Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Artificial gene synthesis wikipedia , lookup
Catalytic triad wikipedia , lookup
Point mutation wikipedia , lookup
Gene therapy of the human retina wikipedia , lookup
Biochemistry wikipedia , lookup
Gene therapy wikipedia , lookup
Biosynthesis wikipedia , lookup
Aminoacidandpeptidemetabolism 67 Disorders of phenylalanine and tyrosine metabolism Biochemistry Phenylketones Phenylalanine Phenylalanine and tyrosine metabolism PAH takes place in the cytosol.A deficiency 4-OH-phenylTyrosine oftheenzymephenylalanine hydroxylase compounds Aminotransferase (PAH)orthecofactortetrahydrobiopterin (BH4)causestheaccumulationofphenyl4-OH-Phenylpyruvate 4-OH-phenylalaninewhichistransaminatedtophenylcompounds Dioxygenase pyruvate. The cleavage of the phenolic ringisonlypossiblebydioxygenationof BenzoquinoneHomogentisate homogentisate. acetate Dioxygenase AdeficiencyoftheenzymefumarylacetoacetasecausesaccumulationoffumarylSuccinylMaleylacetoacetate acetoacetateandsuccinylacetoacetateand acetoacetate, Succinylacetone -acetone. These highly toxic substances Fumarylacetoacetate inhibit several enzymes incl. 4-OHFumarylacetoacetase phenylpyruvatedioxygenaseandaminolaevulinatedehydrataseandarecarcinoFumarate Acetoacetate genic(alkylationofDNA). Phenylketonuria (PKU) PKUwasoneofthefirstneurogeneticdisordersidentified(Følling1934),thefirstsuccessfully treatedinbornerrorofmetabolism(diet:Bickel1953)andthedisorderthatwasinstrumentalfor theintroductionofneonatalpopulationscreening(driedbloodspots:Guthrie1963). Clinical: Untreated:severebraindamagewithintellectualdisability,seizures,spasticity Variants: PKU:requiresdiet(differencesindiseaseseverity/Phetolerance:severePKU=homozygousnullmutation,mildPKU=atleastonehypomorphic/residualfunctionmutation) MHP:mildhyperphenylalaninaemia,doesnotrequirediettherapy(Phe<600 µmol/l inGermany,<400 µmol/lintheUK,<420 µmol/lintheUSA) “BH4-sensitive PKU”:reductionofPhelevelsafterBH4supplementationinmanypatientswithmildPKU(stabilisation/activationofmutantprotein) Enzyme: Phenylalaninehydroxylase;PAHgene Genetics: >600mutationsinthePAHgene,varyingresidualactivities(seePAHmutationdatabase:www.pahdb.mcgill.ca) Incidence: InEuropeupto1:4,400(Ireland),average~1:8,000 Diagn.: Newbornscreening(filterpapercard),AA(plasma):↑ Phe,n–↓ Tyr;mutationanalysismayallowpredictionofseverityandBH4sensitivity DD: BH4cofactordeficiency(seepage 153) Therapy: Phe-restricteddiet,supplementationofessentialaminoacids+traceelements(exact recommendationsdifferbetweencountries;seebelowfortheGermanrecommendations);BH4supplementationinmildPKU(notallpatients) Progn.: Normaldevelopmentandintelligencewithimmediateandefficienttreatment Maternal PKU FetopathyinpregnantmotherswithPKU(Phe>360 µmol/l);strictdiettreatmentmustbestartedbeforeconceptionandmaintainedthroughoutpregnancy! 68 Metabolicpathwaysandtheirdisorders German recommendations for PKU treatment Phevalues40–240 µmol/l(0.7–4mg/dl) Goal: 1st–10thyr: Phevalues40–900 µmol/l(0.7–15mg/dl) 11th–16thyr: Phevalues<1,200 µmol/l(<20mg/dl) After16yrs: Phevalues120–360 µmol/l(2–6mg/dl) Duringpregnancy: Follow-up: 1styr: Labevery1–2wks,clinicalevery3mths Labevery2–4wks,clinicalevery3–6mths 2nd–10thyr: Labevery4wks,clinicalevery6mths 11th–16thyr: Labevery2–3mths,clinicalevery6–12mths After16yrs: Tyrosinaemia type I Clinical: Acute (neonate/infant):severeliverfailure,vomiting,bleeding,septicaemia,hypoglycaemia,renaltubulopathy(Fanconisyndrome) Chronic:hepatomegaly,cirrhosis,growthretardation,rickets,haematoma,tubulopathy,neuropathy,neurologicalcrises(duetoporphyrins) Enzyme: Fumarylacetoacetase;FAHgene Diagn.: OA(urine):(n–) ↑ Succinylacetone(diagnostic),↑ 4-OH-phenylderivatives;AA(plasma):(n–)↑ Tyr,↑ Met(!);(n–)↑ a-fetoprotein(serum);porphyrins(urine):↑ d-aminolaevulinicacid;aminolaevulinatedehydrataseactivity(possibleinDBS) DD: Liverdisorders,inparticular“neonatalhepatitis”,respiratorychaindefects,galactosaemia,fructoseintolerance,bileacidsynthesisdisorders Therapy: Nitisinone(NTBC)1(–2)mg/kgin2doses(inhibitorof4-OH-phenylpyruvatedioxygenase,blockstheaccumulationoftoxicmetabolites;bewareof↑Tyr);Phe-+Tyrrestricteddiet;livertransplantationprobablynotlongerneededinmostpatients Progn.: Withnitisinonegood(long-termprognosisstillunclear) Compl.s: Hepatocellularcarcinoma(watchAFP),renalfailure Tyrosinaemia type II Clinical: Painfulcorneallesions(lacrimation,photophobia,scars),hyperkeratosis(soles,palms), mildintellectualdisability Enzyme: Cytosolictyrosineaminotransferase;TATgene Diagn.: AA(plasma):↑↑ Tyr,↑ Phe;OA(urine):4-OH-phenylpyruvate,-lactate,-acetate Therapy: Phe-andTyr-restricteddiet Alkaptonuria Clinical: Enzyme: Diagn.: Therapy: Black/brown/redurinediscolourationatalkalinepH;arthritis,cardiacvalvedisease Homogentisatedioxygenase;HGDgene OA(urine):↑↑ homogentisicacid Low-proteindiet,possiblyNTBC(study) Other disorders of tyrosine metabolism • TyrosinaemiatypeIII:4-Hydroxyphenylpyruvatedioxygenasedeficiency,HPDgene;uncertainclinicalrelevance,noskinlesions;aPheandTyr-restricteddietisrecommended • Hawkinsinuria:unknownenzyme;doubtfulclinicalrelevance;failuretothrive,acidosis 69 Aminoacidandpeptidemetabolism Disorders of the metabolism of sulphur amino acids Biochemistry (incl. folic acid cycle/cytosolic methyl group transfer) Folic acid Serine Methionine Tetrahydrofolate Glycine S-Adenosylmethionine 5,10 Methylene tetrahydrofolate Vitamin B12 MTHFR 5-Methyl tetrahydrofolate MS Methylation reactions Betaine S-Adenosylhomocysteine Homocysteine Serine CBS Cystathionine CTH Homoserine Cysteine Sulphite SO Sulphate S-Adenosylmethionine (SAM), is the most important methyl group donor in cellular metabolism.Remethylationofhomocysteinetomethionineiscatalysedmainlybythecobalamin-(vit.B12-)dependentmethioninesynthase(MS)oralternativelybetaine-homocysteine methyltransferase (methyl group donor betaine). The methyl group is transferred onto cob(I) alamin(cblI)from5,10-methylenetetrahydrofolatewhichisregeneratedinthefolate cycle.Thebreakdownofhomocysteinetocysteineiscatalysedbythevit.B6-dependentenzymescystathioninebeta-synthase(CBS)undcystathioninegamma-lyase(CTH).Cysteineis furthercatabolisedviacysteinesulphinate(precursoroftheaminoacidtaurine,acomponent ofthebileacids)tosulphitewhichisoxidisedtosulphatebythemolybdenum-containing enzymesulphiteoxidase(SO)andexcretedintheurine. 70 Metabolicpathwaysandtheirdisorders Methionineandhomocysteineplayacentralroleincytosolicmethylgrouptransferrequiredfor arangeoffunctionsincl.thesynthesisofcreatine,cholineandadrenalineaswellasDNAmethylation.Disordersofthecytosolicmethylgrouptransfermayalsobeduetoprimarydisordersof cobalamin(vit.B12)orfolatemetabolism(seepages 156, 157);theyfrequentlycausesevereneurologicaldisorders;symptomsmayalsoberelatedtovascularcomplicationsofelevatedhomocysteine. Homocysteine(Hcy)andcysteine(Cys)areusuallyfoundasdisulphides(homocystineandcystine)intheextracellularspace.MildelevationsofHcyinplasma(centrifugeimmediately,analysisseepage 33)canonlybedetectedthroughaspecificmethod(e.g.HPLC).Classicalhomocystinuria,however,mayalsoberecognisedbyapositivenitroprussidetest(Brandreaction,see page 31)intheurine.Cystinosis(page 141)andcystinuria(page 76)arecausedbylysosomaland renaltransportdefects. Isolated hypermethioninaemia Clinical: Oftenasymptomatic,cabbage-likeodour,intellectualdisability,neurologicaldisease, demyelination Enzyme: MethionineadenosyltransferaseI/III;MAT1Agene Diagn.: ↑↑ Met Therapy: Insymptomaticpatients,Met-restricteddietand/orSAMadministration DD: Glycine N-methyltransferase deficiency(GNMTgene):↑↑ Met,SAM;↓ S-adenosylhomcysteine;maybeacoincidentalfinding S-Adenosylhomocysteine hydrolase deficiency Clinical: Progressiveintellectualdisability,neurologicaldisease,hypomyelinationandwhite matteratrophy Diagn.: ↑ Met;↑↑ SAM; S-adenosylhomcysteine;↑ CK;gene: AHCY Therapy: Met-restricteddiet Methionine synthase deficiency (cblG disease) Clinical: Megaloblasticanaemia,progressiveintellectualdisability,neurologicaldisease,psychiatricdisturbance Diagn.: ↑ Hcy(>150 µmol/l);AA(plasma):n–↓ Met;OA(urine):↑ methylmalonicacid(cobalamindefects);nitroprussidetestpositive;gene: MTR Therapy: HO-cobalamin(1mg/day–weeki.m.,dosedependsondefect);considerbetaine(75 mg/kg/day)andfolicacid5–10mg/day DD: Methionine synthase reductase deficiency:cblEdisease,MTRRgene;activation/regenerationofcatalyticallyinertcblII(formedevery200–1,000MScatalyticcycles)to cblI