單基因遺傳病課件

單基因遺傳病（B）

2.InbornErrorsofMetabolism

Inbornerrorsofmetabolismareraregeneticdisordersinwhichthebodycannotturnfoodintoenergy(metabolizefood)normally.Thedisordersareusuallycausedbydefectsintheenzymesinvolvedinthebiochemicalpathwaysthatbreakdownfoodcomponents.In1904thedoctorArchibaldE.Garroddescribedalkaptonuria,adiseaseheclassifiedasalifelongcongenitalchemicalalteration.Lateron,in1909,hedescribedotherdiseases:albinism,cystinuria,porphyriaandpentosuria,whichhenamed"InbornErrorsofMetabolism".Garrod's

conclusionswerecompletelycorrectinrelationtothegeneticbasisofmetabolicdisordersandthegene-enzymeconcept.Thegenedefectcancauseaparticularenzymetobedefectiveormissing.Andbecausetheenzymeisn'tdoingwhatitissupposedtodoforthebody,poorhealthmayresult.

Simplyput,enzymeshelpthebodybystimulatingbiologicalreactionsinsidecells.Enzymesareproteinsthathelpthebodyusefood,produceenergy,anddowork.Whenaparticularenzymeisdefectiveormissing,thenthebodyisn'tabletodosomethingthatitshoulddotomaintainhealth.Theenzymeinvolveddetermineswhatthebodycan'tdoandwhattheresultingphysicalfeaturesare.

Inbornerrorsofmetabolismaffectabout1inevery5,000babiesborn.Someofthemorefamiliarinbornerrorsofmetabolismarecysticfibrosis,hypothyroidism,,phenylketonuria

(PKU)andTay-Sachsdisease.

Thesymptomsofinbornerrorsofmetabolismvarygreatly.Eachonemustbereviewedseparatelytoknowwhatthephysicalfeaturesare.Often,aninfantwillshowsignsoffailuretothrivebyfailingtogainweight,noteatingwell,andgenerallyshowingdevelopmentaldelay.Vomitinganddiarrheaareamongothersymptomsthatmaysignalthehealthcareprovidertotestforaninbornerrorofmetabolism.

MetabolicdefectResultsinOnsetExampleEnergygenerationEnergydeficitHypoglycemiaConfusionAcuteLOCComaEarlyFirstyearoflifewhenthebabyneedtogeneratehisownenergyUnderstress,whenhavingotherconcurrentillness,URTIFattyacidoxidationdefect(hypoketotic

hypoglycemia)Intoxication,accumulationoftoxicmetabolitesToxicitiytoBrainLiverKidneyDependsonexposuretotoxicsubstance(couldbeearlyorlate)Brain:seizure,confusion,coma,motordysfunction,mentalretardationLiver:cirrhosis,jaundiceGlutaric

aciduriaTypeI,PKUTyrosinemiaInabilitytobreakdownmetabolitesStoragediseasesin:LiverMuscleBrainLeukocytesUsuallylateonsetStoragetakestimestoaccumulateandproducesymptomsMucopolysarrcharidosisGlycogenstoragediseasesUreacycleUnabletoconvertammoniatoureaNeurological:vomiting,coma^^NH3OTCCitrullinemiaLacticacidosisDifferentdisorders^Lactate(frommildtosevere)ClinicalsymptomscommonlyspecificforaparticulardisorderKearn-SayreMELASReye’ssyndromelikeAcuteintoxication

hepaticencephalopathyDependsonspecificdefectVariousdisordersWhatarethesymptomsinIMD

Theenzymedefectsthatleadtotheinbornerrorsofmetabolismarecausedbyabnormalgenes.Inmostcases,theabnormalgeneisautosomalrecessiveincharacter.2.1Phenylketonuria，PKU

Phenylketonuriaisoneofthecommonestinheriteddisorders-occurringinapproximately1in10,000babiesbornintheU.S.Itoccursinbabieswhoinherittwomutantgenesfortheenzymephenylalaninehydroxylase(PAH).Thisenzymenormallybreaksdownmoleculesoftheaminoacidphenylalaninethatareinexcessofthebody'sneedsforproteinsynthesis.Becauseweinherittwocopiesofthegenefortheenzyme,bothmustbedefectivetoproducethedisease.AlaboratorytestthatmeasureshowquicklyaninjectionofphenylalanineisremovedfromthebloodcandistinguishapersonwhohasonePKUgenefromapersonwhohasnone,butthepersonwithoneisperfectlyhealthybecausetheunmutatedalleleproducesenoughoftheenzyme.However,theseheterozygousindividualsare"carriers"ofthedisease.

Thephenylalaninetolerancetest:Ashorttimeafteradministeringameasuredamountofphenylalaninetothesubject,theconcentrationofphenylalanineinthebloodplasmaismeasured.ThelevelisusuallysubstantiallyhigherinpeoplewhocarryonePKUgene(eventhoughtheyshownosignsofdisease)thaninindividualswhoarehomozygousfortheunmutatedgene.Bothparentsmustbeheterozygous(i.e.,mustbe"carriers"ofthetrait)toproduceachildwithPKU.Thechanceoftheirdoingsois1in4.Inabilitytoremoveexcessphenylalaninefromthebloodduringinfancyandearlychildhoodproducesavarietyofproblemsincludingmentalretardation.Fortunately,asimpletest(needingonlyadropofblood)doneshortlyafterbirthcanidentifythegeneticdefectand,withcloseattentiontotheamountofphenylalanineintheirdiet,thechildrencandevelopnormally.Geneticscreeningfor"a"(NOTE:not"the"-manydifferentmutationsinthePKUgenehavebeenidentified)PKUallele.Bytreatment,hersister,whosufferedfromPKUtoo,gotmarriedhealthily.2.2albinism

Albinismisadefectofmelaninproduction.Thisdefectresultsinthepartialorfullabsenceofpigmentfromtheskin,hair,andeyes.InType1albinismdefectsinthemetabolismoftyrosineleadtofailureinconvertingthisaminoacidtomelanin.Thisisduetoageneticdefectintyrosinase--theenzymeresponsibleformetabolizingtyrosine.Type2albinismisduetoadefectinthe"P"gene.Thosewiththistypehaveslightpigmentationatbirth.Inthemostsevereformofalbinism(calledoculocutaneousalbinism),thoseaffectedappeartohavehair,skin,andiriscolorthatarewhiteorpinkaswellasvisiondefects.Thisisinheritedviaanautosomalrecessiveprocess.Apatientwithoculocutaneousalbinismwithwhiteeyebrowsandlashes.Leftfundusofapatientwithalbinism.Notethelackof

RPEpigmentwhichallowsthechoroidalvesselstobecome

clearlyvisible.Thepatientalsohasmaculahypoplasia,

thetemporalarcadeoftheretinalvesselsrunalmost

horizontally.

2.3alkaptonuria

Alkaptonuriaisarareinheriteddisorderofmetabolism,characterizedbyurine

thatturnsblackwhenexposedtoair.Anothercharacteristicisthedevelopmentofarthritisinadulthood.

Alkaptonuriaisanautosomalrecessiveinheriteddisorder.Inaffectedindividuals,anaminoacidknownastyrosineisnotproperlymetabolized,duetoadefectinanenzymecalledhomogentisicacidoxidase.Becauseofthedefect,homogentisicacidisexcretedintheurineandturnsabrowncoloruponexposuretoair.Thisistheresultofadarkpigmentwithanochrecolor(earthyredoryellow),whichledtothenameochronosis.Thebonesandcartilageofthebody

maybebrown-colored.2.4WilsonsdiseaseWilson'sdiseaseisaninheriteddisorderwherethereisexcessiveamountsofcopperinthebody.Thiscausesavarietyofeffects,includingliverdiseaseanddamagetothenervoussystem.Wilson'sdiseaseisarareinheriteddisorder.IfbothparentscarryanabnormalgeneforWilson'sdisease,thereisa25%chancethateachoftheirchildrenwilldevelopthedisorder(i.e.,itisanautosomalrecessivedisease).Wilson'sdiseasecausesthebodytoabsorbandretainexcessiveamountsofcopper.Thecopperdepositsintheliver,brain,kidneys,andtheeyes.Molecularmechanism:ATP7B(wilsoncoppertransportingATPase)Thedepositsofcoppercausetissuedamage,deathofthetissues,andscarring,whichcausestheaffectedorganstostopfunctioningproperly.Liverfailureanddamagetothecentralnervoussystem(brain,spinalcord)arethemostpredominant,andthemostdangerous,effectsofthedisorder.Ifnotcaughtandtreatedearly,Wilson'sdiseaseisfatal.ApatientwithWilson'sdisease

Kayser-Fleischerrings

Labfindingsmayinclude:Serumceruloplasmin-low(althoughitisnormalin5%ofcases)Serumcopper-lowinspiteofthecopperdepositsintissuesUrinecopper-highCBC-mayshowhemolyticanemiaordecreasedwhitebloodcellcountSerumuricacidlevels-lowThefollowingmedicationsmaybeused:Zincacetate(Galzin),whichblockstheabsorptionofcopperintheintestinaltract.Trientine(Syprine),whichbindsorchelatesthecopperandleadstoincreasedurinaryexcretionofthemetal.Penicillamine(Cuprimine,Depen),whichalsobindsorchelatescopperandleadstoincreasedurinaryexcretion.2.5galactosemia

Galactosemiaistheinabilityofthebodytouse(metabolize)thesimplesugargalactose(causingtheaccumulationofgalactose1-phosphate),whichthenreacheshighlevelsinthebody,causingdamagetotheliver,centralnervoussystem,andvariousotherbodysystems.

Galactosemiaisaninheriteddisorder(transmittedasanautosomalrecessivetrait).Itoccursatarateofapproximately1outof60,000births.Thereare3formsofthedisease:galactose-1phosphateuridyl

transferasedeficiency(classicgalactosemia,themostcommonandmostsevereform),deficiencyofgalactose

kinase,anddeficiencyofgalactose-6-phosphateepimerase.Peoplewithgalactosemiaareunabletofullybreakdownthesimplesugargalactose.Galactosemakesuphalfoflactose,thesugarfoundinmilk.Lactoseiscalledadisaccharide(dimeaning2andsaccharidemeaningsugar)becauseitismadeupoftwosugars,galactoseandglucose,boundtogether.Ifaninfantwithgalactosemiaisgivenmilk,derivativesofgalactosebuildupintheinfant'ssystem,causingdamagetotheliver,brain,kidneys,andeyes.Individualswithgalactosemia

cannottolerateanyformofmilk(humanoranimal)andmustcarefullywatchintakeofothergalactose-containingfoods.Exposuretomilkproductsmayresultinliverdamage,mentalretardation,cataractformation,andkidneyfailure.cataractTreatment

Oncethediseaseisrecognized,treatmentconsistsofstrictlyavoidingallmilkandmilk-containingproducts.Theinfantcanbefedwithsoyformula,meat-baseformula,orNutramigen(aproteinhydrolysateformula),orotherlactose-freeformula.Theconditionislifelongandrequiresabstinencefrommilkandmilkproductsforlife.Parentsneedtotakecareandeducatethechildtoavoidnotonlymilkandmilkproducts,butalsothosefoodsthatcontaindrymilkproducts.Forthisreason,itisessentialtoreadproductlabelsandbeaninformedconsumer.2.6G-6-PDdeficiency

G-6-PDdeficiencyisahereditary,sex-linkedenzymedefectthatresultsinthebreakdownofredbloodcellswhenthepersonisexposedtothestressofinfectionorcertaindrugs.G-6-PDdeficiencyisaninheritable,X-linkedrecessivedisorderwhoseprimaryeffectisthereductionoftheenzymeG-6-PDinredbloodcells,causingdestructionofthecells,calledhemolysis.Ultimately,thishemolysisleadstoanemia--eitheracutehemolyticorachronicspherocytictype.Threeclassesofdeficiencyaredescribed,correspondingtothreetypesofenzymaticvariants.Thisclassificationisbasedontheenzymeresidualactivity.class1:veryseveredeficiency,activitycloseto0%class2:severedeficiency,activity<10%class3:moderatedeficiency,activitybetween10and60%class4:variantswithnormalactivityDrugsthatcanbringonthisreactioninclude:antimalarialagentssulfonamides(antibiotic)aspirinnonsteroidalanti-inflammatorydrugs(NSAIDs)nitrofurantoin

quinidine

quinineothers2.8glycogenstoragedisease，GSD

Glucoseisalargeenergysourceforthebody.Itisstoredbythebodyintheformofglycogenandlaterreleasedintothebodywiththehelpofenzymes.

Glycogenstoragedisease(GSD)isagroupofinherited(bornwith)disorderswhereanabnormalamountortypeofglycogensettlesintheliverandcausesfailureoftheliver'sabilitytobreakdownglycogentosupplyglucosetotherestofthebody.Thishappenswhenoneormoreofthemanyenzymes(proteinsproducedbythebody)neededtoconvertsugar(glucose)intoitsstorageform(glycogen)aremissing.typesofGSD

diseasesOMIMdefectedgenesymptomsGSD0240600肝糖原合酶AR,12p12.2GSDⅠa232200葡萄糖-6-磷酸酶AR,17q21低血糖血癥GSDⅠb232220微體葡萄糖-6-磷酸轉(zhuǎn)運AR,11q23巨舌，肌張力減退GSDⅠc232240微體磷酸吡咯轉(zhuǎn)運AR,11q23GSDⅡ232300α-1，4-葡糖苷酶AR,17q25.2GSDⅡb300257α-1，4-葡糖苷酶XR,Xq24GSDⅢ232400淀粉-1，6-葡糖苷酶AR,1p21與I型相似GSDⅣ232500淀粉-(1,4;1,6)轉(zhuǎn)葡糖苷酶AR,3p12肝脾腫大，肝硬化GSDⅤ232600肌磷酸化酶AR,11q13肌無力，肌痙攣GSDⅥ232700肝磷酸化酶AR,14q21低血糖癥生長遲緩GSDⅦ232800肌磷酸果糖激酶AR,12q13.3肌痙攣肌無力肌痛GSDⅧ306000磷酸化酶激酶XR,Xp22.2輕型低血糖癥白內(nèi)障GSDⅨc604549AR2.9Mucopolysaccharidosis

Oneofaseriesofinheritedmetabolicdisordersaffectingatypeofcomplexcarbohydratecalledamucopolysaccharidethatisdepositedinbodytissuesbecausethepersonlacksthespecificenzymeneededtometabolizeit.Thedepositionofmucopolysaccharideintissuesdamagesanddistortsthem,stuntsthechild'sgrowthanddevelopment,limitstheirjointmovementandinsome(butnotall)typesofMPScausesmentalretardation.Theconditionusuallybecomesevidentinearlychildhood.Thatsomethingiswrongmaybenoticedbyparentsordoctors.Thediagnosismaybesuspectedbytheclinicalfeatures.Confirmationofthediagnosis,however,requiresbiochemicaltestsofblood,urine,ortissues.PrenataldiagnosisisfeasibleinalltypesofMPS.Theclassification(asof2001)isasfollows:MPStypeI--Hurlersyndrome,Scheiesyndrome,andHurler-Scheiesyndrome--duetovaryingdegreesofdeficiencyoftheenzymealpha-L-iduronidase

MPStypeII--Huntersyndrome--duetodeficiencyoftheenzymeiduronate

sulfatase

MPStypeIIIA--Sanfilipposyndrome--duetodeficiencyoftheenzymeheparanN-sulfatase

MPStypeIIIB--Sanfilipposyndrome--duetodeficiencyoftheenzymealpha-N-acetylglucosaminidase

MPStypeIIIC--Sanfilipposyndrome--duetodeficiencyoftheenzymeacetylCoA:alpha-glucosaminide

acetyltransferase

MPStypeIIID--Sanfilipposyndrome--duetodeficiencyoftheenzymeN-acetylglucosamine6-sulfataseMPStypeIVA--Morquiosyndrome--duetodeficiencyoftheenzymeN-acetylgalactosamine-6-sulfatesulfatase

MPStypeIVB--Morquiosyndrome--duetodeficiencyoftheenzymebeta-galactosidase

MPStypeVI--Maroteaux-Lamysyndrome--duetodeficiencyoftheenzymeN-acetylgalactosamine-4-sulfataseMPStypeVII--Slysyndrome--duetodeficiencyoftheenzymebeta-glucuronidase

MPStypeVIII--DiFerrantesyndrome--duetodeficiencyoftheenzymeglucosamine-6-sulfateAlltypesofMPSareinheritedasrecessivetraits.Withoneexception,theyareautosomal(notsex-linked).Boysandgirlsalikecanhavethesediseasesiftheyreceivetwocopiesoftherelevantgene,onefromeachoftheirparents.Theriskforeachsubsequentchildis1in4.AlltypesofMPSarelysosomalstoragediseases.Theyinvolveenzymesfoundwithinthecellinlysosomes,miniaturestructuresthatarepacketsofdegradativeenzymes.Inthisrespect,MPSislikealltheotherdisordersoflysosomalstoragesuchasGaucherdisease,Fabrydisease,andPompedisease.Symptomsmayinclude:GrowthfailureMusclecrampsLowbloodsugarAgreatlyenlargedliverAswollenbellyMPStypeIMPStypeII2.10Lesch-Nyhansyndrome

Lesch-Nyhansyndromeisaconditioncharacterizedbytheoverproductionofuricacid,anitrogen-containingcompoundfoundinurine.Problemswiththenervoussystemandbehavioraldisturbancesarecharacteristicofthisdisorder.Theoverproductionofuricacidcancausegoutyarthritis(arthritiscausedbyuricacidinthejoints),aswellaskidneyandbladderstones.Abnormalinvoluntarymusclemovementssuchasflexing,jerking,flinging,andflailingareoftendisplayed.Self-injurythroughbitingandheadban