maple syrup urine disease msud by jenny morrison 836445 l.
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Deficiency in branched chain alpha-keto acid dehydrogenase complex (BCKAD) – located in mitochondrial inner membrane Caused by mutation in 4 possible genes BCKDHA, BCKDHB, DBT, and DLD that encode for the BCKAD

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maple syrup urine disease msud by jenny morrison 836445
Deficiency in branched chain alpha-keto acid dehydrogenase complex (BCKAD) – located in mitochondrial inner membrane

Caused by mutation in 4 possible genes BCKDHA, BCKDHB, DBT, and DLD that encode for the BCKAD

Results in defect in metabolism of branched chain amino acids (BCAA): Valine, Leucine and Isoleucine

Accumulation of BCAA and their keto acid derivatives

5 clinical subtypes: “classic” “intermittent”, “mild”, Thiamine responsive, and E3-deficient with lactic acidosis.

Classification of subtypes according to nature of gene mutation by genetic complementation analysis after somatic cell hybridisation (1980)

Classic MSUD is the most severe and most common form

Maple Syrup Urine Disease (MSUD)By Jenny Morrison (836445)
4 of the msud clinical subtypes

Symptoms – “classic” MSUD

4 of the MSUD clinical subtypes
  • Onset in the first week of life:
  • Maple syrup odour (in urine

and on body)

  • Feeding difficulties and

vomiting

  • Shrill cry
  • Hypertonicity (episodes

alternate with flaccidity)

  • No Moro reflex and

suppressed deep tendon

reflexes

  • Frequent convulsions
  • Survivors suffer from severe

mental retardation & motor

development retardation

(Bondy & Rosenberg, 1980)

slide3
Inheritance
  • Autosomal recessive
  • Frequency:
    • 1 in 185,000 newborns world wide (Chuang et al, 1995)
    • 1 in 176 newborns in the Mennonite population of Lancaster, Pennsylvania (due to consanguinity)
  • Panethnic distribution

Genetic Counselling

  • Relatives of the affected individual have high genetic risks (1 in 4)
  • Extremely low risks to offsprings of healthy sibs or more distant

relatives

molecular genetics of the bckad
Molecular genetics of the BCKAD
  • each molecular phenotype can have > 1 clinical phenotype as different mutations in the same subunit may have different effects on the stability and function of the polypeptide.
  • MSUD type II constitute the majority of mutations reported
msud type ia
MSUD Type IA

E1α

mRNA sequence

1 gccggaccgc tgagtggttg ttagccaaga tggcggtagc gatcgctgca gcgagggtct

61 ggcggctaaa ccgtggtttg agccaggctg ccctcctgct gctgcggcag cctggggctc

121 ggggactggc tagatctcac ccccccaggc agcagcagca gttttcatct ctggatgaca

181 agccccagtt cccaggggcc tcggcggagt ttatagataa gttggaattc atccagccca

241 acgtcatctc tggaatcccc atctaccgcg tcatggaccg gcaaggccag atcatcaacc

301 ccagcgagga cccccacctg ccgaaggaga aggtgctgaa gctctacaag agcatgacac

361tgcttaacac catggaccgc atcctctatg agtctcagcg gcagggccgg atctccttct

421acatgaccaa ctatggtgag gagggcacgc acgtggggag tgccgccgcc ctggacaaca

481 cggacctggt gtttggccag taccgggagg caggtgtgct gatgtatcgg gactaccccc

541tggaactatt catggcccag tgctatggca acatcagtga cttgggcaag gggcgccaga

601tgcctgtcca ctacggctgc aaggaacgcc acttcgtcac tatctcctct ccactggcca

661cgcagatccc tcaggcggtg ggggcggcgt acgcagccaa gcgggccaat gccaacaggg

721tcgtcatctg ttacttcggc gagggggcag ccagtgaggg ggacgcccat gccggcttca

781acttcgctgc cacacttgag tgccccatca tcttcttctg ccggaacaat ggctacgcca

841tctccacgcc cacctctgag cagtatcgcg gcgatggcat tgcagcacga ggccccgggt

901atggcatcat gtcaatccgc gtggatggta atgatgtgtt tgccgtatac aacgccacaa

961aggaggcccg acggcgggct gtggcagaga accagccctt cctcatcgag gccatgacct

1021acaggatcgg gcaccacagc accagtgacg acagttcagc gtaccgctcg gtggatgagg

1081tcaattactg ggataaacag gaccacccca tctcccggct gcggcactat ctgctgagcc

1141aaggctggtg ggatgaggag caggagaagg cctggaggaa gcagtcccgc aggaaggtga

1201tggaggcctt tgagcaggcc gagcggaagc ccaaacccaa ccccaaccta ctcttctcag

1261acgtgtatca ggagatgccc gcccagctcc gcaagcagca ggagtctctg gcccgccacc

1321tgcagaccta cggggagcac tacccactgg atcacttcga taagtgagac ctgctcagcc

1381cacccccacc catcctcagc taccccgaga ggtagcccca ctctaagggg agcaggggga

1441cctgacagca caccactgtc ttccccagtc agctccctct aaaatactca gcggccaggg

1501cggctgccac tcttcacccc tgctcctccc ggctgttaca ttgtcagggg acagcatctg

1561cagcagttgc tgaggctccg tcagccccct cttcacctgt tgttacagtg ccttctccca

1621ggggctgggt gagggcacat tcaggactag aagcccctct gggcatgggg tggacatggc

1681aggtcagcct gtggaacttg cgcaggtgcg agtggccagc agaggtcacg aataaactgc

1741atctctgcgc ctggctctct accaaaaaaa aaaaaaaaaa a

Protein Sequence

MAVAIAAARVWRLNRGLSQAALLLLRQPGARGLARSHPPRQQQQFSSLDDKPQFPGASAEFIDKLEFIQPNVISGIPIYRVMDRQGQIINPSEDPHLPKEKVLKLYKSMTLLNTMDRILYESQRQGRISFYMTNYGEEGTHVGSAAALDNTDLVFGQYREAGVLMYRDYPLELFMAQCYGNISDLGKGRQMPVHYGCKERHFVTISSPLATQIPQAVGAAYAAKRANANRVVICYFGEGAASEGDAHAGFNFAATLECPIIFFCRNNGYAISTPTSEQYRGDGIAARGPGYGIMSIRVDGNDVFAVYNATKEARRRAVAENQPFLIEAMTYRIGHHSTSDDSSAYRSVDEVNYWDKQDHPISRLRHYLLSQGWWDEEQEKAWRKQSRRKVMEAFEQAERKPKPNPNLLFSDVYQEMPAQLRKQQESLARHLQTYGEHYPLDHFDK

msud type ib
MSUD Type IB

E1β

mRNA transcript variant 2

1 aggcggcgtg cggctgcata gcctgagaat cccggtggtg agcggggatg gcggttgtag

61 cggcggctgc cggctggcta ctcaggctca gggcggcagg ggctgagggg cactggcgtc

121 ggcttcctgg cgcggggctg gcgcggggct ttttgcaccc cgccgcgact gtcgaggatg

181 cggcccagag gcggcaggtg gctcatttta ctttccagcc agatccggag ccccgggagt

241 acgggcaaac tcagaaaatg aatcttttcc agtctgtaac aagtgccttg gataactcat

301 tggccaaaga tcctactgca gtaatatttg gtgaagatgt tgcctttggt ggagtcttta

361 gatgcactgt tggcttgcga gacaaatatg gaaaagatag agtttttaat accccattgt

421 gtgaacaagg aattgttgga tttggaatcg gaattgcggt cactggagct actgccattg

481 cggaaattca gtttgcagat tatattttcc ctgcatttga tcagattgtt aatgaagctg

541 ccaagtatcg ctatcgctct ggggatcttt ttaactgtgg aagcctcact atccggtccc

601 cttggggctg tgttggtcat ggggctctct atcattctca gagtcctgaa gcattttttg

661 cccattgccc aggaatcaag gtggttatac ccagaagccc tttccaggcc aaaggacttc

721 ttttgtcatg catagaggat aaaaatcctt gtatattttt tgaacctaaa atactttaca

781 gggcagcagc ggaagaagtc cctatagaac catacaacat cccactgtcc caggccgaag

841 tcatacagga agggagtgat gttactctag ttgcctgggg cactcaggtt catgtgatcc

901 gagaggtagc ttccatggca aaagaaaagc ttggagtgtc ttgtgaagtc attgatctga

961 ggactataat accttgggat gtggacacaa tttgtaagtc tgtgatcaaa acagggcgac

1021 tgctaatcag tcacgaggct cccttgacag gcggctttgc atcggaaatc agctctacag

1081 ttcaggagga atgtttcttg aacctagagg ctcctatatc aagagtatgt ggttatgaca

1141 caccatttcc tcacattttt gaaccattct acatcccaga caaatggaag tgttatgatg

1201 cccttcgaaa aatgatcaac tattgaccat atagaaaagc tggaagatta tgactagata

1261 tggaaatatt ttttctgaat ttttttttat atttcctccg acttacctct ttttgaaaag

1321 agagttttta ttaaatgaac catcatgata ttggctgaaa agttctacat tctattattg

1381 tattgtaaca cacatgtatt gatgattttc attaagagtt tcagattaac tttgaaaaat

1441 attccacatg gtaatcttat aaattctgtt taattacatc tgtaaatatt atgtgtgtga

1501 tagtattcaa taaagtaaaa tcaaattgtc aaaaaaaaaa aaaaaaaaaa aa//

Protein sequence

MAVVAAAAGWLLRLRAAGAEGHWRRLPGAGLARGFLHPAATVEDAAQRRQVAHFTFQPDPEPREYGQTQKMNLFQSVTSALDNSLAKDPTAVIFGEDVAFGGVFRCTVGLRDKYGKDRVFNTPLCEQGIVGFGIGIAVTGATAIAEIQFADYIFPAFDQIVNEAAKYRYRSGDLFNCGSLTIRSPWGCVGHGALYHSQSPEAFFAHCPGIKVVIPRSPFQAKGLLLSCIEDKNPCIFFEPKILYRAAAEEVPIEPYNIPLSQAEVIQEGSDVTLVAWGTQVHVIREVASMAKEKLGVSCEVIDLRTIIPWDVDTICKSVIKTGRLLISHEAPLTGGFASEISSTVQEECFLNLEAPISRVCGYDTPFPHIFEPFYIPDKWKCYDALRKMINY

Alternate splicing results in 2 transcripts that encode the same protein

msud type ib cont
MSUD Type IB cont.

1921 cccagctaat tttttatatt tttagtagag acggggtttc accatgttgg ccaggatggt

1981 ctcgatctct tgaccttgtg ttccacccgt cttggcctcc caaagcgctg gaattacagg

2041 catgagccac cgcgcctggc ctgtatatgt gatttctaaa aaatagatgc atgcatatgt

2101 taacattgaa tagtcaatca ctagatgaag atgctctcta ccatggttta gattgcaagt

2161 gtactttata ccattgtttc aacttcaacc tttatttttg tatatatttt ttcaactact

2221 taaactgttc atgaataggc gtactttctg tatttaaaaa tggcccctca agcaccgtta

2281 atttacattc cagttattta catgataatt catgacattc tgaaacttgc ctgtatatta 2341 tctgaaaaat ggatttcttg aggaaaagat ctgtttattg tatgtaagga aaaattttac 2401 ctgaaaacaa acaaacaaac cctaaaactc agcaccacta ccatttccag aagctttttt 2461 agcaagtgaa tattttttac ataatggata ataaatggta tttattcatc atgattttct 2521 aagtaatgct tatcagcccc ttcagtggtg ttattctaac aaaatgaata cattacaaat 2581 tattaagtta gcttttcaga gttttaatat agaagttact agcactgaca cactgatttt 2641 gaaatgtttc aaaatgagta gatacgatta gatcctttac cttttaatat ctagtttttc 2701 caaaaatgat agtaatatct tttgaagaac tatgcttttt caaaagcaaa atcaactctg 2761 tataatagca cattctctac tttttaaaga tcagaaatgc tagaattctt gacttttgtg 2821 tatgggtagt aaatctagct cactgaaaat cagagtgaaa cgcctttaca tttgtgcgga 2881 tagagaagtt aactctccct catatgtcac tgtgctacca taatccctac attttctgtc 2941 tgttctagtc taagaatatt gttatagatg gaagttagga ccattagccc acagatgcgt 3001 gtattctctc agacataccg gtgtagatgc catatttctg atgtcttctt aatgtctgtg 3061 aaagcaactg gcatctacaa taaatcacac ttagaactgg ttagaggact ccctcacttt 3121 tgttgtccat gtggttccct tccgtggacc agccgtaata aagagccaag gtagtgatgg 3181 tggccacgtg cctcgttgct atttttaaag taatattcag atgtggtttt aaatttagat 3241 tatgtattcc ttttgaaaca taagaaaaac atttaaacct atgctgaaaa tacgataaaa 3301 gaaaaacaac tccaatatgc taaaagttaa atatggtatt taagaaaata gtcatgtatg 3361 caattgagaa agtctataat ttattttaca gaaaagctgg aagattatga ctagatatgg 3421 aaatattttt tctgaatttt tttttatatt tcctccgact tacctctttt tgaaaagaga

3481 gtttttatta aatgaaccat catgatattg gctgaaaagt tctacattct attattgtat

3541 tgtaacacac atgtattgat gattttcatt aagagtttca gattaacttt gaaaaatatt 3601 ccacatggta atcttataaa ttctgtttaa ttacatctgt aaatattatg tgtgtgatag 3661 tattcaataa agtaaaatca aattgtcaaa aaaaaaaaaa aaa

mRNA transcript variant 1

1 aggcggcgtg cggctgcata gcctgagaat cccggtggtg agcggggatg gcggttgtag

61 cggcggctgc cggctggcta ctcaggctca gggcggcagg ggctgagggg cactggcgtc

121 ggcttcctgg cgcggggctg gcgcggggct ttttgcaccc cgccgcgact gtcgaggatg

181 cggcccagag gcggcaggtg gctcatttta ctttccagcc agatccggag ccccgggagt

241 acgggcaaac tcagaaaatg aatcttttcc agtctgtaac aagtgccttg gataactcat

301 tggccaaaga tcctactgca gtaatatttg gtgaagatgt tgcctttggt ggagtcttta

361 gatgcactgt tggcttgcga gacaaatatg gaaaagatag agtttttaat accccattgt

421 gtgaacaagg aattgttgga tttggaatcg gaattgcggt cactggagct actgccattg

481 cggaaattca gtttgcagat tatattttcc ctgcatttga tcagattgtt aatgaagctg

541 ccaagtatcg ctatcgctct ggggatcttt ttaactgtgg aagcctcact atccggtccc

601 cttggggctg tgttggtcat ggggctctct atcattctca gagtcctgaa gcattttttg

661 cccattgccc aggaatcaag gtggttatac ccagaagccc tttccaggcc aaaggacttc

721 ttttgtcatg catagaggat aaaaatcctt gtatattttt tgaacctaaa atactttaca

781 gggcagcagc ggaagaagtc cctatagaac catacaacat cccactgtcc caggccgaag

841 tcatacagga agggagtgat gttactctag ttgcctgggg cactcaggtt catgtgatcc

901 gagaggtagc ttccatggca aaagaaaagc ttggagtgtc ttgtgaagtc attgatctga

961 ggactataat accttgggat gtggacacaa tttgtaagtc tgtgatcaaa acagggcgac

1021 tgctaatcag tcacgaggct cccttgacag gcggctttgc atcggaaatc agctctacag

1081 ttcaggagga atgtttcttg aacctagagg ctcctatatc aagagtatgt ggttatgaca

1141 caccatttcc tcacattttt gaaccattct acatcccaga caaatggaag tgttatgatg

1201 cccttcgaaa aatgatcaac tattgaccat ataggtaggt atgcatcttg agaaagctac

1261 tatgtgcccc tgacattaac gtactgttaa ccaagacaca gcaatcatca gtgttttgat

1321 ggtaacaaac tttgatggta aagttgataa aaggcaactt tcagaagaaa ataatgtgct

1381 ttagaaaaaa aattcaaatt tatagtagta tatttacatt tttgttgttg ttgttctgag

1441 atggagtctc actctgtcgc ccaggctaga ctgcagtggt gcaatctcag ctcactgcaa

1501 cctcccccct acccccgagt tcaagcaatt ctcctgcctc agcctgctga gtagttggga

1561 ttacaggtgc ccaccaccat gcccagctaa tttttgtgtt tttattggag gtggggtttc

1621 actatgttgg ctcagctgat ttcaaattcc tgacctcaag tgatccacct gccttagcct

1681 cccaaagtgc tgggattaca ggcatgagcc actgcacctg gctatattta catttaatag

1741 aaacatatct agcatatgta tatgtgattt tttttttttt tgagaccgag tctcactctg

1801 tcaccaggct ggagtgcagt ggtgcgatct tggctcatgg caacctccgc ctcccaggtt

1861 caagcgattg tcctgcctca gtctcctgag tagctgggac tacaggtgtg caccaacatg

slide8

MSUD Type II

E2

mRNA sequence

1 atttccgggg taagatggct gcagtccgta tgctgagaac ctggagcagg aatgcgggga

61 agctgatttg tgttcgctat tttcaaacat gtggtaatgt tcatgttttg aagccaaatt

121 atgtgtgttt ctttggttat ccttcattca agtatagtca tccacatcac ttcctgaaaa

181 caactgctgc tctccgtgga caggttgttc agttcaagct ctcagacatt ggagaaggga

241 ttagagaagt aactgttaaa gaatggtatg taaaagaagg agatacagtg tctcagtttg

301 atagcatctg tgaagttcaa agtgataaag cttctgttac catcactagt cgttatgatg

361 gagtcattaa aaaactctat tataatctag acgatattgc ctatgtgggg aagccattag

421 tagacataga aacggaagct ttaaaagatt cagaagaaga tgttgttgaa actcctgcag

481 tgtctcatga tgaacataca caccaagaga taaagggccg aaaaacactg gcaactcctg

541 cagttcgccg tctggcaatg gaaaacaata ttaagctgag tgaagttgtt ggctcaggaa

601 aagatggcag aatacttaaa gaagatatcc tcaactattt ggaaaagcag acaggagcta

661 tattgcctcc ttcacccaaa gttgaaatta tgccacctcc accaaagcca aaagacatga

721 ctgttcctat actagtatca aaacctccgg tattcacagg caaagacaaa acagaaccca

781 taaaaggctt tcaaaaagca atggtcaaga ctatgtctgc agccctgaag atacctcatt

841 ttggttattg tgatgagatt gaccttactg aactggttaa gctccgagaa gaattaaaac

901 ccattgcatt tgctcgtgga attaaactct cctttatgcc tttcttctta aaggctgctt

961 ccttgggatt actacagttt cctatcctta acgcttctgt ggatgaaaac tgccagaata

1021 taacatataa ggcttctcat aacattggga tagcaatgga tactgagcag ggtttgattg

1081 tccctaatgt gaaaaatgtt cagatctgct ctatatttga catcgccact gaactgaacc

1141 gcctccagaa attgggctct gtgggtcagc tcagcaccac tgatcttaca ggaggaacat

1201 ttactctttc caacattgga tcaattggtg gtacctttgc caaaccagtg ataatgccac

1261 ctgaagtagc cattggggcc cttggatcaa ttaaggccat tccccgattt aaccagaaag

1321 gagaagtata taaggcacag ataatgaatg tgagctggtc agctgatcac agagttattg

1381 atggtgctac aatgtcacgc ttctccaatt tgtggaaatc ctatttagaa aacccagctt

1441 ttatgctact agatctgaaa tgaagactga taagacattc ttgaactttt tgagcttcca

1501 aagagtatgt aaaccctagc tgtgccagca catgttcatc tttacaattt atattgtaaa

1561 cgatttgtat cgtatgatta aggatctaag gcacaatatt tgtcactgtt ctattagact

1621 ttttactgaa aatgaataat ggtgtaatgg ttctcctggg gctgtcacat tttataggtc

1681 agagtgtgac ttcttaatat ggtgctgatg tttttgtgtc aatggcttga aactggcaag

1741 attaacaaaa ttaggccggg catggtggct cacgcctgta atccagcact ttgggaggcc

1801 caggtggggc gatcacctga ggttagaagt ttgagaccag cctggccaac atggtgaaac

1861 ctggcctcta cctaaaaaat acaaaattga ccgggtgtgg tggtgggtac cgctacttgg

1921 gaggctgagg caggagaatc gcttgaacct gggaggtgga ggttgcagtg agctgagatc

1981 gtgctattgc actccagcct gggcgacaga gcaagacgcc atctcaaaaa caaaaaaaac

2041 aaaattcatg ttactaaaag acaggtagcc atatacagac agtatatgcc ctattttttt

2101 taactgactc ttaatgaaac tttaatttta cttaattaag aaatggaatt tatatacaaa

2161 aatattttcc atttccgtta ttatgctaat tgttgtatga aataagtgca attatacttc

2221 tcttttgaga tatccaagag tatattcttg ctctgtatag agaatatcat ctgatagtgt

2281 cttatttata ttaattaatg tctttgaaaa gggaaaagta taaactggcc ttaaaattgt

2341 ccaattatag ttttataacc agtctattaa aggtgtttgt ttaaaatgga tatagtttta

2401 gatttgtggt aatgctttgg tattttcttg gggaagacct tcacctttgc aaacttccct

2461 catgtaagga aggtacttta aatgtagcag ccactgacat ttcttttttt aaaaaaaatt 2521 tgagaagtct acttcctttt aacttttttg gtcttcagct aaaaaatagg ataagaaatt 2581 aaggtctatt ccattctcca tatcctgggt aagaatgtaa ataagaggag aaggaagagt 2641 ctaatagtaa ttatggatat aaaaaataag aaattttgta tagaaatgaa ggtttcataa 2701 tgatcatttt gttaaaggtc tactttaatc agaaatagca acgagatgaa tgtatccaac 2761 atttcaattt gcattcggaa atccatgttg tttctaatat tgtccagttg aaaactgtat

2821 gccaaaatta gttgtttaag tgaagttttg tgacagaaaa aaggttgttt taatatctac 2881 ttggtttttc tcaaaatgga aataatttta aaatcaggaa agaataaatc agccaggtgt 2941 gatgacttgt aactgtaatc ccagttatag gggaggctga agcaggagga tcacttgagg 3001 ccaggagttt gagaccagcc tgggcaacat agtgagatcc catctcaaaa aacattattt 3061 ttaaaattag cctggtggct cacgcctgta atcccagcac tttgggaggc cgaggtggcc 3121 agatcacctg aggtcaggag ttcgagacca ccctggccaa catggtgaaa ccccatctct 3181 acagttttgt aaaaatacaa aaattacctg ggcctggtgc acaggcctgt agtcccagct 3241 acttgggagg ctgaggcagg agaattgctt gagcccaaga ggtggaggtt acagtgagca

3301 gagatcacac cactgcactc cagcctgggt ggcagagcaa cacttcgtct cagaaaaaaa 3361 aaaaaaaacc aaaaaccaaa aagccaagtg tggtggtgtg cacctatagt cccagctact 3421 caggaagctg agacaagagg atcaattgag cccaggagtt caaagctgta gtgagctgtc 3481 attgtgccac tatcctccag tatgggtgac agagtgagac ctggtctcta aaaat

Protein sequence

MAAVRMLRTWSRNAGKLICVRYFQTCGNVHVLKPNYVCFFGYPSFKYSHPHHFLKTTAALRGQVVQFKLSDIGEGIREVTVKEWYVKEGDTVSQFDSICEVQSDKASVTITSRYDGVIKKLYYNLDDIAYVGKPLVDIETEALKDSEEDVVETPAVSHDEHTHQEIKGRKTLATPAVRRLAMENNIKLSEVVGSGKDGRILKEDILNYLEKQTGAILPPSPKVEIMPPPPKPKDMTVPILVSKPPVFTGKDKTEPIKGFQKAMVKTMSAALKIPHFGYCDEIDLTELVKLREELKPIAFARGIKLSFMPFFLKAASLGLLQFPILNASVDENCQNITYKASHNIGIAMDTEQGLIVPNVKNVQICSIFDIATELNRLQKLGSVGQLSTTDLTGGTFTLSNIGSIGGTFAKPVIMPPEVAIGALGSIKAIPRFNQKGEVYKAQIMNVSWSADHRVIDGATMSRFSNLWKSYLENPAFMLLDLK

msud type iii
MSUD Type III

E3

mRNA sequence

1 gcgcagggag gggagacctt ggcggacggc ggagccccag cggaggtgaa agtattggcg

61 gaaaggaaaa tacagcggaa aaatgcagag ctggagtcgt gtgtactgct ccttggccaa

121 gagaggccat ttcaatcgaa tatctcatgg cctacaggga ctttctgcag tgcctctgag

181 aacttacgca gatcagccga ttgatgctga tgtaacagtt ataggttctg gtcctggagg

241 atatgttgct gctattaaag ctgcccagtt aggcttcaag acagtctgca ttgagaaaaa

301 tgaaacactt ggtggaacat gcttgaatgt tggttgtatt ccttctaagg ctttattgaa

361 caactctcat tattaccata tggcccatgg aacagatttt gcatctagag gaattgaaat

421 gtccgaagtt cgcttgaatt tagacaagat gatggagcag aagagtactg cagtaaaagc

481 tttaacaggt ggaattgccc acttattcaa acagaataag gttgttcatg tcaatggata

541 tggaaagata actggcaaaa atcaagtcac tgctacgaaa gctgatggcg gcactcaggt

601 tattgataca aagaacattc ttatagccac gggttcagaa gttactcctt ttcctggaat

661 cacgatagat gaagatacaa tagtgtcatc tacaggtgct ttatctttaa aaaaagttcc

721 agaaaagatg gttgttattg gtgcaggagt aataggtgta gaattgggtt cagtttggca

781 aagacttggt gcagatgtga cagcagttga atttttaggt catgtaggtg gagttggaat

841 tgatatggag atatctaaaa actttcaacg catccttcaa aaacaggggt ttaaatttaa

901 attgaataca aaggttactg gtgctaccaa gaagtcagat ggaaaaattg atgtttctat

961 tgaagctgct tctggtggta aagctgaagt tatcacttgt gatgtactct tggtttgcat

1021 tggccgacga ccctttacta agaatttggg actagaagag ctgggaattg aactagatcc

1081 tagaggtaga attccagtca ataccagatt tcaaactaaa attccaaata tctatgccat

1141 tggtgatgta gttgctggtc caatgctggc tcacaaagca gaggatgaag gcattatctg

1201 tgttgaagga atggctggtg gtgctgtgca cattgactac aattgtgtgc catcagtgat

1261 ttacacacac cctgaagttg cttgggttgg caaatcagaa gagcagttga aagaagaggg

1321 tattgagtac aaagttggga aattcccatt tgctgctaac agcagagcta agacaaatgc

1381 tgacacagat ggcatggtga agatccttgg gcagaaatcg acagacagag tactgggagc

1441 acatattctt ggaccaggtg ctggagaaat ggtaaatgaa gctgctcttg ctttggaata

1501 tggagcatcc tgtgaagata tagctagagt ctgtcatgca catccgacct tatcagaagc

1561 ttttagagaa gcaaatcttg ctgcgtcatt tggcaaatca atcaactttt gaattagaag

1621 attatatatt tttttttctg aaatttcctg ggagcttttg tagaagtcac attcctgaac

1681 aggatattct cacagctcca agaatttcta ggactgaatt atgaaacttt tggaaggtat

1741 ttaataggtt tggacaaaat ggaatactct tatatctata ttttacataa atttagtatt

1801 ttgtttcagt gcactaatat gtaagacaaa aaggactact tattgtagtc atcctggaat

1861 atctccgtca actcatattt tcatgctgtt catgaaagat tcaatgcccc tgaatttaaa

1921 tagctctttt ctctgataca gaaaagttga attttacatg gctggagcta gaatttgata

1981 tgtgaacagt tgtgtttgaa gcacagtgat caagttattt ttaatttggt tttcacattg

2041 gaaacaagtc agtcattcag atatgattca aatgtctata aaccaaactg atgtaagtaa

2101 atggtctctc acttgtttta tttaacctct aaattctttc attttagggg tagcatttgt

2161 gttgaagagg ttttaaagct tccattgttg tctgcaactc tgaagggtaa ttatatagtt

2221 acccaaatta agagagtcta tttacggaac tcaaatacgt gggcattcaa atgtattaca

2281 gtggggaatg aagatactga aataaacgtc ttaaatattc

Protein Sequence

MQSWSRVYCS LAKRGHFNRI SHGLQGLSAV PLRTYADQPI DADVTVIGSG PGGYVAAIKA

AQLGFKTVCI EKNETLGGTC LNVGCIPSKA

LLNNSHYYHM AHGTDFASRG IEMSEVRLNL

DKMMEQKSTA VKALTGGIAH LFKQNKVVHV NGYGKITGKN QVTATKADGG TQVIDTKNIL

IATGSEVTPF PGITIDEDTI VSSTGALSLK

KVPEKMVVIG AGVIGVELGS VWQRLGADVT

AVEFLGHVGG VGIDMEISKN FQRILQKQGF KFKLNTKVTG ATKKSDGKID VSIEAASGGK

AEVITCDVLL VCIGRRPFTK NLGLEELGIE LDPRGRIPVN TRFQTKIPNI YAIGDVVAGP

MLAHKAEDEG IICVEGMAGG AVHIDYNCVP SVIYTHPEVA WVGKSEEQLK EEGIEYKVGK

FPFAANSRAK TNADTDGMVK ILGQKSTDRV LGAHILGPGA GEMVNEAALA LEYGASCEDI

ARVCHAHPTL SEAFREANLA ASFGKSINF

metabolic functions
Metabolic functions
  • Branched chain dehydrogenase complex (BCKAD)
    • 3 catalytic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3)
    • 2 regulatory enzymes: kinase and phosphotase
    • Encoded by 6 genetic loci
    • Mutation in any of the loci can result in defect
  • Defect in BCKAD causes a block in BCKA oxidative decarboxylation
    • Accumulation of BCKA

(1) transamination by BCAA amino transferase

(2) oxidative decarboxylation by BCKAD

(3) dehydrogenation by isovaleryl-CoA dehydrogenase

(4) dehydrogenation by alpha-methyl branched chain

cyl-CoA dehydrogenase

(Chuang & Shih, 1995)

screening and diagnosis
Screening and Diagnosis
  • Prenatal diagnosis
    • analysis of cultured amniocytes obtained at mid-trimester amniocentesis
    • direct analysis of tissues or cultured cells from chorionic villi sample taken during first trimester
    • Use allele-specific oligonucleotide (ASO) probe following PCR to detect mutation in DNA obtained from amniocytes
    • Attempts at measuring amniotic fluid concentration of BCAA, BCKA and α-hydroxyacids have been unsuccessful
  • Routine newborn screening
    • Guthrie bacterial inhibition assay

Increase leucine levels in blood spots

Detect classic, intermediate and E3-deficient MSUD but intermediate

may be missed due to lower leucine levels than classic

    • Tandem mass spectroscopy coupled with fast atom bombardment (FAB) ionisation

Detect organic acids and amino acids abnormalities in blood and urine

samples on filter paper

screening and diagnosis cont
Screening and Diagnosis cont.
  • General diagnosis or genetic studies
    • Urine 2,4-dinitrophenylhydrazine (DNPH) test
    • Gas chromatographic mass spectroscopy (GC-MS)
    • Enzymic studies of cell cultures (skin fibroblasts and lymphoblasts)
    • Allele-specific oligonucleotide (ASO) probing

Historical perspective

  • Diagnosis relied on the recognition of clinical symptoms and signs and Chemical and enzymological analysis were performed if indicated (Galjaard 1980)
therapies and management
Therapies and Management

History of dietary therapies

Dietary therapies started in 1959.

Gelatin has low BCAA and was used as a source of BCAA in England in the early days. A synthetic formula was developed by Snyderman et al in the United States which consisted of 18 amino acids (based on breastmilk composition) carbohydrates, fat, minerals and vitamins. Based on this formula, other commercial medical diets have since been created.

Long term dietary management

  • Restrict intake of BCAA in diet to the amount essential for growth
  • Start as soon as possible and continue for life
  • Treat classic and intermediate MSUD patients the same way
  • For intermittent MSUD, decrease protein intake during episodes
  • Monitor plasma BCAA levels weekly for the first 6 months and keep as close to normal as possible
  • A trial of thiamine therapy is recommended to determine thiamine responsiveness in all new patients
therapies and management cont
Therapies and Management cont.

Acute-phase management

  • Infection and stress can cause a significant accumulation of BCAA and BCKA which can be life threatening
  • Treatment involves:
    • Rapid removal of toxic metabolites

Exchange transfusion (early 1960’s) achieved limited success

Peritoneal dialysis (1969) produced significant improvement within hours.

It is simple to implement and has become an established procedure for

treating patients in crisis

Hemodialysis is equally successful but requires specialised equipment

and personnel

Continuous arteriovenous hemoperfusion can be used for adults but

hastechnical limitations when applied to newborns

    • Parenteral Nutritional therapy

BCAA-free L-amino acid mixture combined with glucose, lipid, electrolytes

and vitamins

    • Minimise catabolic state and/or promote anabolism

use insulin and carbohydrate to promote anabolism

key references

Therapies and Management cont.

Key References
  • Other therapies
  • Introducing subunits of BCKDH enzyme into cells using a retrovirous
  • Liver transplant
  • Somatic gene therapy
  • Bondy, P.K. & Rosenberg, L.C. 1980, Metabolic Control and Disease, 8th Edition, W.B. Saunders Company, Philadelphia
  • Galjaard, H. 1980, Genetic Metabolic Diseases: Early Diagnosis and Prenatal Analysis, Elsevier/North-Holland Biomedical Press, Amsterdam
  • Chuang, D.T. & Shih, V.E. 1995, ‘Disorders of Branched Chain Amino Acid and Keto Acid Metabolism’, in The Metabolic and Molecular Bases of Inherited Diseases, vol. 1,7th Edition, eds Scriver et al., McGraw-Hill, New York
  • OMIM, URL: http://www3.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=248600
  • Ensemble, URL: http://www.ensembl.org/homo_sapians/genereview?gene=ENSG00000137992 (ENSG00000142046, ENSG00000083123, ENSG00000091140)