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

National Institute of Environmental Health Sciences (NIEHS)

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

Children are not small adults, but rather young, developing individuals whose physiologic makeup makes them potentially more vulnerable than adults to adverse environmental effects. Chemical exposures that have negligible effects in adults may have devastating effects in infants or children. This enhanced vulnerability of children is due to three factors:

  • Organ systems in children are still developing and thus are more susceptible to disruption and damage caused by environmental agents.

  • Body mass in children is much smaller than in adults. Compared to an adult, a child consumes more food and water and breathes more air in proportion to his or her body mass. This means children generally receive a proportionally larger dose of toxic agents in contaminated food, water, or air than do adults.

  • Common early childhood behaviors such as crawling, putting objects into the mouth, and ingesting dirt put infants and very young children in closer contact than adults with some toxic agents in the environment.

The consequences of childhood effects of environmental toxins can last a lifetime, which makes it imperative to focus on reduction of childhood exposures as a critical component of environmental public policy. NIEHS has traditionally played a pivotal role in shaping public policy in ways that protect the health of children, and the Institute continues to define how environmental exposures affect risks of diseases and disorders such as birth defects, neurological damage, cancers, and asthma. This information will inform policy-makers of changes in safety standards designed to ensure the safety of children.

Recent Scientific Advances in Rare Diseases in Children Research

Tristetraprolin and Related Proteins in Inflammatory Diseases

One major area of study in the laboratory began with the cloning of a gene that was rapidly induced by insulin. The protein encoded by this gene, known as tristetraprolin, is the prototype of a novel class of CCCH zinc finger proteins. Tristetraprolin is rapidly induced, translocated from the nucleus to the cytosol, and phosphorylated on serine residues by insulin and by many other mitogens and growth factors. Mice deficient in this protein develop a complex syndrome consisting of arthritis, wasting, dermatitis, and early death.

During the past year, NIEHS scientists demonstrated that tristetraprolin deficiency in mice also led to increased stability of the mRNA-encoding granulocyte-macrophage colony stimulating factor (GM-CSF), a cytokine important for maintenance of the normal white blood cell count. Studies in cell-free systems and in cultured cells are under way to identify inhibitors of this interaction, which might be useful therapies for neutropenic states. Concerning the mechanism of action of tristetraprolin and its relatives, NIEHS reported that these proteins can destabilize certain mRNAs, even when those mRNAs do not contain polyA tails, indicating that initial deadenylation is not required for subsequent mRNA degradation. "Rules" that govern the binding of this novel class of RNA-binding proteins to its target sequences were established. Finally, researchers identified a number of protein-coding polymorphisms and one non-expressing mutation in the human gene-encoding members of this family of proteins. Studies are under way to determine the biochemical and clinical significance of some of these variants. (FY 2000 through FY 2005)

Effect of Diet on Occurrence of Chronic Disease

Diet may affect the risk of several chronic human diseases. This research project has two main foci: 1) the study of diet-cancer relations and 2) the study of diet in relation to risk of amyotrophic lateral sclerosis (ALS).

Defects in antioxidant defenses (e.g., superoxide dismutase 1 [SOD1]) are a cause of ALS, and thus it is reasonable to suspect that antioxidant intake may also affect the incidence or progression of this disease. One research focus on diet and ALS has been an analysis of dietary data from a case-control study of ALS. NIEHS examined the dietary intake of calcium, magnesium, and antioxidants among 107 ALS cases and 262 community controls. Overall, these dietary factors were not related to risk of ALS, though modestly protective associations were suggested for magnesium and lycopene.

A second study of the same relationship is an add-on to a large cohort study under way at NCI. The cohort consists of members of the American Association of Retired Persons (AARP) who have completed a dietary questionnaire (approximately 600,000 people). Researchers expect approximately 150 cases of ALS to develop in this cohort by 2002. (FY 2000 through FY 2005)

Systemic Lupus Erythematosus (SLE)

SLE is a severe, disabling autoimmune disease. Approximately 90% of lupus patients are women. Although few studies provide detailed data pertaining to the prevalence of this disease, conservative estimates indicate that 100,000 women in the United States are living with SLE. Researchers recently finished data collection in the Carolina Lupus Study, the largest population-based case-control study of hormonal and environmental risk factors for the development of SLE conducted to date. Four specific analyses based on these data were presented at the annual meeting of the American College of Rheumatology in 1999 and 2000. These analyses include hormonal and reproductive risk factors, medical history risk factors (i.e., allergies, infections), occupational silica dust exposure, and demographic differences in the clinical and immunologic presentation of the disease. Manuscripts for these and other analyses have been submitted for publication. (FY 2000 through FY 2005)

Friedreich's Ataxia (FRDA)

FRDA is the most common cause of recessive ataxia and occurs at an incidence of 1 in 30,000 Caucasians. The yeast homologue of the FRDA gene, YFH1, which codes for the protein frataxin, is responsible for regulating the amount of iron in the mitochondria. The absence of frataxin leads to iron accumulation and the production of radicals. NIEHS scientists have established that frataxin limitation leads to nuclear as well as mitochondrial DNA damage. This novel finding has implications for the pathological symptoms associated with the disease and potential treatment strategies. It also has many implications for possible origins of aging and cancer. (FY 2000 through FY 2005)

Lung Hemorrhage in Cleveland, Ohio Infants

Over the past five years a relatively rare disorder, acute pulmonary hemosiderosis, or hemorrhage, has been found in a large number of infants in inner-city Cleveland. There have been 37 cases in a limited area of Cleveland resulting in 12 deaths, including 7 deaths originally thought to be due to sudden infant death syndrome (SIDS). The environmental mold Stachybotrus chartarum has been identified as the causative agent, with the young child's developing lung being particularly vulnerable. NIEHS is supporting a pilot study that will allow a local physician to further define the environmental components for a condition that has a 30% mortality rate and is disproportionately affecting inner-city children. The researchers have identified environmental tobacco smoke as a possible trigger for the acute bleeding. Additionally, the research has led to the development of a home remediation program that completely eliminates the mold spores from contaminated homes. (FY 2000 through FY 2005)

Diethylstilbestrol (DES)

Once used by pregnant women to prevent miscarriage, the potent synthetic estrogen DES was shown to cause health problems in women exposed to DES in utero ("DES daughters"). These women were at risk of developing clear cell adenocarcinoma, a rare vaginal cancer, as well as having reproductive abnormalities. To date, "DES sons" have shown increased reproductive tract abnormalities but not an increased cancer risk, although this is a possibility as the population ages. A recent NIEHS study shows the unexpected, that the environmental exposures of one's parents and grandparents can have adverse effects on our own health, even if we have never been directly exposed to a particular compound.

Although this multi-generational effect has only been demonstrated with DES, it suggests new avenues of investigation for assessing the many "environmental estrogens" that have been developed. Although these compounds have a far weaker estrogenic effect than DES, the possibility exists that subtle adverse effects could show up in our sons, daughters, grandsons, and granddaughters. More immediately, this research proves that the sons of "DES daughters" need to be closely monitored by their physicians. (FY 2000 through FY 2005)

Incontinentia Pigmenti (IP)

IP is a genetic disorder characterized by unusual patterns of discolored skin. Males with this disorder usually die before birth, so females are the major patient group. In rare cases, IP can cause developmental abnormalities such as dwarfism and club foot. NIEHS studies have definitively linked IP with deficiency of IKKy/NEMO expression. This connection provides additional evidence for the importance of the IKK complex and NFkB for prevention of programmed cell death in mice and in humans. IKKy/NEMO-deficient mice can be used as a model for studying IP, which will help women with IP to make more informed reproductive decisions. (FY 2000 through FY 2005)

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

Refsum's Disease

NIEHS scientists are studying phytol metabolites, which are activators for the nuclear receptor RXR. Patients with Refsum's disease accumulate the metabolite phytanic acid to levels that are approximately 100 times normal values. Since it is alleged that phytanic acid has its sole origins from the diet, NIEHS is examining the effects of its removal from the diets of rodents. (Through FY 2001)

SGD Syndrome

Lactoferrin is an antibacterial and antiviral protein. It is the major protein in the specific granules of the neutrophils. The only genetic disease linked to lactoferrin is SGD syndrome, in which patients lack the specific granules in neutrophils. SGD is characterized by lactoferrin deficiency with recurrent infections. Defects in lactoferrin gene expression and function in children due to either genetic or regulatory means could cause recurrent infections, as shown in SGD syndrome. (At least through FY 2005)

Friedreich's Ataxia (FRDA)

FRDA is an autosomal recessive neurological disease that affects mitochondrial iron homeostasis. Deletion of the yeast homolog of this gene causes mitochondrial iron accumulation and a petite phenotype. Experiments have indicated nuclear DNA damage in yeast by reactive oxygen species. These experiments therefore have implications in the treatment of this disease and establish a novel paradigm of mitochondrial proteins having a nuclear-protective role. (At least through FY 2005)

Ataxia Telangiectasia Cancer

This research effort investigates the molecular mechanisms involved in cell cycle checkpoint responses to exposures to ionizing radiation (IR) and other environmental agents in both normal human fibroblasts and fibroblasts that lack normal function of the ataxia telangiectasia cancer susceptibility gene products. Researchers are interested in the role of the ataxia telangiectasia mutated (ATM) gene product in cell cycle checkpoint responses to exposures to environmental carcinogens and the signaling pathways that are generated from broken DNA to the inactivation of cyclin/CDK protein kinase complexes. In addition to aiding the understanding of the process of carcinogenesis, these studies hold great potential for providing insight into the mechanism of action of non-genotoxic environmental carcinogens. By understanding the underlying pathways impacted by the lack of ATM function in ataxia telangiectasia syndrome, it may be possible to design therapeutic approaches that will be able to prevent or minimize the devastating accompanying pathologies, such as the death of Purkinje cells and immune defects, in affected individuals. (At least through FY 2005)

Nijmegen Breakage Syndrome (NBS)

NBS is a rare autosomal recessive disorder characterized by increased sensitivity to IR, defective cell cycle checkpoint responses, and elevated cancer incidence. Both NBS and a related ataxia telangiectasia-like disorder are caused by mutations in the chromosomal DNA repair genes hNBS1 and hMRE11, respectively. Functional homologs of the human genes, referred to as XRS2 and MRE11, are present in the genetically tractable budding yeast Saccharomyces cerevisiae. NIEHS scientists and others have demonstrated that these genes perform similar functions in both yeast and human cells, leading to the view that the MRE11 and XRS2 proteins are components of a complex with DNA ex- and endonuclease activities. The nuclease function has been found to be critical for repair of broken chromosomal DNA by homologous recombination, but not for recombination-independent mechanisms of repair performed by the complex. In addition, these proteins may be important in dealing with categories of double-strand breaks that differ from those induced by IR. This information will be useful in understanding consequences of the genetic defect. (At least through FY 2005)

DNA Triplet-Repeat-Based Diseases

There are more than 14 rare neurological and neuromuscular diseases (including Haw River syndrome, affecting a small group of African American families in North Carolina) that result from the expansion of triplet-repeat DNA sequences. NIEHS scientists are investigating the underlying systems responsible for triplet-repeat expansion and have proposed a molecular model in which triplet expansion is due to a deficiency of 5'-flap cleavage during DNA replication. In particular, the interaction of the human enzyme responsible for 5'-flap cleavage (FEN1) with other components of DNA metabolism (such as proliferating cell nuclear antigen [PCNA] and DNA polymerases delta and epsilon) is being addressed genetically.

Researchers have now established that the nuclease function of the replication protein DNA polymerase delta may also play an important role in processing replication intermediates. During lagging strand synthesis, a replication intermediate is created that must be processed by either DNA polymerase delta or the FEN1 nuclease. The lack of processing is proposed to lead to a double-strand break that may be instrumental in triplet-repeat expansion. This research will provide further understanding of how the disease might arise and the possible consequences of variations in the relevant DNA metabolic proteins. (At least through FY 2005)


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Last Reviewed: May 15, 2003
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