Maple Syrup Urine Disease Maple Syrup Urine Disease (MSUD) (MSUD) By Jenny Morrison (836445) By Jenny Morrison (836445) Deficiency in branched Deficiency in branched chain alpha-keto acid chain alpha-keto acid dehydrogenase complex dehydrogenase complex (BCKAD) – located in (BCKAD) – located in mitochondrial inner mitochondrial inner membrane membrane Caused by mutation in 4 Caused by mutation in 4 possible genes BCKDHA, possible genes BCKDHA, BCKDHB, DBT, and DLD that BCKDHB, DBT, and DLD that encode for the BCKAD encode for the BCKAD Results in defect in Results in defect in metabolism of branched metabolism of branched chain amino acids (BCAA): chain amino acids (BCAA): Valine, Leucine and Valine, Leucine and Isoleucine Isoleucine Accumulation of BCAA and Accumulation of BCAA and their keto acid derivatives their keto acid derivatives 5 clinical subtypes: 5 clinical subtypes: “classic” “classic” “intermittent”, “mild”, “intermittent”, “mild”, Thiamine responsive, Thiamine responsive, and E3-deficient with and E3-deficient with lactic acidosis. lactic acidosis. Classification of Classification of subtypes according to subtypes according to nature of gene mutation nature of gene mutation by genetic by genetic complementation complementation analysis after somatic analysis after somatic cell hybridisation cell hybridisation (1980) (1980) Classic MSUD is the Classic MSUD is the most severe and most most severe and most common form common form
16
Embed
Maple Syrup Urine Disease (MSUD) By Jenny Morrison (836445) Deficiency in branched chain alpha-keto acid dehydrogenase complex (BCKAD) – located in mitochondrial.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Deficiency in branched chain Deficiency in branched chain alpha-keto acid alpha-keto acid dehydrogenase complex dehydrogenase complex (BCKAD) – located in (BCKAD) – located in mitochondrial inner membranemitochondrial inner membrane
Caused by mutation in 4 Caused by mutation in 4 possible genes BCKDHA, possible genes BCKDHA, BCKDHB, DBT, and DLD that BCKDHB, DBT, and DLD that encode for the BCKADencode for the BCKAD
Results in defect in Results in defect in metabolism of branched chain metabolism of branched chain amino acids (BCAA): Valine, amino acids (BCAA): Valine, Leucine and Isoleucine Leucine and Isoleucine
Accumulation of BCAA and Accumulation of BCAA and their keto acid derivativestheir keto acid derivatives
5 clinical subtypes: “classic” 5 clinical subtypes: “classic” “intermittent”, “mild”, Thiamine “intermittent”, “mild”, Thiamine responsive, and E3-deficient responsive, and E3-deficient with lactic acidosis.with lactic acidosis.
Classification of subtypes Classification of subtypes according to nature of gene according to nature of gene mutation by genetic mutation by genetic complementation analysis after complementation analysis after somatic cell hybridisation somatic cell hybridisation (1980)(1980)
Classic MSUD is the most Classic MSUD is the most severe and most common formsevere and most common form
4 of the MSUD 4 of the MSUD clinical subtypesclinical subtypes
Onset in the first week of life:Onset in the first week of life: Maple syrup odour (in urineMaple syrup odour (in urine and on body)and on body) Feeding difficulties andFeeding difficulties and vomitingvomiting Shrill cryShrill cry Hypertonicity (episodesHypertonicity (episodes alternate with flaccidity)alternate with flaccidity) No Moro reflex and No Moro reflex and suppressed deep tendonsuppressed deep tendon reflexesreflexes Frequent convulsionsFrequent convulsions Survivors suffer from severeSurvivors suffer from severe mental retardation & motormental retardation & motor development retardationdevelopment retardation
1 in 185,000 newborns world wide (Chuang et al, 1995) 1 in 185,000 newborns world wide (Chuang et al, 1995) 1 in 176 newborns in the Mennonite population of Lancaster, 1 in 176 newborns in the Mennonite population of Lancaster,
Pennsylvania (due to consanguinity)Pennsylvania (due to consanguinity) Panethnic distributionPanethnic distribution
Genetic CounsellingGenetic Counselling Relatives of the affected individual have high genetic risks (1 in 4)Relatives of the affected individual have high genetic risks (1 in 4)
Extremely low risks to offsprings of healthy sibs or more distantExtremely low risks to offsprings of healthy sibs or more distant
relatives relatives
Molecular genetics of the BCKADMolecular 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
Protein SequenceProtein SequenceMAVAIAAARVWRLNRGLSQAALLLLRQPGARGLARSHMAVAIAAARVWRLNRGLSQAALLLLRQPGARGLARSHPPRQQQQFSSLDDKPQFPGASAEFIDKLEFIQPNVISGIPPRQQQQFSSLDDKPQFPGASAEFIDKLEFIQPNVISGIPIYRVMDRQGQIINPSEDPHLPKEKVLKLYKSMTLLNTPIYRVMDRQGQIINPSEDPHLPKEKVLKLYKSMTLLNTMDRILYESQRQGRISFYMTNYGEEGTHVGSAAALDNTMDRILYESQRQGRISFYMTNYGEEGTHVGSAAALDNTDLVFGQYREAGVLMYRDYPLELFMAQCYGNISDLGKGDLVFGQYREAGVLMYRDYPLELFMAQCYGNISDLGKGRQMPVHYGCKERHFVTISSPLATQIPQAVGAAYAAKRRQMPVHYGCKERHFVTISSPLATQIPQAVGAAYAAKRANANRVVICYFGEGAASEGDAHAGFNFAATLECPIIFFANANRVVICYFGEGAASEGDAHAGFNFAATLECPIIFFCRNNGYAISTPTSEQYRGDGIAARGPGYGIMSIRVDGCRNNGYAISTPTSEQYRGDGIAARGPGYGIMSIRVDGNDVFAVYNATKEARRRAVAENQPFLIEAMTYRIGHHSTNDVFAVYNATKEARRRAVAENQPFLIEAMTYRIGHHSTSDDSSAYRSVDEVNYWDKQDHPISRLRHYLLSQGWWSDDSSAYRSVDEVNYWDKQDHPISRLRHYLLSQGWWDEEQEKAWRKQSRRKVMEAFEQAERKPKPNPNLLFSDEEQEKAWRKQSRRKVMEAFEQAERKPKPNPNLLFSDVYQEMPAQLRKQQESLARHLQTYGEHYPLDHFDKDVYQEMPAQLRKQQESLARHLQTYGEHYPLDHFDK
Protein sequenceMAVVAAAAGWLLRLRAAGAEGHWRRLPGAGLARGFLHPAATVEDAAQRRQVAHFTFQPDPEPREYGQTQKMNLFQSVTSALDNSLAKDPTAVIFGEDVAFGGVFRCTVGLRDKYGKDRVFNTPLCEQGIVGFGIGIAVTGATAIAEIQFADYIFPAFDQIVNEAAKYRYRSGDLFNCGSLTIRSPWGCVGHGALYHSQSPEAFFAHCPGIKVVIPRSPFQAKGLLLSCIEDKNPCIFFEPKILYRAAAEEVPIEPYNIPLSQAEVIQEGSDVTLVAWGTQVHVIREVASMAKEKLGVSCEVIDLRTIIPWDVDTICKSVIKTGRLLISHEAPLTGGFASEISSTVQEECFLNLEAPISRVCGYDTPFPHIFEPFYIPDKWKCYDALRKMINY
Alternate splicing results in 2 transcripts that encode the same protein
2 regulatory enzymes: kinase and 2 regulatory enzymes: kinase and phosphotasephosphotase
Encoded by 6 genetic lociEncoded by 6 genetic loci Mutation in any of the loci can result in Mutation in any of the loci can result in
defectdefect Defect in BCKAD causes a block in BCKA Defect in BCKAD causes a block in BCKA
oxidative decarboxylationoxidative decarboxylation Accumulation of BCKAAccumulation 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 DiagnosisScreening and Diagnosis Prenatal diagnosisPrenatal diagnosis
analysis of cultured amniocytes obtained at mid-trimester analysis of cultured amniocytes obtained at mid-trimester amniocentesisamniocentesis
direct analysis of tissues or cultured cells from chorionic villi sample direct analysis of tissues or cultured cells from chorionic villi sample taken during first trimestertaken during first trimester
Use allele-specific oligonucleotide (ASO) probe following PCR to detect Use allele-specific oligonucleotide (ASO) probe following PCR to detect mutation in DNA obtained from amniocytes mutation in DNA obtained from amniocytes
Attempts at measuring amniotic fluid concentration of BCAA, BCKA Attempts at measuring amniotic fluid concentration of BCAA, BCKA and and αα-hydroxyacids have been unsuccessful-hydroxyacids have been unsuccessful
Increase leucine levels in blood spotsIncrease leucine levels in blood spotsDetect classic, intermediate and E3-deficient MSUD but intermediateDetect classic, intermediate and E3-deficient MSUD but intermediatemay be missed due to lower leucine levels than classicmay be missed due to lower leucine levels than classic
Tandem mass spectroscopy coupled with fast atom bombardment Tandem mass spectroscopy coupled with fast atom bombardment (FAB) ionisation (FAB) ionisation
Detect organic acids and amino acids abnormalities in blood and Detect organic acids and amino acids abnormalities in blood and urineurine
samples on filter papersamples on filter paper
Screening and Diagnosis cont.Screening and Diagnosis cont. General diagnosis or genetic studiesGeneral diagnosis or genetic studies
Urine 2,4-dinitrophenylhydrazine (DNPH) testUrine 2,4-dinitrophenylhydrazine (DNPH) test Gas chromatographic mass spectroscopy (GC-MS)Gas chromatographic mass spectroscopy (GC-MS) Enzymic studies of cell cultures (skin fibroblasts and lymphoblasts)Enzymic studies of cell cultures (skin fibroblasts and lymphoblasts) Allele-specific oligonucleotide (ASO) probingAllele-specific oligonucleotide (ASO) probing
Historical perspectiveHistorical perspective
Diagnosis relied on the recognition of clinical symptoms and signs and Diagnosis relied on the recognition of clinical symptoms and signs and Chemical and enzymological analysis were performed if indicated Chemical and enzymological analysis were performed if indicated (Galjaard 1980)(Galjaard 1980)
Therapies and Management Therapies and Management Long term dietary managementLong term dietary management Restrict intake of BCAA in diet to Restrict intake of BCAA in diet to
the amount essential for growththe amount essential for growth Start as soon as possible and Start as soon as possible and
continue for lifecontinue for life Treat classic and intermediate Treat classic and intermediate
MSUD patients the same wayMSUD patients the same way For intermittent MSUD, decrease For intermittent MSUD, decrease
protein intake during episodesprotein intake during episodes Monitor plasma BCAA levels Monitor plasma BCAA levels
weekly for the first 6 months and weekly for the first 6 months and keep as close to normal as keep as close to normal as possiblepossible
A trial of thiamine therapy is A trial of thiamine therapy is recommended to determine recommended to determine thiamine responsiveness in all thiamine responsiveness in all new patientsnew patients
History of dietary therapiesHistory of dietary therapiesDietary therapies started in 1959.Dietary therapies started in 1959.Gelatin has low BCAA and was Gelatin has low BCAA and was used as a source of BCAA in used as a source of BCAA in England in the early days. A England in the early days. A synthetic formula was developed by synthetic formula was developed by Snyderman et al in the United Snyderman et al in the United States which consisted of 18 amino States which consisted of 18 amino acids (based on breastmilk acids (based on breastmilk composition) carbohydrates, fat, composition) carbohydrates, fat, minerals and vitamins. Based on minerals and vitamins. Based on this formula, other commercial this formula, other commercial medical diets have since been medical diets have since been created. created.
Therapies and Management cont.Therapies and Management cont.Acute-phase managementAcute-phase management Infection and stress can cause a significant accumulation of BCAA and BCKA which can Infection and stress can cause a significant accumulation of BCAA and BCKA which can
be life threateningbe life threatening Treatment involves:Treatment involves:
Rapid removal of toxic metabolitesRapid removal of toxic metabolitesExchange transfusionExchange transfusion (early 1960’s) achieved limited success (early 1960’s) achieved limited successPeritoneal dialysisPeritoneal dialysis (1969) produced significant improvement within hours. (1969) produced significant improvement within hours.
It is simple to implement and has become an established procedure forIt is simple to implement and has become an established procedure for treating patients in crisis treating patients in crisis
HemodialysisHemodialysis is equally successful but requires specialised equipment is equally successful but requires specialised equipment and personneland personnel
CContinuous arteriovenous hemoperfusion ontinuous arteriovenous hemoperfusion can be used for adults butcan be used for adults but hashas technical limitations when applied to newbornstechnical limitations when applied to newborns Parenteral Nutritional therapyParenteral Nutritional therapy
BCAA-freeBCAA-free L-amino acid mixture combined with glucose, lipid, electrolytes L-amino acid mixture combined with glucose, lipid, electrolytes and vitaminsand vitamins Minimise catabolic state and/or promote anabolismMinimise catabolic state and/or promote anabolism
use use insulin and carbohydrateinsulin and carbohydrate to promote anabolism to promote anabolism
Key ReferencesKey References Bondy, P.K. & Rosenberg, L.C. 1980, Bondy, P.K. & Rosenberg, L.C. 1980, Metabolic Control and Disease, Metabolic Control and Disease, 8th 8th
Edition, W.B. Saunders Company, PhiladelphiaEdition, W.B. Saunders Company, Philadelphia Galjaard, H. 1980, Galjaard, H. 1980, Genetic Metabolic Diseases: Early Diagnosis and Prenatal Genetic Metabolic Diseases: Early Diagnosis and Prenatal
and Keto Acid Metabolism’, in and Keto Acid Metabolism’, in The Metabolic and Molecular Bases of The Metabolic and Molecular Bases of Inherited Diseases, Inherited Diseases, vol. 1,vol. 1, 77thth Edition, eds Scriver et al., McGraw-Hill, New Edition, eds Scriver et al., McGraw-Hill, New YorkYork
Other therapiesOther therapies Introducing subunits of BCKDH enzyme into cells using a retrovirousIntroducing subunits of BCKDH enzyme into cells using a retrovirous Liver transplantLiver transplant Somatic gene therapySomatic gene therapy
Therapies and Management cont.Therapies and Management cont.