Maple Syrup Urine Maple Syrup Urine DiseaseDisease

MSUDMSUD Maple Syrup Urine Disease Maple Syrup Urine Disease

is a genetic disease in which is a genetic disease in which the amino acids leucine, the amino acids leucine, isoleucine and valine cannot isoleucine and valine cannot be broken down by be broken down by branched-chain alpha-keto branched-chain alpha-keto acid dehydrogenase. acid dehydrogenase.

http://www.msud-support.org/overv.htmhttp://www.msud-support.org/overv.htm

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

General InformationGeneral Information Introns: 8Introns: 8 Size of mRNA: 1781 bpSize of mRNA: 1781 bp Size of Protein: 445 aaSize of Protein: 445 aa Location: 19q13.1-13.2Location: 19q13.1-13.2 Domains: 4Domains: 4

http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgihttp://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi

DomainsDomains E1_dh, Dehydrogenase E1 component E1_dh, Dehydrogenase E1 component Transketolase_N, Transketolase Transketolase_N, Transketolase AcoA, Pyruvate/2-oxoglutarate dehydrogenase AcoA, Pyruvate/2-oxoglutarate dehydrogenase

complex complex TktA, Transketolase TktA, Transketolase

http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgihttp://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi

Genes and ProteinGenes and Protein 4 Genes that could be possibly mutated:4 Genes that could be possibly mutated:

BCKDHA *BCKDHA * BCKDHBBCKDHB DBTDBT DLDDLD

Protein affectedProtein affected: branched-chain alpha-keto : branched-chain alpha-keto acid dehydrogenase (BCKD) acid dehydrogenase (BCKD)

StructureStructure

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

Types of MSUDTypes of MSUD Classical: little or no enzyme activity <2%Classical: little or no enzyme activity <2% Intermediate: more enzyme activity 3-8%Intermediate: more enzyme activity 3-8%

Can tolerate greater amount of leucineCan tolerate greater amount of leucine Intermittent: even more enzyme activity 8-Intermittent: even more enzyme activity 8-

15%15% Thiamine-responsive: thiamine to increase Thiamine-responsive: thiamine to increase

enzyme activityenzyme activity http://www.msud-support.org/overv.htmhttp://www.msud-support.org/overv.htm

MutationsMutations 4 mutations in the BCKDHA gene that can 4 mutations in the BCKDHA gene that can

result in MSUDresult in MSUD Classic: Tyrosine to Asparagine at aa 394Classic: Tyrosine to Asparagine at aa 394 Classic: 8bp deletion from nucleotide 887-894Classic: 8bp deletion from nucleotide 887-894 Intermediate: Glycine to Arginine at aa 245Intermediate: Glycine to Arginine at aa 245 Intermediate: Phenylalanine to Cysteine at aa 364Intermediate: Phenylalanine to Cysteine at aa 364 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608348http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608348

Results of Mutations in BCKDHAResults of Mutations in BCKDHA Cannot breakdown amino acids leucine, Cannot breakdown amino acids leucine,

isoleucine, and valineisoleucine, and valine Build up to toxic levelsBuild up to toxic levels Nervous system degenerationNervous system degeneration Can lead to encephalopathyCan lead to encephalopathy

About MSUDAbout MSUD Recessive genetic disease – meaning that both Recessive genetic disease – meaning that both

parents must carry a mutation for the disease.parents must carry a mutation for the disease. Each person has two genes that code for Each person has two genes that code for

enzyme activity. If only one gene is mutated, enzyme activity. If only one gene is mutated, then the person is just a carrier of MSUD.then the person is just a carrier of MSUD.

If parents are both carriers,If parents are both carriers, 1 in 4 chance that baby has MSUD1 in 4 chance that baby has MSUD 2 in 4 chance that baby will be carrier2 in 4 chance that baby will be carrier 1 in 4 chance that baby will not have mutation1 in 4 chance that baby will not have mutation

Characteristic SymptomsCharacteristic Symptoms Symptoms occur in newborns within the first four to seven Symptoms occur in newborns within the first four to seven

days of birth.days of birth. Infants with this disease have poor feeding habits.Infants with this disease have poor feeding habits. VomitingVomiting Infants show poor weight gain due to improper feeding.Infants show poor weight gain due to improper feeding. Increased lethargy – deep sleep, sluggish Increased lethargy – deep sleep, sluggish Sweet smell to urine is the major characteristic symptom for Sweet smell to urine is the major characteristic symptom for

this disease.this disease. Muscle spasms and seizuresMuscle spasms and seizures Could lead to death if not treated, but is manageable.Could lead to death if not treated, but is manageable. http://rarediseases.about.com/od/rarediseases1/a/062004.htmhttp://rarediseases.about.com/od/rarediseases1/a/062004.htm

Diagnosis/ ScreeningDiagnosis/ Screening Mandatory State Screening ProgramsMandatory State Screening Programs

Some states don’t include this test in newborn Some states don’t include this test in newborn screeningsscreenings

Some infants are only tested after symptoms occurSome infants are only tested after symptoms occur Blood Tests to look at amino acid levelsBlood Tests to look at amino acid levels

TreatmentTreatment Restrict their diet to foods without Restrict their diet to foods without

leucine, isoleucine, and valineleucine, isoleucine, and valine Must continue throughout life or Must continue throughout life or

symptoms will reoccursymptoms will reoccur During times of metabolic During times of metabolic

decompensation, patients can be decompensation, patients can be treated with intra-venous treated with intra-venous hyperalimentation.hyperalimentation.

Supplements can be taken so that Supplements can be taken so that patients receive those essential patients receive those essential amino acids.amino acids.

HypothesisHypothesis MSUD is only a mammalian disease.MSUD is only a mammalian disease. Based on the principle that urination in Based on the principle that urination in

mammals is different than many other species.mammals is different than many other species.

Evidence Against HypothesisEvidence Against Hypothesis Some of the organisms that showed up in the Some of the organisms that showed up in the

BLAST search:BLAST search: Saccharomyces cerevisiae (yeast) ... 129 (yeast) ... 129 3 hits

[[ascomycetes] ] Danio rerio (zebra fish) --- 680 (zebra fish) --- 680 3 hits [ [

bony fishes] ] Gallus gallus (chickens) --- 714 (chickens) --- 714 1 hit [birds] [birds] http://www.ncbi.nih.gov/BLAST/Blast.cgi?CMD=Get&RID=1145026779-9124-http://www.ncbi.nih.gov/BLAST/Blast.cgi?CMD=Get&RID=1145026779-9124-

17383991185.BLASTQ4&FORMAT_OBJECT=TaxBlast&NCBI_GI=on&DESCRIPTIONS17383991185.BLASTQ4&FORMAT_OBJECT=TaxBlast&NCBI_GI=on&DESCRIPTIONS=500&ALIGNMENTS=250&FORMAT_BLOCK_ON_RESPAGE=Top&MASK_COLOR=1=500&ALIGNMENTS=250&FORMAT_BLOCK_ON_RESPAGE=Top&MASK_COLOR=1&MASK_CHAR=2&MASK_CHAR=2

Another HypothesisAnother Hypothesis While investigating our first hypothesis, we While investigating our first hypothesis, we

discovered that many organisms must have a discovered that many organisms must have a mechanism to metabolize potentially harmful mechanism to metabolize potentially harmful amino acids such as isoleucine, leucine and amino acids such as isoleucine, leucine and valine.valine.

Conserved DomainsConserved Domains These two domains were shown to be These two domains were shown to be

conserved over the whole taxa.conserved over the whole taxa. Dehydrogenase E1 componentDehydrogenase E1 component Pyruvate/2-oxoglutarate dehydrogenase Pyruvate/2-oxoglutarate dehydrogenase

complexcomplex

ResultsResults Taxonomy ReportTaxonomy Report Conclusion: While amino acids are essential Conclusion: While amino acids are essential

building blocks for proteins, buildup of these building blocks for proteins, buildup of these amino acids can be toxic. Every living amino acids can be toxic. Every living organism must have a mechanism to organism must have a mechanism to metabolize these amino acids.metabolize these amino acids.