Cannot have any clinical or laboratory abnormality of Grade 3 or greater according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity).May not have an active infection (viral or bacterial) or any condition which may exacerbate their MSUD causing metabolic decompensation.May not have used sodium phenylbutyrate within 30 days of Visit 1.Abstinence is an acceptable form of birth control, though appropriate contraception must be used if the subject becomes sexually active. Appropriate contraceptive methods include hormonal contraceptives (oral, injected, implanted, or transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier methods. All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception throughout the study.Negative pregnancy test for all females of childbearing potential.Must be capable of completing study procedures, including taking oral or G- tube medication.Signed informed consent by subject and/or subject's legally acceptable representative.Participants must have a history of compliance to diet and treatment. Must have a diagnosis of maple syrup urine disease (MSUD) confirmed by the presence of plasma alloisoleucine (>5 micromol/L) and/or genetic testing showing mutations in both alleles of any subunit of BCKDHA (E1alpha subunit gene, MSUD type 1A), BCKDHB (E1beta subunit gene, MSUD type 1B), or DBT (E2 subunit gene, MSUD type 2).Must be 3 years or older at enrollment.A treatment option that could prevent or decrease the accumulation of BCAA and BCKA during states of catabolism induced by fasting or intercurrent illnesses, and thereby minimize or prevent the neurologic sequelae and loss of human potential that result, would greatly benefit society. If study findings show sodium phenylbutyrate lowers BCAA and BCKA levels in these patients, it may prove to be an effective adjunct treatment for these patients. Subjects will be randomly assigned to receive either sodium phenylbutyrate (PB) or placebo for 2 weeks, and then crossed over to receive the other treatment for 2 weeks. This will be a single-site, randomized, active-controlled, double-blind, cross-over study designed to enroll subjects with MSUD. This led us to hypothesize that NaPBA has effects on BCAA metabolism. In our extensive studies with UCDs, we noted that patients on therapy with NaPBA had decreased plasma levels of BCAA. Sodium phenylbutyrate is has been used to treat patients with urea cycle disorders (UCDs). Our study seeks to investigate the potential small molecule inhibition of the kinase that regulates BCKDC by applying a novel activity of sodium phenylbutyrate (NaPBA), in MSUD. However, mental and social impairment are still present in the majority of these patients in spite of dietary management. Current treatment is based on dietary manipulations with protein restriction and a synthetic formula with reduced BCAA content. The disorder typically manifests with potentially lethal episodes of intoxication presenting with acute neurological deterioration, feeding problems, weight loss, and a maple syrup odor to the urine. Maple syrup urine disease is a severe inborn error of amino acid metabolism caused by deficiency of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) resulting in the accumulation of branched-chain amino acids (BCAA) (isoleucine, leucine, and valine) and their corresponding branched-chain alpha-ketoacids (BCKA) in tissues and plasma. Condition or diseaseĭrug: Phenylbutyrate Drug: Placebo powder The results will be compared once the study is over. They will be given the same amount of powder and undergo the same laboratory testing during both of the two-week treatment periods. Subjects with MSUD will take phenylbutyrate (NaPBA) in powder form for a two-week treatment period and powder placebo, a substance with no effect on the body, for a two-week treatment period. The investigators hope is that through this research the investigators will be better able to treat these patients. Through this study, the investigators will try to find out how well phenylbutyrate (NaPBA), also known by name brand "Buphenyl-TM", decreases BCAA and branched chain keto chain acids in the blood of patients with MSUD. The investigators have learned in past research that the drug phenylbutyrate can decrease the amounts of branched chain amino acids and their byproducts in the bloodstreams of healthy volunteer patients and also patients with certain disorders of protein breakdown including maple syrup urine disease. Why Should I Register and Submit Results?.
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