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Maple syrup urine disease

Maple syrup urine disease. Anne lehman 8/29/13 . 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

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Maple syrup urine disease

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  1. Maple syrup urine disease Anne lehman 8/29/13

  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 1st 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 • 1st 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 treatment 68 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 • E1αsubunit 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.

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