National Institute of General Medical Sciences (NIGMS)
Overview of NIGMS Rare Diseases in Children Research Activities, FY 2000FY 2005
NIGMS supports broad-based fundamental research that is not targeted to any specific organ system or
disease. In general, support of investigations related to specific diseases, unless of wide applicability across disease or organ system lines, is not the responsibility of NIGMS, but rather would be assigned to
one of the categorical Institutes.
NIGMS does not provide support specifically for rare diseases in children but does provide funding for the
Human Genetic Cell Repository, which provides a valuable resource for investigators studying genetic disorders, many of which affect children. The Repository, located at the Coriell Institute for Medical Research in Camden, New Jersey collects, characterizes, maintains, and distributes cell lines from patients
and families with a wide variety of genetic disorders and from normal persons whose tissues serve as controls. More than 6,600 cell lines representing more than 500 different diseases are available to qualified
investigators. The Repository stimulates research on rare diseases by providing access to cell lines, and DNA samples derived from these cell lines, that are not otherwise readily available. Among the cell lines requested most frequently in the last year are those that affect children, such as ataxia telangiectasia, xeroderma pigmentosum, cystic fibrosis (CF), Bloom syndrome, fragile X-linked mental retardation, Nijmegen breakage syndrome (NBS), Cockayne syndrome, and glycogen storage disease.
Recent acquisitions for the collection include samples from patients with the following rare disorders:
ceroid lipofuscinosis, Rett syndrome,
Friedreich's ataxia (FRDA),
glutaric acidemia, atransferrinemia,
factor X deficiency, and immuno-osseous dysplasia. These cell lines, as well as those previously acquired,
are used for biochemical, cellular, and molecular studies to help elucidate the causes of genetic defects.
The Repository has a growing collection of cell lines in which the mutation has been characterized at the
molecular level. These include samples with characterized trinucleotide expansions from patients with fragile X and characterized mutations in Bloom syndrome, hemochromatosis, and CF.
The Institute has no specific plans at this time to support additional research directly relevant to rare
disease in children as NIGMS primarily supports investigator-initiated research, which will largely
determine the research portfolio.
Recent Scientific Advances in Rare Diseases in Children Research
Carbohydrate-Deficient Glycoprotein Syndromes (CDGS)
CDGS are a collection of human metabolic disorders that involve the absence or inappropriate addition of
sugar residues to proteins, as they are made in the cell. The majority of these disorders result in neurological impairment with mental and psychomotor retardation. NIGMS provided approximately $850,000 in support of CDGS research in FY 2000. One CDGS project is currently funded through FY 2002, and one project is soon to receive funding for a competitive renewal through FY 2005.
Two NIGMS-supported investigators have been instrumental in identifying defects in the metabolism of the
sugars that result in CDGS. One researcher has demonstrated that the sugar mannose, rather than
glucose, is imported into the body's cells from the bloodstream and is used as the primary source of sugar
in human glycosylation. Additionally, this researcher has discovered the specific membrane protein that
transports mannose into the cell. Initial results of a clinical trial suggest that one form of CDGS can be reversed by daily oral administration of mannose to increase the blood serum levels of this sugar and improve the import of this sugar into the cell for use in glycosylation of proteins.
Another NIGMS-supported researcher is examining a second form of CDGS. Leukocyte adhesion
deficiency II (LADII) syndrome, a member of the CDGS group of disorders, is a syndrome in which
reduced amounts of the sugar L-fucose are incorporated into glycoconjugates. The syndrome results in
severe growth and mental retardation, unusual facial appearance, and recurrent infection. Initial evidence
suggested LADII is caused either by a defect(s) in fucose biosynthesis, the conversion of GDP-mannose to
GDP-fucose in the cell, or a defect in the transport of fucose into the lumen of the Golgi apparatus for use
in glycosylation of proteins. The researcher has identified, purified, and characterized a protein that transports fucose into the Golgi of the cell and is attempting to clone the gene for this transporter to facilitate its further study.