Maple Syrup Urine Disease 2012

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 affected patients urine, which is caused by high levels of sotolon [1] in the patient's urine.

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.

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. 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

Reference sequence

Reference sequence (uniprot)

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