A N N E L E H M A N 8 / 2 9 / 1 3

MAPLE SYRUP URINE DISEASE

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

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

DISEASE ETIOLOGY

• Remember biochemistry….• Branched-chain α-

ketoacid dehydrogenase (BCKDH)

• Build-up of Valine, Isoleucine, Leucine, and respective keto-acids

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

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

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

HOW MIGHT A MSUD PT LOOK?

HOW MIGHT A MSUD PT LOOK?… ON THE INSIDE.

16 days old; no prior treatment

68 days old; cont’d treatment

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

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

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

PEDIGREE OF VARIOUS FAMILIES

• E1αsubunit of BCKDH

• Each family features two heterozygous parents• Risk: 25-50-25%

pattern

BASIC PRINCIPLES

• Autosomal Recessive

• Founder Effect

• Locus Heterogeneity

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.