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Research Summary: Vivian E. Shih, M.D.

INHERITED METABOLIC DISORDERS IN HUMAN CEREBRAL DISEASE

The research interests of our laboratory are studies of the molecular, biochemical, clinical, and pathological aspects of human hereditary metabolic disorders of amino acids, organic acids, fatty acids, and related compounds. These disorders cause mental retardation and other neurological and metabolic complications, and often are amenable to early treatment. Some of the various projects underway are described below:

Fumarase deficiency is a very rare metabolic disorder causing severe neurological disease and often death in early childhood. We are currently characterizing the enzyme abnormalities and performing molecular analysis of the fumarase gene in a series of patients of different ethnic backgrounds. We have reported the first mutations to be identified in this disorder — a transition mutation and an inframe 3 bp insertion.

Homocystinuria due to cystathionine ß-synthase (CBS) deficiency is a multisystem disease and the clinical features include mental retardation, dislocated optical lenses, vascular occlusions, and arteriosclerosis-like pathology. Our analysis of the molecular basis of CBS deficiency has revealed that there is a common transition mutation present in 50% of the alleles in patients of Celtic ancestry who have the pyridoxine nonresponsive form of the disorder. A different gene mutation is prevalent in patient with the pyridoxine responsive form of CBS deficiency. We are establishing a database of the molecular pathology in CBS deficiency that may be useful in providing genetic confirmation for reports suggesting that mild homocystinemia is both a risk factor for arteriosclerosis and is more common in heterozygotes for CBS deficiency. A long-term treatment trial with an experimental medication is in process to assess its effects on the biochemical status of patients and its ability to prevent some of the clinical complications of homocystinuria.

Also under investigation are other projects which focus on various aspects of urea cycle disorders, the hyperornithinemia-hyperammonemia homocitrullinuria (HHH) syndrome, maple syrup urine disease, and maternal and child health in women with inborn errors of metabolism. We have ongoing studies of the long-term effects of prospective treatments for patients with inborn errors who were detected by routine newborn screening.

Selected Recent Publications:

Fumarase deficiency caused by homozygous P131R mutation and paternal partial isodisomy of chromosome 1. Am J Med Genet A. 2006 Mar 30

Fetal fatty acid oxidation defects and maternal liver disease in pregnancy. Obstet Gynecol. 2006 107:115-20.

Ornithine aminotransferase deficiency: diagnostic difficulties in neonatal presentation. J Inherit Metab Dis. 2005;28:673-9.

Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature. Pediatrics. 2005 116:757-66.

Successful long-term treatment of hepatic carnitine palmitoyltransferase I deficiency and a novel mutation. J Inherit Metab Dis. 2004;27:679-84.

Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency. Neurology 2003;60:275-9.

Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema. J Pediatr. 2003 142:349-52.

Reproductive fitness in maternal homocystinuria due to cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2002;25:299-314.

Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program. Clin Chem. 2001;47:1945-55.

Cloning and characterization of Putative Human D-2-Hydroxyacid Dehydrogenase in Chromosome 9q. Biochem and Biophys Res Commun, 2000;268:298-301.