1. ANNE LEHMAN 8/29/13 MAPLE SYRUP URINE DISEASE

2. BACKGROUND Autosomal recessive metabolic disorder Mutation in genes encoding Branched-chain α- ketoacid dehydrogenase (BCKDH) 4 different genes BCKDHA, BCKDHB, DBD, DLT Toxic accumulation of branched chain amino acids Toxicity in brain leading to mental retardation, death if untreated Urine smells sweet due to excretion of accumulated metabolic products

3. PHENOTYPE AND NATURE HISTORY Increased incidence in Old Order Mennonite, Amish, Ashkenazi Jew Populations History of disease: First described in 1954 60’s were a time of booming research Testing possible- assay for enzyme levels in the newborn

4. DISEASE ETIOLOGY Remember biochemistry…. Branched-chain α- ketoacid dehydrogenase (BCKDH) Build-up of Valine, Isoleucine, Leucine, and respective keto- acids

5. PATHOGENESIS “Mechanisms for toxic effects of increased branched-chain amino acids and keto acids remain largely unelucidated.” -van der Knapp & Valk, 2005 General problems: neurotransmission, energy depletion, myelin damage

6. PHENOTYPIC FEATURES Variable severity depending on effectiveness (or lack thereof) BCKDH Classical MSUD: Presentation in 1 st week Untreated: cerebral edema, coma, death within 1 month With treatment: possible mental retardation, metabolic derrangement during future illnesses Intermediate MSUD Neonatal period free of acute severe illness 1 st year of life: poor mental development Intermittent MSUD Normal early development “Stress” triggers metabolic decompensation Vaccinations, infection, sudden increase in protein intake Thiamine- responsive MSUD Mild, similar to intermediate Very responsive to treatment AND thiamine supplement

7. HISTORY AND PHYSICAL FINDINGS How might a patient present? (classical phenotype) lethargy feeding problems alternating hyper/hypotonia convulsions bulging fontanel irregular respiration apnea possible MS odor in urine

8. HOW MIGHT A MSUD PT LOOK?

9. HOW MIGHT A MSUD PT LOOK? … ON THE INSIDE. 16 days old; no prior treatment68 days old; cont’d treatment

10. METHODS OF DIAGNOSIS Past 1960’s: Column chromatography to quantify levels of a.a.’s Current Standard newborn screening in IN Via tandem mass spectrometry Looking for abnormal Leu/Ile levels If family history of disease DNA testing (PCR) within 24 hrs birth Prenatal diagnosis possible

11. TREATMENT AND MANAGEMENT Life-long dietary restriction Protein restriction Minimal B.C. a.a. intake necessary for life function B.C. a.a.-free formula for babies Metabolic crisis management Liver transplant

12. RISK OF INHERITANCE Risk of inheritance from parents Standard autosomal recessive If both parents carriers, 25% chance of being affected Risk of inheritance of phenotype Worldwide: 1: 225,000 live births Ashkenazi Jews: 1:26,000 live births Old Order Mennonites: 1:150 live births

13. PEDIGREE OF VARIOUS FAMILIES E 1 αsubunit of BCKDH Each family features two heterozygous parents Risk: 25-50-25% pattern

14. BASIC PRINCIPLES Autosomal Recessive Founder Effect Locus Heterogeneity

15. REFERENCES Allen, R. (1993). A brief history of Maple Syrup Urine Disease (MSUD). Retrieved from http://www.msud-support.org/index.php?option=com_content&view=article&id=41:a-brief- history-of-maple-syrup-urine-disease-msud&catid=13:volume-11-2&Itemid=5 Carleton, S., Peck, D., Grasela, J., Dietiker, K., & Philip, C. (2010). DNA Carrier Testing and Newborn Screening for Maple Syrup Urine Disease in Old Order Mennonite Communities. Genetic Testing and Molecular Biomarkers, 14(2), 205-208. DOI: 10.1089/gtmb.2009.01.07 Indiana State Department of Health. (2012). Newborn Screenings: Heelstick. Retrieved from: http://www.in.gov/isdh/20360.htm Lin, Y., et. al. (2012). Serial MR Images and MRS Following Treatment in a Newborn with Maple Syrup Urine Disease. Journal of Radiological Science, 37, 133-138. http://www.rsroc.org.tw/db/Jrs/article/V37/N3/370307.pdf Mitsubuchi, H., et. al. (1992). Gene Analysis of Mennonite Maple Syrup Urine Disease Kindred Using Primer-Specific Restriction Map Modification. Journal of Inherited Metabolic Disorders, 15, 181-187. Online Mendelian Inheritance in Man, OMIM ®. Johns Hopkins University, Baltimore, MD. MIM Number: {608348, 248611, 248610, 238221}: {5/23/2012}:. World Wide Web URL: http://omim.org/ Van der Knapp, M., & Valk, J. (2005). Magnetic Resonance of Myelination and Myelin Disorders. Heidelberg, Germany: Springer.