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Maple Syrup Urine Disease

Maple Syrup Urine Disease. MSUD. Maple Syrup Urine Disease is a genetic disease in which the amino acids leucine, isoleucine and valine cannot be broken down by branched-chain alpha-keto acid dehydrogenase. http://www.msud-support.org/overv.htm.

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Maple Syrup Urine Disease

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  1. Maple Syrup Urine Disease

  2. MSUD • Maple Syrup Urine Disease is a genetic disease in which the amino acids leucine, isoleucine and valine cannot be broken down by branched-chain alpha-keto acid dehydrogenase. • http://www.msud-support.org/overv.htm

  3. http://www.newbornscreening.info/tools/GraphicsLib/MSUD.jpg

  4. General Information • Introns: 8 • Size of mRNA: 1781 bp • Size of Protein: 445 aa • Location: 19q13.1-13.2 • Domains: 4 http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi

  5. Domains • E1_dh, Dehydrogenase E1 component • Transketolase_N, Transketolase • AcoA, Pyruvate/2-oxoglutarate dehydrogenase complex • TktA, Transketolase http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi

  6. Genes and Protein • 4 Genes that could be possibly mutated: • BCKDHA * • BCKDHB • DBT • DLD • Protein affected: branched-chain alpha-keto acid dehydrogenase (BCKD)

  7. Structure • http://ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?db=t&form=6&dopt=s&uid=12936

  8. Types of MSUD • Classical: little or no enzyme activity <2% • Intermediate: more enzyme activity 3-8% • Can tolerate greater amount of leucine • Intermittent: even more enzyme activity 8-15% • Thiamine-responsive: thiamine to increase enzyme activity • http://www.msud-support.org/overv.htm

  9. Mutations • 4 mutations in the BCKDHA gene that can result in MSUD • Classic: Tyrosine to Asparagine at aa 394 • Classic: 8bp deletion from nucleotide 887-894 • Intermediate: Glycine to Arginine at aa 245 • Intermediate: Phenylalanine to Cysteine at aa 364 • http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608348

  10. Results of Mutations in BCKDHA • Cannot breakdown amino acids leucine, isoleucine, and valine • Build up to toxic levels • Nervous system degeneration • Can lead to encephalopathy

  11. About MSUD • Recessive genetic disease – meaning that both parents must carry a mutation for the disease. • Each person has two genes that code for enzyme activity. If only one gene is mutated, then the person is just a carrier of MSUD. • If parents are both carriers, • 1 in 4 chance that baby has MSUD • 2 in 4 chance that baby will be carrier • 1 in 4 chance that baby will not have mutation

  12. Characteristic Symptoms • Symptoms occur in newborns within the first four to seven days of birth. • Infants with this disease have poor feeding habits. • Vomiting • Infants show poor weight gain due to improper feeding. • Increased lethargy – deep sleep, sluggish • Sweet smell to urine is the major characteristic symptom for this disease. • Muscle spasms and seizures • Could lead to death if not treated, but is manageable. • http://rarediseases.about.com/od/rarediseases1/a/062004.htm

  13. Diagnosis/ Screening • Mandatory State Screening Programs • Some states don’t include this test in newborn screenings • Some infants are only tested after symptoms occur • Blood Tests to look at amino acid levels

  14. Treatment • Restrict their diet to foods without leucine, isoleucine, and valine • Must continue throughout life or symptoms will reoccur • During times of metabolic decompensation, patients can be treated with intra-venous hyperalimentation. • Supplements can be taken so that patients receive those essential amino acids.

  15. Hypothesis • MSUD is only a mammalian disease. • Based on the principle that urination in mammals is different than many other species.

  16. Evidence Against Hypothesis • Some of the organisms that showed up in the BLAST search: • Saccharomyces cerevisiae (yeast) ... 129 3 hits [ascomycetes] • Danio rerio (zebra fish) --- 680 3 hits [bony fishes] • Gallus gallus (chickens) --- 714 1 hit [birds] • http://www.ncbi.nih.gov/BLAST/Blast.cgi?CMD=Get&RID=1145026779-9124-17383991185.BLASTQ4&FORMAT_OBJECT=TaxBlast&NCBI_GI=on&DESCRIPTIONS=500&ALIGNMENTS=250&FORMAT_BLOCK_ON_RESPAGE=Top&MASK_COLOR=1&MASK_CHAR=2

  17. Another Hypothesis • While investigating our first hypothesis, we discovered that many organisms must have a mechanism to metabolize potentially harmful amino acids such as isoleucine, leucine and valine.

  18. Conserved Domains • These two domains were shown to be conserved over the whole taxa. • Dehydrogenase E1 component • Pyruvate/2-oxoglutarate dehydrogenase complex

  19. Results • Taxonomy Report • Conclusion: While amino acids are essential building blocks for proteins, buildup of these amino acids can be toxic. Every living organism must have a mechanism to metabolize these amino acids.

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