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Clinical Genetics and Metabolism
Research
The Section of Clinical Genetics and Metabolism pursues clinical and basic research on numerous inherited conditions. Research involves the identification of the genetic basis of inherited disorders, both rare and common. In several rare genetic diseases, current research delineates the spectrum of mutations and how they can predict outcome. Translational research efforts are bringing these new findings to clinical care through our service laboratories. Mutagenesis studies review the impact of environmental variables on producing genetic changes. Several of our Section’s large studies involve gene discovery in complex diseases, including various autoimmune diseases and cleft lip and palate, one of the most common birth defects. We have organized VitGene, an international consortium of 38 investigators in 20 countries, and are now performing a very large genomewide association study of generalized vitiligo (one of the most common autoimmune diseases), which is studying autoimmune thyroid disease in development. We have also carried out an extensive examination of the developmental genetics of facial development in the mouse, with the long-term goal of identifying genes responsible for human facial development that may play important roles in cleft lip and palate.
For select genetic conditions, we are examining the mechanisms by which genetic changes lead to clinical symptoms. This research involves basic scientific concepts, such as mechanisms of neuronal development, and opens the possibility for new therapeutic avenues, which we can then further pursue in translational clinical studies. Efforts are under way to explore conditions as varied as glutaric aciduria type I, homosytinuria due to cystathionine beta-synthase deficiency, nonketotic hyperglycinemia, mitochondrial liver disorders, and Down syndrome. We are performing treatment studies that include the use of stem cell treatment for genetic conditions including Down syndrome.
Clinical research in our Section includes studies to describe the clinical spectrum of disorders, such as skeletal dysplasias, and studies on comprehensive care, including new treatments for neurofibromatosis, lysosomal storage disorders, and phenylketonuria. An extensive regional study on the long-term outcome of patients identified through newborn screening is coordinated by our Section.
The Section is also involved in educational research studies on the effectiveness of education in biochemical and clinical genetics for groups of professionals.
The Intellectual and Developmental Disabilities Research Center aids investigators in our Section in research into mental retardation and related conditions. Major areas of research include:
- Neurodevelopmental disorders, in particular neurofibromatosis, tuberous sclerosis, early seizure disorders, autism, mental retardation, Down syndrome, glutaric aciduria type I
- Syndromes of malformation, specifically skeletal dysplasia, VATER, pigmentation disorders, microdeletion-duplication disorders, cleft lip and palate, recombinant (8) syndrome
- Energy and metabolism disorders including homocystinuria, proprionic and methylmalonic acidurias, phenylketonuria, lysosomal disorders, trimethylaminuria, fatty acid oxidation disorders, multiple acyl-CoA dehydrogenase deficiency, mitochondrial disorders, glutaric aciduria type I, disorders of glycine metabolism, pyridoxine dependent seizures
- Multifactorial and multigene disorders, including autoimmune disorders, pigmentation disorders, genetic ophthalmologic disorders
Faculty Research Interests
Dr. Gary Bellus is interested in the genetic etiology of skeletal dysplasias and genodermatoses as well as in conducting clinical trials in the treatment of plexiform neurofibromas in patients with neurofibromatosis, type 1. Laurie Bernstein, MS, RD, FADA’s research involves the long-term dietary management of metabolic disorders. Dr. Kimberly Bjugstad's research is focused on treating Parkinson’s disease and Down syndrome using cell replacement or enhancement strategies. Dr. Pei-Wen Chiang is combining DNA diagnosis with research on genetic diseases including pigmentation diseases, eye diseases, autism, mental retardation, and several other rare genetic diseases. Dr. Ellen Elias is a leader in the study of the physiological effects of the cholesterol deficiency seen in the genetic disorder Smith-Lemli-Opitz Syndrome (SLOS). Dr. Paul Fennessey's work involves the application of stable isotopes and mass spectrometry to clinical questions, with a focus on nutrient metabolism and uptake in the developing fetus and in the newborn. Cynthia Freehauf, RN, MS, CGC's research interests are focused on clinical case studies, clinical care issues in PKU, and translational research in homocystinuria due to cystathionine beta synthase deficiency. Dr. Frank Frerman researches the structure and mechanism of mitochondrial electron transfer proteins and the inherited diseases that affect these proteins. Dr. Renata Gallagher's research interests are the optimal diagnosis and management of children with inborn errors of metabolism, particularly urea cycle disorders. Dr. Katheleen Gardiner’s work focuses on the identification of targets for therapeutic intervention in Down syndrome learning/memory deficits using molecular, behavioral, and pharmacological analysis of mouse models combined with computational analysis. Dr. Stephen Goodman studies the inborn errors of amino, organic and fatty acid oxidation, with a particular interest in the pathogenesis of striatal degeneration in glutaric academia type 1. Dr. Hua Jiang’s research focuses on the etiopathology of non-alcoholic steatohepatitis (NASH) and epigenetic mechanism in mental retardation associated with cystathionine beta synthase-deficient homocystinuria (CBSDH) with a view towards the rational design of novel treatments. Dr. Ying Jin’s research focuses on the genetics of generalized vitiligo and associated autoimmune and autoinflammatory diseases and the effects of iodine on autoimmune thyroid disease. Dr. Jan Kraus is interested in inborn errors of metabolism, homocystinuria, and propionic acidemia in particular. Dr. Kenneth Maclean's research group uses a range of molecular, biochemical, and behavioral techniques in conjunction with transgenic and knockout mouse models to investigate the pathological mechanisms that underlie the clinical sequelae of cystathionine beta-synthase deficient homocystinuria, Down syndrome, and Fragile X syndrome. Dr. David Manchester's research interests include mutagenesis and genotype-phenotype relationships. Dr. Karl Pfenninger's laboratory studies the fundamental processes of brain development as well as disease mechanisms underlying neurodevelopmental disorders. Of particular interest are the control of neuronal network formation and plasticity and the perturbation of these processes in Down syndrome and cystathionine beta-synthase deficiency. Dr. Gunter Scharer’s research focus is on the metabolic disorders associated with neonatal epilepsy (glycine encephalopathy and pyridoxine responsive seizures). His secondary research interest is chromosomal imbalances (microdeletions/duplications) causing complex birth defects and/or intellectual and developmental disabilities. His clinical focus is genetic disorders associated with abnormal growth. Dr. John Sladek, Jr. is interested in the analysis of brain repair mechanisms utilizing cell replacement as a potential therapy for the progressive motor disabilities associated with Parkinson's disease and Down syndrome. His recent work with human embryonic stem cells suggests that host brain cells can be protected from further damage by growth factors produced by newly implanted stem cells. Dr. Elaine Spector is interested in transitioning research findings in inherited disorders such as glutaric acidemia and non-ketotic hyperglycinemia into clinical testing for the disorder. Dr. Richard Spritz investigates the genetic and molecular basis of vitiligo and associated autoimmune diseases, albinism and diseases of melanocyte biogenesis, and cleft lip and palate. Dr. Johan Van Hove’s research involves the development of new therapies for genetic metabolic diseases, particularly for diseases of mitochondrial metabolism and for neurometabolic diseases such as nonketotic hyperglycinemia.
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