Melanie Gillingham, PhD
3181 SW Sam Jackson Park Road
Mail Code: L103
Portland, OR 97239
Office: 503 494-1682
Fax: 503 494-6886
During periods of moderate exercise, fasting or illness, the oxidation of fatty acids provides essential energy for the heart and muscle. Inherited disorders in the ability to oxidize fatty acids can present with severe hypoglycemia (low blood glucose) and cardiomyopathy in infancy or exercise intolerance and rhabdomyolysis in adolescents and adults. Over 22 different disorders of the fatty acid oxidation pathway have been identified. Our laboratory investigates the metabolic consequences of genetic disorders in the fatty acid oxidation pathway including inherited deficiency of very-long chain acyl CoA dehydrogenase (VLCAD), long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD), carnitine palmitoyltransferase 2 (CPT2), and carnitine palmitoyltransferase 1A (CPT1A). The goal of our research is to develop novel treatments for these rare disorders of fatty acid metabolism.
The treatment for long-chain fatty acid oxidation disorders has been primarily with a modified diet including avoiding fasting, and frequent high carbohydrate meals. We have been investigating alternative nutritional approaches including using medium-chain triglyceride (MCT) supplements prior to exercise to improve exercise tolerance, and high protein, low-fat diets to increase lean body mass and improve metabolic control.
We are currently enrolling subjects in a study investigating the effects of triheptanoin or C7, an odd carbon medium-chain fatty acid supplement, on myopathy and muscle pain in long-chain fatty acid oxidation disorders. More information about our clinical trial can be found here: http://clinicaltrials.gov/ct2/show/NCT01379625
Fatty Acid Oxidation and Retina:
One of the complications of LCHAD deficiency is vision loss because of a degeneration of the retina, a part of the eye that is essential for us to see. This degeneration of the retina is called retinopathy and the cause of retinopathy in children with LCHAD is not known. We are currently conducting a study in cells to investigate the cause of LCHAD retinopathy
Our previous study found a correlation between blood levels of an LCHAD metabolite, long chain 3-hydroxyacylcarnitines and progression of retinopathy. Our hypothesis is that these metabolites are toxic to the retina. We have not been able to test this hypothesis because an LCHADD animal or LCHADD retinal cell culture model does not exist. Recent advances in science have made it possible to directly reprogram cultured skin cells or fibroblasts into stem cells; cells that have the potential to become any type of cell in the body. Fibroblasts are frozen from skin biopsies of patients obtained to diagnosis LCHADD. If patient fibroblasts were reprogrammed, the stem cells would have LCHAD deficiency like the original fibroblast from which they were derived. The LCHADD stem cells can then be programmed to become retina cells.
In this project we propose to generate stem cells from the cultured skin cells of patients with LCHADD. We will then program the LCHAD deficient stem cells to become retinal cells to create an LCHAD deficient retinal cell. We hypothesize that the LCHADD retinal cells will accumulate long-chain 3-hydroxyacylcarnitines. The accumulation of these metabolites will result in cell death. If our hypothesis is true, we will have evidence for the cause of retinopathy of LCHAD deficiency and we can develop potential treatments. Our goal is to develop new treatment options for LCHAD retinopathy.
Support Fatty Acid Oxidation and Retina Research Today
Donations can also be made by check; please make check(s) payable to: OHSU Foundation Account 23711 Genetics Research
Mail to:OHSU Foundation Mail Stop 45PO Box 4000Portland, OR 97208-9852
Contact the OHSU Foundation for questions about giving: www.ohsufoundation.org
(Phone) 800 462-6608
Gillingham MB, Purnell JQ, Jordan J, Stadler D, Haqq AM, Harding CO. Effects of higher dietary protein intake on energy balance and metabolic control in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Molecular Genetics and Metabolism, 90:64-69, 2007.
Gillingham MB, Scott B, Elliott D, Harding CO. Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Molecular Genetics and Metabolism 89:58-63, 2006.
Gillingham, MB, Weleber RG, Neuringer M, Connor WE, Mills M, Van calcar S, Verhoeve J, Wolff J, Harding CO. Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) and trifunctional protein (TFP) deficiency. Molecular Genetics and Metabolism 86:124-133, 2005.
Gillingham MB, Hirschfeld M, Lowe S, Matern D, Shoemaker J, Lambert WE, Koeller DM. Impaired fasting tolerance among Alaska native children with a common carnitine palmitoyltransferase 1A sequence variant. Molecular genetics and metabolism. Nov 2011;104(3):261-264. 10.1016/j.ymgme.2011.06.017
Behrend AM, Harding CO, Shoemaker JD, Matern D, Sahn DJ, Elliot DL, Gillingham MB. Substrate oxidation and cardiac performance during exercise in disorders of long chain fatty acid oxidation. Molecular Genetics and Metabolism. Jan 2012;105(1):110-115. 10.1016/j.ymgme.2011.09.030
Fletcher AL, Pennesi ME, Harding CO, Weleber RG, Gillingham, MB. Observations regarding retinopathy in mitochondrial trifunctional protein deficiencies. Molecular Genetics and Metabolism In press doi.org/10.1016/j.ymgme.2012.02.015