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

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

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

The mission of NIAAA is to conduct and support research activities on the causes, consequences, and treatment of alcoholism and alcohol abuse. Alcoholism results in widespread and damaging consequences to the health of children, both psychologically in child abuse and neglect and physically in mental retardation and birth defects associated with fetal alcohol syndrome (FAS). Please see "Ongoing, New, and Planned Research Initiatives" for more information. In terms of funding, many NIAAA FAS studies are funded through FY 2004. Funding for research on other diseases and conditions discussed in this report is assured, although specifics in terms of funding allocation are linked to progress and Principal Investigator evaluation of scientific merit.

Recent Scientific Advances in Rare Diseases Research Relevant to Children

Friedreich's Ataxia (FRDA)

FRDA is an autosomal recessive disease clinically characterized by progressive ataxia, hypertrophic cardiomyopathy, early onset of insulin-resistant diabetes, invalidism, and premature death. Current therapy for FRDA is palliative. FRDA is caused by a deficiency of frataxin, a 210 amino acid nuclear-encoded mitochondrial protein, resulting from the expansion of an intronic GAA repeat that leads to inhibition of transcription in the nucleus, leading to decreased message. In yeast, frataxin appears to be involved in iron export from mitochondria. In experiments, yeast cells with deleted frataxin accumulated mitochondrial iron, showed a high sensitivity to oxidation damage, and showed decreased mitochondrial respiration. In human cells, however, FRDA patients show a decrease in activity of the mitochondrial enzyme aconitase (EC, the enzyme responsible for conversion of citrate to isocitrate, the first step in the Krebs (also known as citric acid or TCA) cycle. Over-expression of frataxin in mammalian cells results in increases in the flux through the TCA cycle, in the electric potential between mitochondria and cytoplasm, and in the cellular adenosine triphosphate (ATP) content. These findings in mammalian cells indicate that deficiency of frataxin in human patients results primarily from defects in the TCA cycle and not from mitochondrial iron overload.

The clinical phenotype of FRDA patients is indistinguishable from the phenotype of patients with familial -tocopherol (vitamin E) deficiency, and is different from patients with iron overload. Recent work shows that elevation of blood ketone bodies, a normal response to fasting, can increase mitochondrial citrate and isocitrate contents, thus overcoming the block in aconitase found in FRDA. In addition, ketone bodies increase the electric potential between mitochondria and cytoplasm, and with that, the energy contained in ATP. At the same time, ketone bodies oxidize coenzyme Q, thus decreasing the major source of mitochondrial free radicals. Ketone bodies also reduce the free NADP + ,which is the major source of the detoxification of free radicals. It is proposed that a diet containing ketone bodies might prove an effective therapy for this currently untreatable disease. Such dietary therapy could provide an earlier treatment for this group of patients than attempting to transfect the gene for frataxin into heart, muscle, and brain.

GLUT1-deficient Epilepsy

GLUT1 is the enzyme responsible for the transport of glucose from blood into the brain across the blood-brain barrier. The activity of this enzyme is not responsive to insulin. GLUT1-deficient epilepsy results from several types of mutation in the gene of GLUT1, located on the short arm of chromosome 1. The phenotypic expression of this mutation is infantile seizures (often refractory to anti-epileptic medication), delay of development, and acquired microcephaly with subsequent mental retardation. Under most conditions, the brain is entirely dependent upon blood glucose for all its energy needs; however, ketone bodies can provide a source of energy that can enter the cell on its own transporter, which differs from the glucose transporter. With the transport of glucose blocked as it is in these patients, ketone bodies provide the only physiologically normal alternative nutrient for the brain. Administering a diet rich in ketone bodies can provide a way to maintain normal brain growth and development and reduce or eliminate seizures. Feeding high-fat diets, the normal procedure for the treatment of drug-resistant epilepsy, can lead to elevation of blood cholesterol with consequently accelerated atherosclerosis. Therefore, a high-fat diet cannot be continued past age 17. A diet high in ketone bodies cannot lead to increased cholesterol synthesis, because ketone bodies are not utilized by the liver (the source of cholesterol synthesis). High-ketone diet therapy may therefore become a practical method for lifelong treatment of these patients.

Leprechaunism and Rabson-Mendenhall Syndrome

Leprechaunism and Rabson-Mendenhall syndrome are rare syndromes that result from mutations in the gene for the insulin receptor, which leave it incapable of binding insulin. These mutations produce the most extreme form of insulin resistance, leading to persistent hyperglycemia and attendant pathology and retardation of growth. The current treatment consists of administration of increasing doses of insulin (up to several thousand units per day). This treatment, if producing a result at all, yields only a very partial result due to the absence of insulin binding by its receptor. Treatment with insulin-like growth factor, while potentially effective, is unavailable to these children. Survival into the teens is rare. Ketone bodies in physiological amounts have been shown to mimic the effects of insulin's stimulation of the PDH multienzyme complex. Ketone bodies can increase the Krebs TCA cycle metabolite contents, increase the energy of ATP, and enhance metabolic efficiency. A ketone-rich, low-carbohydrate diet might prove an effective treatment of these conditions, which are currently without effective therapy.

Lafora Body Disease

Lafora body disease is an autosomal recessive form of progressive myoclonic epilepsy resulting from a mutation on chromosome 6 in a region encoding a calcium-activated protein phosphatase. Lafora body disease is pathologically characterized by the deposition of polyglucan inclusion bodies in the skin, liver, and brain. Patients present with progressive myoclonic epilepsy, mild liver disease, rapid intellectual deterioration, and insulin resistance, usually without frank diabetes; death results within 10 years of the onset of clinical symptoms. Currently, there is no treatment other than the administration of a high-fat, ketogenic diet. However, because the patients are often in their teens at presentation, the use of the ketogenic diet is not desirable due to its long-term atherogenic potential. A diet high in ketone bodies may prove an effective palliative step in the treatment of these patients.

Fetal Alcohol Syndrome (FAS)

FAS is a set of specific birth defects caused by maternal alcohol consumption during pregnancy. Unlike most other birth defects, FAS has the potential to be entirely preventable, because its direct cause, maternal drinking, is presumed to be a controllable behavior.

Scientists have shown that exposure to alcohol at critical times during brain development can induce excessive cell death during normal programmed death (apoptosis) or trigger apoptosis at inappropriate times. The result is smaller or abnormal brain structures with fewer connections between brain cells. This type of damage translates into developmental delays and permanent cognitive and behavioral disabilities. Because normal cell death is triggered by a highly regulated biochemical pathway inside the cells, researchers have examined alcohol's effects on various steps in the pathway in sensitive cells. Evidence from several models and different neuronal cell populations showed that alcohol reduces the availability or effectiveness of regulatory molecules (neurotrophic factors) that promote cell growth and survival by inhibiting the cell death pathway. When certain sensitive neuronal cells were removed from the brain and grown in culture in the presence of alcohol, their survival rate was diminished. The survival rate was restored to control levels by the addition of specific neurotrophic factors. Current research continues to elucidate the exact mechanisms by which alcohol interacts with these growth factors. Furthermore, scientists are now testing whether alcohol's deleterious effects can be prevented in the living animal by treatments that restore the effectiveness of these regulatory factors.

Recent advances in FAS research have been related to this general theme of potential in vivo treatments for amelioration of alcohol's effects on factors that support cell survival. For the first time, a mammalian model (mouse) has demonstrated that enhanced endogenous expression of a neurotrophic factor (nerve growth factor [NGF]) can protect against ethanol-induced cell death in a sensitive neuronal cell population of the cerebellum. The results provide strong in vivo evidence that the neurotoxic effects of ethanol on this cell population are mediated by interactions with a neurotrophic factor that is known to regulate apoptosis.

Another recent discovery is that performance on a learning discrimination task is normal in animals exposed to ethanol prenatally when their diet is supplemented with choline shortly after birth. Choline is a nutrient that has multiple actions on prenatal and early postnatal brain development, including elevation of NGF. As expected, ethanol-exposed animals with no choline treatment performed much more poorly than non-exposed animals. Importantly, ethanol-exposed animals who received the choline treatment performed at a level equal to that of the non-exposed animals, with or without choline. The mechanisms by which choline enhances learning are unknown. However, the importance of choline in development has led to a recent recommendation by the Institute of Medicine for a minimum amount of choline in the diets of pregnant and lactating women.

During brain development, the neurotransmitter serotonin stimulates the release of S100, which promotes serotonergic neuron differentiation and growth of connective projections. Scientists had previously shown that alcohol reduces the level of serotonin during a critical period of development. New findings suggest that during ethanol exposure, insufficient serotonin levels diminish the ability of the serotonin receptor to release S100, thus causing further loss of neurons and glia. Treatment of the mother with serotonin agonists enhances the ability of the remaining receptor-containing cells to mediate S100 release.

N-methyl-D-aspartate (NMDA) receptors are critical for growth, proliferation, differentiation, migration, and programmed death of neurons in the developing brain. Recent research has resulted in the first report that alcohol's well-documented deleterious actions on the NMDA receptor may be mediated through selective inhibition of neurosteroids. The findings may explain the previously reported diminished behavioral response of alcohol-exposed rat pups to maternal separation-induced stress after treatment with an exogenous neurosteroid.

In an advance related to genetic influences on apoptosis in FAS, a series of chick strains expressing differential sensitivity to ethanol has provided major insights into the relationship between alcohol-induced apoptotic events and variability in expression of craniofacial dysmorphology, one of the landmarks of FAS. After exposure to ethanol during early embryogenesis, changes in facial morphology were correlated with severity of ethanol-induced apoptosis. Ethanol treatment resulted in multiple facial alterations that varied from strain to strain; however, the responses to ethanol were consistent and reproducible within strains. Thus, the genetic background modulated the ethanol response. The study demonstrates the power of using genetically distinct strains of animals with differential sensitivity to ethanol as tools to tease out the complex relationships between ethanol-induced molecular insults and manifestations of the FAS phenotype.

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

Ketone-Based Diet

Attempts are now being made to encourage the production of sufficient quantities of palatable ketone body esters, which can be used in an artificial diet for use in FRDA, GLUT1-deficient epilepsy, leprechaunism, Rabson-Mendenhall syndrome, and lafora body disease. Because it is estimated that patients may require 100 to 200 g per day of these ketones, industrial collaboration will be required. Attempts to obtain this collaboration are now under way. Trials of this therapy in selected cases of this type are being planned for when collaboration is obtained and animal toxicity tests performed.

Fetal Alcohol Syndrome (FAS)

More than 110 projects now contribute to the NIAAA FAS portfolio, many of them with a particular focus on minority health and health disparity issues. In addition, an ongoing RFA on DNA microarrays has recently garnered a number of FAS proposals. Many of the NIAAA's FAS-related projects and initiatives are funded through FY 2004. Funding has not yet been allocated for FY 2005 research.

Rare Disease-Specific Workshops, Symposia, and Meetings

A workshop seeking to identify candidate biomarkers of maternal alcohol use and/or fetal ethanol exposure that can be used to identify women at high risk of giving birth to a child with FAS is scheduled for June 2001. Because early diagnosis and intervention have been shown to improve developmental outcomes for many birth defects, a prenatal or neonatal screen would be desirable for patient counseling and identifying high-risk infants before or at birth. Approaches to be discussed include identifying metabolites, hormones, or proteins altered by ethanol and using DNA arrays to identify altered gene expression patterns. In addition, developmental stages and/or processes that would be likely targets for in utero intervention will be identified and potential in utero intervention strategies discussed. A research agenda to help focus efforts to advance this area of research will be developed.

In either the presence or the absence of diagnosable FAS, other significant medical and behavioral problems may arise from prenatal alcohol exposure and the resulting damage to the developing brain, spinal cord, and central nervous system. A conference to address the possible link observed between sudden infant death syndrome (SIDS) and drinking during pregnancy is planned for 2001. The conference will cover the scope of these health problems in specific American Indian/Alaskan Native communities, which exhibit a very high prevalence of maternal drinking during pregnancy. Goals are to define the research questions applicable to addressing the prenatal alcohol use/SIDS connection to design a research study using a collaborative multidisciplinary approach.

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Last Reviewed: May 15, 2003
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