Difference between revisions of "Maple Syrup Urine Disease 2012"

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== Summary ==
  
== Summary ==
−
Maple Syrup Urine Disease is an autosomal recessive disorder, which affects the degradation of the branched amino acids Leu, Ile, Val. The name comes from a maple syrup odor of the urine of affected patients.
 +
Maple Syrup Urine Disease is an autosomal recessive disorder, which affects the degradation of the branched chain amino acids(BCAA) Leu, Ile, Val. The name comes from a maple syrup odor of affected patients urine, which is caused by high levels of sotolon [http://de.wikipedia.org/wiki/Sotolon] in the patient's urine. A world wide study in 2001 described a frequency of 1 affected per 185.000 births.
−
[[File:Autosomal recessive.jpg|230x230px|right|border|testcaption]]
 +
[[File:Autosomal recessive.jpg|230x230px|right|border|autosomal recessive inheritence]]
   
 
== Phenotype ==
  
== Phenotype ==
  +
Symptoms shown almost immediately after birth include poor feeding, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis, coma and neurological decline [http://en.wikipedia.org/wiki/Maple_syrup_urine_disease]. Within a week after birth the neurological damage is irreversible. The most prominent symptom is probably the sweet smelling urine, that is often characterized as maple syrup like, hence the name. In Mediterranean or eastern countries, where maple syrup is rather uncommon, it is reminiscent as fenugreek[http://omim.org/entry/248600#clinicalFeatures].
  +
  +
MSUD is classified in four categories, according to the amount and type of remaining enzyme activity[http://www.msud-support.org/index.php?option=com_content&view=article&id=307&Itemid=88]:
  +
*Classic severe MSUD. The most common variant. Remaining enzymatic activity below 2%. Symptoms usually show within the first few days of life. Severely restricted diet necessary.
  +
*Intermediate MSUD. Remaining enzymatic activity usually between 3-8%. Somewhat better branched chain amino acid tolerance, when healthy. During illness tolerance is usually reduced. Treatment similar to classic MSUD.
  +
*Intermittent MSUD. Remaining enzymatic activity usually between 8-15%. Symptoms only show during episodes (mostly caused by illness or huge protein intake).
  +
*Thiamine-responsive MSUD. Medication with large amounts of Thiamine restores enzymatic function. Only moderate diet necessary. Unfortunately not very common variant.
  +
  +
  +
== Diagnosis ==
  +
Fortunately MSUD can be diagnosed both prenatal (by detection of enzymatic deficiency in the aminon) or by checking the Leu-levels in blood or urine during newborn screening.
  +
  +
== Treatment ==
  +
* Patients with Thiamine-responsive MSUD can be treated with aforementioned drug are able to process branched chain amino acids. There is no, to very little dietary restriction and observation necessary for Thiamine-responsive patients.
  +
* Other forms of MSUD need to uphold a life long diet and observation to avoid to high BCAA levels.
  +
   
 
== Biochemical disease mechanism ==
  
== Biochemical disease mechanism ==
−
MSUD affects a protein called branched-chain alpha-keto acid dehydrogenase complex (BCKDHC), which is involved in the degradation of branched amino acids (Val, Leu, Ile). The inability of degrading these amino acids, leads to an enrichment of those in the body. The elevated levels of amino acids in the urine generate the smell, which is reminiscent of maple syrup.
+
MSUD affects a protein called branched-chain alpha-keto acid dehydrogenase complex (BCKDHC), which is involved in the degradation of branched amino acids (Val, Leu, Ile). The inability of degrading these amino acids, leads to an enrichment of those and their toxic byproducts in the body.
 
BCKDHC consists of four subunits:
  
BCKDHC consists of four subunits:
   
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|}
  
|}
   
−
[[File:Kegg-pathway-marked.jpg]]
 +
[[File:Kegg-pathway-marked.jpg|border|center|Kegg-pathway-branched aa´s degradation]]
   
 
== Mutations ==
  
== Mutations ==
 
= Reference sequence =
  
= Reference sequence =
 
[[Reference sequence (uniprot)]]
  
[[Reference sequence (uniprot)]]
  +
  +
[[Reference Sequence (pdb)]]
  +
 
= Mutated sequence =
  
= Mutated sequence =
−
* Nonsense/missense mutatet sequence BCKDHA
 +
* Nonsense/missense mutated sequence BCKDHA
   
 
>sp|P12694|ODBA_HUMAN 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial OS=Homo sapiens GN=BCKDHA PE=1 SV=2
  
>sp|P12694|ODBA_HUMAN 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial OS=Homo sapiens GN=BCKDHA PE=1 SV=2
Line 40: Line 59:
 
QLRKQQESLARHLQTYGEH<font color=red>N</font>PLDHFDK
  
QLRKQQESLARHLQTYGEH<font color=red>N</font>PLDHFDK
   
−
* Nonsense/missense mutatet sequence BCKDHB
 +
* Nonsense/missense mutated sequence BCKDHB
   
   
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RVCGYDTPFPHIF<font color=red>|</font>PFYIPDKWKC<font color=red>|</font>DALRKMINY
  
RVCGYDTPFPHIF<font color=red>|</font>PFYIPDKWKC<font color=red>|</font>DALRKMINY
   
−
* Nonsense/missense mutatet sequence DBT (leading to type 1)
 +
* Nonsense/missense mutated sequence DBT (leading to type 1)
   
   
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LK
  
LK
   
−
* Nonsense/missense mutatet sequence DBT (leading to type 2)
 +
* Nonsense/missense mutated sequence DBT (leading to type 2)
   
 
>sp|P11182|ODB2_HUMAN Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial OS=Homo sapiens GN=DBT PE=1 SV=3
  
>sp|P11182|ODB2_HUMAN Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial OS=Homo sapiens GN=DBT PE=1 SV=3
Line 80: Line 99:
   
   
−
* Nonsense/missense mutatet sequence DLD
 +
* Nonsense/missense mutated sequence DLD
   
 
>sp|P09622|DLDH_HUMAN Dihydrolipoyl dehydrogenase, mitochondrial OS=Homo sapiens GN=DLD PE=1 SV=2
  
>sp|P09622|DLDH_HUMAN Dihydrolipoyl dehydrogenase, mitochondrial OS=Homo sapiens GN=DLD PE=1 SV=2
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FPFAANSRAKTNADTDGMVKILGQKSTDRVLGAHILGPGAGEMVNEAALALEYGASCEDI
  
FPFAANSRAKTNADTDGMVKILGQKSTDRVLGAHILGPGAGEMVNEAALALEYGASCEDI
 
ARVCHAH<font color=red>L</font>TLSEAF<font color=red>G</font>EANLAASFGKSINF
  
ARVCHAH<font color=red>L</font>TLSEAF<font color=red>G</font>EANLAASFGKSINF
  +
  +
  +
  +
= Tasks =
  +
*[[Task 2: Multiple Sequence Alignment]]
  +
*[[Task 3: odba_human Sequence-based predictions]]
  +
*[[Task 4: Homology-based structure prediction]]
  +
*[[Task 5: Researching SNPs]]
  +
*[[Task 6: MSUD - Sequence-based mutation analysis]]
  +
*[[Task 7: MSUD - Structure-based mutation analysis]]
  +
*[[Task 8: MSUD - Molecular Dynamics Simulations]]
  +
*[[Task 9: MSUD - Normal Mode Analysis]]
  +
  +
= Final Report =
  +
The final report will be uploaded here once it is finished.

Latest revision as of 13:22, 21 February 2013

Summary

Maple Syrup Urine Disease is an autosomal recessive disorder, which affects the degradation of the branched chain amino acids(BCAA) Leu, Ile, Val. The name comes from a maple syrup odor of affected patients urine, which is caused by high levels of sotolon [1] in the patient's urine. A world wide study in 2001 described a frequency of 1 affected per 185.000 births.

autosomal recessive inheritence

Phenotype

Symptoms shown almost immediately after birth include poor feeding, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis, coma and neurological decline [2]. Within a week after birth the neurological damage is irreversible. The most prominent symptom is probably the sweet smelling urine, that is often characterized as maple syrup like, hence the name. In Mediterranean or eastern countries, where maple syrup is rather uncommon, it is reminiscent as fenugreek[3].

MSUD is classified in four categories, according to the amount and type of remaining enzyme activity[4]:

  • Classic severe MSUD. The most common variant. Remaining enzymatic activity below 2%. Symptoms usually show within the first few days of life. Severely restricted diet necessary.
  • Intermediate MSUD. Remaining enzymatic activity usually between 3-8%. Somewhat better branched chain amino acid tolerance, when healthy. During illness tolerance is usually reduced. Treatment similar to classic MSUD.
  • Intermittent MSUD. Remaining enzymatic activity usually between 8-15%. Symptoms only show during episodes (mostly caused by illness or huge protein intake).
  • Thiamine-responsive MSUD. Medication with large amounts of Thiamine restores enzymatic function. Only moderate diet necessary. Unfortunately not very common variant.


Diagnosis

Fortunately MSUD can be diagnosed both prenatal (by detection of enzymatic deficiency in the aminon) or by checking the Leu-levels in blood or urine during newborn screening.

Treatment

  • Patients with Thiamine-responsive MSUD can be treated with aforementioned drug are able to process branched chain amino acids. There is no, to very little dietary restriction and observation necessary for Thiamine-responsive patients.
  • Other forms of MSUD need to uphold a life long diet and observation to avoid to high BCAA levels.


Biochemical disease mechanism

MSUD affects a protein called branched-chain alpha-keto acid dehydrogenase complex (BCKDHC), which is involved in the degradation of branched amino acids (Val, Leu, Ile). The inability of degrading these amino acids, leads to an enrichment of those and their toxic byproducts in the body. BCKDHC consists of four subunits:

subunit name chromosomal gene location MSUD-type
BCKDHA Branched chain keto acid dehydrogenase E1, alpha polypeptide 19q13.1-q13.2 1a
BCKDHB branched chain keto acid dehydrogenase E1, beta polypeptide 6q14.1 1b
DBT Dihydrolipoamide branched chain transacylase E2 1p31 1/2
DLD dihydrolipoamide dehydrogenase 7q31-q32 3
Kegg-pathway-branched aa´s degradation

Mutations

Reference sequence

Reference sequence (uniprot)

Reference Sequence (pdb)

Mutated sequence

  • Nonsense/missense mutated sequence BCKDHA
>sp|P12694|ODBA_HUMAN 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial OS=Homo sapiens GN=BCKDHA PE=1 SV=2
MAVAIAAARVWRLNRGLSQAALLLLRQPGARGLARSHPPRQQQQFSSLDDKPQFPGASAE
FIDKLEFIQPNVISGIPIYRVMDRQGQIINPSEDPHLPKEKVLKLYKSMTLLNTMDRILY
ESQRQGRISFYMTNYGEEGTHVGSAAALDNMNLVFGQYWEAGVLMNQDYPLELFMAQCYG
NISDLGKGRKMPVHYGCKERHFVTISSPLATQTPQVVGAAYAAKRANANRVVICYFGEGA
ASEGDAHASFNFTATLEYPIIFFWWNSGYAISTPTSEQYRGDDIPA|GPRYGIMSIC/HVD
SNAVFAVYNARKEA|RRAVAENQPFLTKTMTYRIGHHSTSDDSSAYHSVDEVNYWDKQDH
PISWLRHYLLSQGWWDEEQEKAWRKQSRRKVMEAFEQAERKPKPNPNLLCSDMH/CQEMPA
QLRKQQESLARHLQTYGEHNPLDHFDK
  • Nonsense/missense mutated sequence BCKDHB


>sp|P21953|ODBB_HUMAN 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial OS=Homo sapiens GN=BCKDHB PE=1 SV=2
MAVVAAAAGWLLRLRAAGAEGHWRRLPGAGLARGFLHPAATVEDAAQRRQVAHFTFQPDP
EPREYGQTQKMNLFQSVTSALDNSLAKDPTAVIFGEDVAFGGVFRCTVGL|DKYGKDRGF
NTLLCEQGIGGFGIRIVVTGATAIAEIQFADYIFPAFDKIVN|AAKYH/CYRSWDLFYCGS
LTIPSPWGCDGHGALYHSQSAEAFFAR/YCPGIKVVKPGSPFQARGLLLSCIEDKNPCIFF
EP|ILHRAAAEEAPIEPYNIPLSQAEVI|EGSDVTLVACSTQVHAI|EVASMAKEKLGVS
CEVIDLRTIIPWDVDTICKSVIKTG|LLISHEAPLTGGFALKISSTVQEECFLNLEALIS
RVCGYDTPFPHIF|PFYIPDKWKC|DALRKMINY
  • Nonsense/missense mutated sequence DBT (leading to type 1)


>sp|P11182|ODB2_HUMAN Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial OS=Homo sapiens GN=DBT PE=1 SV=3
MAAVRMLRTWSRNAGKLICVRYFQTCGNVHVLKPNYVCFFGYPSFKYSHPHHFLKTTAAL
RGQVVQFKLSDIGEGIREVTVKEWYVKEGDTVSQFDSMCEVQSDKASVTITSRYDGVIKK
LYYNLDDIAYVRKPLVDTETEALKDSEEDVVETPAVSHDEHTHQEIKGRKTLATPAVRRL
AMENNIKLSEVVG|GKDGRILKEDILNYLEKQTGAILPPSPKV|IMPPPPKPKDMTVPIL
VSKPPVFTGKDKTEPIKGFQKATVKTMSAALKIPHCGYCDEIDLTELVKLREELKPIAFA
RGIKLSSMPFFLNAASLGLLQFPILNASVDENCQNITYKASNNIGIAMDTEQGLIVPNVK
NVQICSIFDIATELNRLQKLGSVSQLSTTGLTGGTFTPSNIGSIGGTFAKQVIMPPEVAI
GALGSIKANPRFNQKGEVYKAQIMNMSWSDDRRVIDGATMSPFSNLWKSYLENPAFMLLD
LK
  • Nonsense/missense mutated sequence DBT (leading to type 2)
>sp|P11182|ODB2_HUMAN Lipoamide acyltransferase component of branched-chain alpha-keto acid dehydrogenase complex, mitochondrial OS=Homo sapiens GN=DBT PE=1 SV=3
MAAVRMLRTWSRNAGKLICVRYFQTCGNVHVLKPNYVCFFGYPSFKYSHPHHFLKTTAAL
RGQVVQFKLSDIGEGIREVTVKEWYVKEGDTVSQFDSMCEVQSDKASVTITSRYDGVIKK
LYYNLDDIAYVRKPLVDTETEALKDSEEDVVETPAVSHDEHTHQEIKGRKTLATPAVRRL
AMENNIKLSEVVG|GKDGRILKEDILNYLEKQTGAILPPSPKV|IMPPPPKPKDMTVPIL
VSKPPVFTGKDKTEPIKGFQKATVKTMSAALKIPHCGYCDEIDLTELVKLREELKPIAFA
RGIKLSSMPFFLNAASLGLLQFPILNASVDENCQNITYKASNNIGIAMDTEQGLIVPNVK
NVQICSIFDIATELNRLQKLGSVSQLSTTGLTGGTFTPSNIGSIGGTFAKQVIMPPEVAI
GALGSIKANPRFNQKGEVYKAQIMNMSWSDDRRVIDGATMSPFSNLWKSYLENPAFMLLD
LK


  • Nonsense/missense mutated sequence DLD
>sp|P09622|DLDH_HUMAN Dihydrolipoyl dehydrogenase, mitochondrial OS=Homo sapiens GN=DLD PE=1 SV=2
MQSWSRVYCSLAKRGHFNRISHGLQGLSAVPLRTYADQPIDADVTVIGSGPGGYVAAIKA
AQLGFKTVCIEENETLGGTCLNVGCIPSKALLNNSHYYHMAHGTDFASRGIEMSEVRLNL
DKMMEQKSTAVKALTGGIAHLFKQNKVVHVNGYGKITGKNQVTATKADGGTQVIDTKNIL
IATGSEVTPFPGITIDEDTIVSSTGALSLKKVPEKMVVIGAGVIGVELCSVWQRLGADVT
AVEFLGHVGGVGIDMEISKNFQRILQKQGFKFKLNTKVTGATKKSDGKIDVSIEAASGGK
AEVITCDVLLVCIGRRPFTKNLGLEELGIEVDPRGRIPVNTRFQTKIPNIYAIGDVVAGP
MLAHKAEDEGIICVEGMAGGAVHIDYNCVPSVIYTHPEVAWVGKSEEQLKEEGIEYKVGK
FPFAANSRAKTNADTDGMVKILGQKSTDRVLGAHILGPGAGEMVNEAALALEYGASCEDI
ARVCHAHLTLSEAFGEANLAASFGKSINF


Tasks

Final Report

The final report will be uploaded here once it is finished.

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