Adipose Organ Transplant for Treatment of Maple Syrup Urine Disease (MSUD)
Open Access
- Author:
- Zimmerman, Heather Ann
- Graduate Program:
- Laboratory Animal Medicine
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- None
- Committee Members:
- Christopher J Lynch, Thesis Advisor/Co-Advisor
- Keywords:
- PP2Cm
BCATm
MSUD
maple syrup urine disease
surgery
adipose tissue transfer
mouse model
intermittent MSUD
classic MSUD - Abstract:
- Maple syrup urine disease (MSUD) is an inborn error of metabolism where affected individuals cannot oxidize the branched-chain amino acids (BCAA) – leucine, isoleucine, and valine. The name of the disease is derived from the distinctive odor of the urine, often described as a “burnt sugar” smell. If left untreated, the disease can lead to seizures, coma, and early death usually before 3 months of age. An estimated 1 in 185,000 infants are affected worldwide, although the incidence is much higher in the Old Order Mennonite population – approximately 1 in 176. Management of any of the five clinical manifestations of MSUD involves a strict diet devoid of BCAA. Several reports in the literature detailing orthotopic liver transplants in children and adults have reported success in controlling plasma BCAA levels to the level of patients with a very mild variant of MSUD, despite non-restrictive diets. However, liver transplantation is a major operative procedure that carries both an elevated surgical risk and a prohibitive financial cost. Recent studies have suggested that adipose tissue has a previously unappreciated high capacity for BCAA metabolism and is already used extensively in reconstructive surgery. Our hypothesis is transplantation of adipose tissue from a wild type mouse into mouse models of MSUD will reduce plasma BCAA levels to that of an unaffected animal. Male and female knockout PP2Cm mice, a model of intermittent MSUD, received either wild type or adipose tissue from affected littermates. Male and female BCATm mice, a mutant model of MSUD, received wild type fat or underwent a sham surgery. Mice were challenged with a variety of diets – BCAA-free, modified BCAA-containing, 18% protein, and 50% protein – and plasma BCAA levels measured. Although circulating plasma BCAA levels were not reduced following abdominal transplant of adipose tissue in PP2Cm mice, they were reduced with subcutaneous transplantation in BCATm mice. Therefore, subcutaneous adipose tissue transplantation may have merit in the treatment of MSUD.