Transcript Maple Syrup Urine Disease

Maple Syrup Urine
Disease
MSUD
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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.
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http://www.msud-support.org/overv.htm
http://www.newbornscreening.info/tools/GraphicsLib/MSUD.jpg
General Information
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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
Domains
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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
Genes and Protein
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4 Genes that could be possibly mutated:
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BCKDHA *
BCKDHB
DBT
DLD
Protein affected: branched-chain alpha-keto
acid dehydrogenase (BCKD)
Structure
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http://ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?db=t&form=6&dopt=s&uid=12936
Types of MSUD
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Classical: little or no enzyme activity <2%
Intermediate: more enzyme activity 3-8%
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Can tolerate greater amount of leucine
Intermittent: even more enzyme activity 815%
Thiamine-responsive: thiamine to increase
enzyme activity
http://www.msud-support.org/overv.htm
Mutations
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4 mutations in the BCKDHA gene that can
result in MSUD
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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
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http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608348
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Results of Mutations in BCKDHA
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Cannot breakdown amino acids leucine,
isoleucine, and valine
Build up to toxic levels
Nervous system degeneration
Can lead to encephalopathy
About MSUD
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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,
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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
Characteristic Symptoms
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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.
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http://rarediseases.about.com/od/rarediseases1/a/062004.htm
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Diagnosis/ Screening
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Mandatory State Screening Programs
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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
Treatment
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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.
Hypothesis
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MSUD is only a mammalian disease.
Based on the principle that urination in
mammals is different than many other species.
Evidence Against Hypothesis
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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=1145026779-912417383991185.BLASTQ4&FORMAT_OBJECT=TaxBlast&NCBI_GI=on&DESCRIPTIONS=
500&ALIGNMENTS=250&FORMAT_BLOCK_ON_RESPAGE=Top&MASK_COLOR=1&
MASK_CHAR=2
Another Hypothesis
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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.
Conserved Domains
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These two domains were shown to be
conserved over the whole taxa.
Dehydrogenase E1 component
Pyruvate/2-oxoglutarate dehydrogenase
complex
Results
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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.