-linked glycans in human embryogenesis and physiology.

It was reported in 1996 that in vitro addition of mannose to fibroblasts of patients with CDG-Type 1A corrected the N-linked synthetic defect in these cells. Brief therapeutic trials were performed with oral and intravenous mannose on six children with CDG-Type 1A in Europe in 1998. While these trials showed some changes in laboratory tests, no major clinical changes were seen in these children. A satellite meeting, "Congenital Disorders of Glycosylation," was held in conjunction with the Society of Glycobiology meetings in Boston in November 2000. At this meeting, a brief report was presented about two children with CDG-Type 1A on oral mannose for two years who are making significant clinical improvement. This report renewed interest in the issue among the clinical experts in this disorder of the need for a randomized therapeutic trial for children with CDG-type 1A. Several investigators also expressed interest in alternative chemical forms of mannose as therapeutic options.

Affected children have significant morbidity related to their failure to thrive, skeletal deterioration, coagulopathy, and stroke-like episodes. If there is any therapeutic intervention worthy of trial, it should be evaluated on children with this devastating disorder.

Genetic And Rare Diseases Information Center

NHGRI and ORD, in order to respond to the public's need for information on genetic and rare disorders, are establishing the NHGRI/ORD Genetic and Rare Diseases Information Center. The Information Center will focus on meeting the information needs of the general public, including patients and their families, health care professionals, and biomedical researchers.

The purposes of the Information Center are to:

  • Serve as a central, national repository of information materials and resources on genetic and rare diseases, conditions, and disorders.

  • Collect, produce, update, and disseminate information on the diagnosis, treatment, and prevention of genetic and rare disorders.

  • Coordinate with organizations and associations interested in genetic and rare disorders to explore networking capabilities, avoid duplication of effort, and identify information gaps.

Planned Research Initiatives, FY 2001 Through FY 2005

As the human genome is further defined, this information will be used by scientists to better understand the genetics of the rare diseases affecting children. Ongoing research activities over the next five years will continue in the areas discussed above.

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Last Reviewed: February 1, 2005
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