此ppt下載后可自行編輯進行性肌營養(yǎng)不良新進展進行性肌營養(yǎng)不良定義分類假肥大型肌營養(yǎng)不良肢帶型肌營養(yǎng)不良面肩肱型肌營養(yǎng)不良強直性肌營養(yǎng)不良PMD的定義PMD是一組進行性發(fā)展的以骨骼肌變性為主要特征的遺傳性疾病，許多類型已經(jīng)確定為某種肌纖維膜或核膜蛋白的異常所致。PMD的定義骨骼肌變性—進行性肌肉萎縮、無力；無感覺障礙遺傳性疾病—有家族史；可以進行基因診斷，基因治療蛋白異常—可以用免疫組化或蛋白印跡方法診斷PMD分類—傳統(tǒng)分類1.假肥大型Duchenne/Becker2.Emery-Dreifuss3.肢帶型Limb-girdle4.面肩肱型Fascioscapulohumeral5.遠端型Distal眼咽型Oculopharyngeal強直型Myotonicdystrophy先天性CongenitalPMD分類—遺傳學分類Sex-linkedMDs

DuchenneBeckerEmery-DreifussAutosomaldominantMDs

Fascioscapulohumeral

（面肩肱型）Limb-girdleDistalOculopharyngeal（眼咽型）MyotonicdystrophyAutosomalrecessiveMD

-limb-girdleformPMD的分子遺傳學分類：依據(jù)基因定位與編碼蛋白DystrophinopathyDuchenne肌營養(yǎng)不良（DMD）Becker肌營養(yǎng)不良（BMD）單獨表現(xiàn)為X連鎖的心肌病單獨表現(xiàn)為股四頭肌肌病肌肉痙攣伴肌紅蛋白尿無癥狀性肌酶升高具DMD/BMD表現(xiàn)的女性攜帶者EtiologyandPathogenesisdystrophin

基因變異目前發(fā)現(xiàn)的人體最大的基因定位在X染色體短臂

(Xp21)

長度接近

3millionbp

編碼79個

exons

dystrophin蛋白缺失或缺乏

是一個

427kd蛋白

定位在肌膜（

sarcolemma）內(nèi)面有

4個功能區(qū)

DystrophinGeneandProteinDystrophin的組織特異性Muscletype,427kd---presentinskeletal,CardiacandsmoothmuscleBraintype,427kd---presentincerebralCortexandhippocampus

（為什么DMD可出現(xiàn)智能減退）Purkinjetype,427kd---presentinPurkinjeCellsFunctionofDystrophin

Dystrophin是肌纖維膜細胞骨架的成分是肌細胞膜和細胞外基底層之間的連系

因此，構成肌纖維收縮和松弛時肌膜保持機械性穩(wěn)定的結構基礎。GeneticsofDMDDMD是最常見和最嚴重的MDX連鎖隱性遺傳

2/3病例具有家族史：母親是攜帶者，患兒已經(jīng)有一兄弟或舅舅或表兄弟患病

1/3病例為散發(fā)：可能是新的突變發(fā)病率：累及約1/3500活產(chǎn)男嬰DMD的臨床表現(xiàn)3-5歲發(fā)病:

1.發(fā)育遲緩：學會走路較正常兒童晚3-6月)---mostcommonway2.CK,ALT,AST升高---多數(shù)在入托查體時驗血發(fā)現(xiàn)ALT、AST高于正常，被懷疑有肝病

第一個突出表現(xiàn)是跑步困難，跳躍不能，上樓梯和爬坡費力

進行性對稱性肌肉萎縮無力近端肌重于遠端肌

早期:骨盆帶肌,腰骶脊肌和肩帶肌

晚期:擴展至小腿、前臂及頸肌肌肉假性肥大腓腸肌、舌肌等由于肌纖維變性壞死，被纖維結締組織取代步態(tài)異常---鴨步搖擺不穩(wěn)，步基寬，脊柱過度前突，跟腱攣縮經(jīng)常摔倒肌無力進行性發(fā)展

7-13歲喪失行走能力

依賴輪椅或臥床15-25歲死于呼吸功能衰竭(90%)或心力衰竭

(10%)其它受累系統(tǒng)

骨骼關節(jié)攣縮：踝、髖、膝關節(jié)

脊柱側突擴張性心肌病

智能障礙:MeanIQ~88(rareinChinesepatients)實驗室檢查血清肌酶升高(amarkerofmusclebreakdown)CK:Veryhigh:50-100倍正常值其它:HighAST,ALT,LDH肌電圖:肌源性改變肌肉活檢:典型的肌營養(yǎng)不良改變

Dystrophin免疫組化WesternblotGene檢測PathologyofDMD肌纖維大小不等:萎縮和肥大肌纖維變性、再生，可見中央核纖維不透明纖維晚期；肌內(nèi)衣纖維化肌纖維被結締組織和脂肪組織取代Dystrophin

免疫組化

:缺乏(DMD)WesternBlotofDystrophinLane1:BMD;Dystrophinhasreducedabundancebutnormalsize.Lane2:BMD;Dystrophinhasreducedsizeandabundance.Lane3:normal;Dystrophinhasnormalsizeandamount.Lane4:DMD;Almostnoproteinispresent.Lane5:outlier;DystrophinhasseverelyreducedabundanceDMD診斷XR遺傳(有家族史)典型的臨床表現(xiàn)血清肌酶顯著升高:CK,LDH,AST,ALT肌電圖:肌源性改變肌肉活檢典型的肌營養(yǎng)不良特征

Dystrophin免疫染色基因檢查:PCRorpointmutationscreeningDifferentialDiagnosis1脊肌萎縮癥肢體近端肌肉無力(Pelvicandshouldergirdle)肌肉萎縮伴纖顫肌酶:正常EMG:神經(jīng)源性改變肌活檢:群組化DifferentialDiagnosis2慢性多發(fā)性肌炎無家族史肌活檢:炎性改變可以治療Treatments目前仍無特異性治療小劑量強的松可能使疾病發(fā)展暫時減慢或增強肌力（0.75mg/kg/天）呼吸支持，理療、外科矯形、糾正攣縮，輪椅等其它設施，心理治療—改善患者生活質(zhì)量有希望的治療成肌細胞移植治療基因治療病毒載體基因治療干細胞治療氨基糖甙類抗生素治療基因治療的難題Dystrophin基因太大難以放入病毒基因載體---微基因相當數(shù)量肌肉細胞有基因表達才能改善肌力免疫排斥問題攜帶者檢出CK肌肉活檢以及dystrophin染色基因分析產(chǎn)前診斷前提條件：先證者檢出外顯子缺失方法：羊水細胞（16周）絨毛膜細胞（8周）PCR或/和Southernblot未來：胚胎種植前的DNA檢測產(chǎn)前診斷前提條件：通過連鎖或單倍體分析發(fā)現(xiàn)基因異常方法：用絨毛膜細胞（8周）DNA行單倍體分析如果上述均未見異常---胎兒肌活檢（孕19周后）檢測dystrophin陰性結論不能保證胎兒一定不是DMD倫理學、法律問題遺傳咨詢有家族史者，容易散發(fā)病例，困難：生殖鑲嵌現(xiàn)象（germlinemosaicism）---再次生育男嬰有7-10%患病危險，母親和姐妹可能是攜帶者BeckerMuscularDystrophy發(fā)生率：1outof30,000livemalebirths臨床表現(xiàn)與DMD相似

發(fā)病較DMD晚（5-15years)，癥狀較DMD輕

15-20歲后仍能行走通常壽命在

30歲以上，甚至接近正常CK一般較DMD患者水平低,但也可能高達10,000IU/LDystrophin免疫染色:reducedstaining/patchydistribution(BMD)BeckerMuscularDystrophy少見臨床表現(xiàn):肌紅蛋白尿伴持續(xù)性CK升高活動后肌肉痙攣和肌痛肢帶型肌營養(yǎng)不良LGMD二十世紀50年代，Walton和Nattrass第一次將LGMD作為一個疾病類型提出來，以區(qū)別于DMD和FSHD.

按上述特征診斷的LGMD實際上包括一大類神經(jīng)肌肉疾病—肢帶綜合征：如慢性進行性脊髓性肌萎縮或Kugelberg-Welander病，多發(fā)性肌炎，內(nèi)分泌性肌病，一些先天性和代謝性肌病。因此，排除其它疾病成了一個重要的診斷標準，而LGMD能否作為一個獨立的疾病類型也引起了神經(jīng)肌肉病學家的廣泛爭論。

分子遺傳學的進步和對歐洲、美洲一些部落中大家系的分析神經(jīng)肌肉病學家提出了一個以基因位點為基礎的分類方法，包括常染色體顯性遺傳型LGMD1A、1B、1C，常染色體隱性遺傳型LGMD2A-2I等類型，是依據(jù)基因位點確定的順序命名的(表)。

Table1.Autosomal

RecessiveLimb-GirdleMuscularDystrophy(LGMD):MolecularGenetics%ofIindividualswithARLGMDDiseaseNamePopulationswithFounderMutationsLocus

NameGene

Symbol

LocusProtein

ProductMolecularGeneticTestAvail-

abilityUpto68%ofindividualswithchildhoodonsetand~10%withadultonset

1

Alpha-

sarcoglycan-opathyNoneLGMD2DSGCA

17q12-

q21.3Alpha-

sarcoglycanClinical

Beta-

sarcoglycan-opathyAmishLGMD2ESGCB

4q12Beta-

sarcoglycanClinical

Gamma-

sarcoglycan-opathy

(formerly

SCARMD)

2

NorthAfricans;Gypsies;

rare

elsewhereLGMD2CSGCG

13q12Gamma-

sarcoglycanClinical

Delta-

sarcoglycan-opathyBrazilian;veryrareelsewhereLGMD2FSGCD

5q33Delta-

sarcoglycanClinical

~10-30%Calpain-opathyAmish,LaReunionIsland,Basque(Spain),TurkishLGMD2ACAPN3

15q15.1-

q21.1Calpain3Clinical

~10%Dysferlin-opathy

Miyoshi

distal

myopathyLibyanJewishLGMD2BDYSF

2p13.3-

p13.1DysferlinClinical

RareTelethonin-opathyItalian(?)LGMD2GTCAP

17q12TelethoninResearchonlyUnknownLGMD2HManitobaHutteritesLGMD2HTRIM32

9q31-

q34.1Zinc-fingerproteinHT2AUnknownLGMD2IUnknownLGMD2IFKRP

19q13.3Fukutin-relatedproteinClinical

Table1.Autosomal

RecessiveLimb-GirdleMuscularDystrophy(LGMD):MolecularGenetics%ofIindividualswithARLGMDDiseaseNamePopulationswithFounderMutationsLocus

NameGene

Symbol

LocusProtein

ProductMolecularGeneticTestAvail-

abilityUpto68%ofindividualswithchildhoodonsetand~10%withadultonset

1

Alpha-

sarcoglycan-opathyNoneLGMD2DSGCA

17q12-

q21.3Alpha-

sarcoglycanClinical

Beta-

sarcoglycan-opathyAmishLGMD2ESGCB

4q12Beta-

sarcoglycanClinical

Gamma-

sarcoglycan-opathy

(formerly

SCARMD)

2

NorthAfricans;Gypsies;

rare

elsewhereLGMD2CSGCG

13q12Gamma-

sarcoglycanClinical

Delta-

sarcoglycan-opathyBrazilian;veryrareelsewhereLGMD2FSGCD

5q33Delta-

sarcoglycanClinical

~10-30%Calpain-opathyAmish,LaReunionIsland,Basque(Spain),TurkishLGMD2ACAPN3

15q15.1-

q21.1Calpain3Clinical

~10%Dysferlin-opathy

Miyoshi

distal

myopathyLibyanJewishLGMD2BDYSF

2p13.3-

p13.1DysferlinClinical

RareTelethonin-opathyItalian(?)LGMD2GTCAP

17q12TelethoninResearchonlyUnknownLGMD2HManitobaHutteritesLGMD2HTRIM32

9q31-

q34.1Zinc-fingerproteinHT2AUnknownLGMD2IUnknownLGMD2IFKRP

19q13.3Fukutin-relatedproteinClinical

Table1.Autosomal

RecessiveLimb-GirdleMuscularDystrophy(LGMD):MolecularGenetics%ofIindividualswithARLGMDDiseaseNamePopulationswithFounderMutationsLocus

NameGene

Symbol

LocusProtein

ProductMolecularGeneticTestAvail-

abilityUpto68%ofindividualswithchildhoodonsetand~10%withadultonset

1

Alpha-

sarcoglycan-opathyNoneLGMD2DSGCA

17q12-

q21.3Alpha-

sarcoglycanClinical

Beta-

sarcoglycan-opathyAmishLGMD2ESGCB

4q12Beta-

sarcoglycanClinical

Gamma-

sarcoglycan-opathy

(formerly

SCARMD)

2

NorthAfricans;Gypsies;

rare

elsewhereLGMD2CSGCG

13q12Gamma-

sarcoglycanClinical

Delta-

sarcoglycan-opathyBrazilian;veryrareelsewhereLGMD2FSGCD

5q33Delta-

sarcoglycanClinical

~10-30%Calpain-opathyAmish,LaReunionIsland,Basque(Spain),TurkishLGMD2ACAPN3

15q15.1-

q21.1Calpain3Clinical

~10%Dysferlin-opathy

Miyoshi

distal

myopathyLibyanJewishLGMD2BDYSF

2p13.3-

p13.1DysferlinClinical

RareTelethonin-opathyItalian(?)LGMD2GTCAP

17q12TelethoninResearchonlyUnknownLGMD2HManitobaHutteritesLGMD2HTRIM32

9q31-

q34.1Zinc-fingerproteinHT2AUnknownLGMD2IUnknownLGMD2IFKRP

19q13.3Fukutin-relatedproteinClinical

%ofIindividualswithARLGMDDiseaseNamePopulationswithFounderMutationsLocus

NameGene

SymbolLocusProtein

ProductMolecularGeneticTestAvail-

abilityUpto68%ofindividualswithchildhoodonsetand~10%withadultonset

Alpha-

sarcoglycan-opathyNoneLGMD2DSGCA

17q12-

q21.3Alpha-

sarcoglycanClinical

Beta-

sarcoglycan-opathyAmishLGMD2ESGCB

4q12Beta-

sarcoglycanClinical

Gamma-

sarcoglycan-opathy

(formerly

SCARMD)

NorthAfricans;Gypsies;

rare

elsewhereLGMD2CSGCG

13q12Gamma-

sarcoglycanClinical

Delta-

sarcoglycan-opathyBrazilian;veryrareelsewhereLGMD2FSGCD

5q33Delta-

sarcoglycanClinical

~10-30%Calpain-opathyAmish,LaReunionIsland,Basque(Spain),TurkishLGMD2ACAPN3

15q15.1-

q21.1Calpain3Clinical

~10%Dysferlin-opathy

Miyoshi

distal

myopathyLibyanJewishLGMD2BDYSF

2p13.3-

p13.1DysferlinClinical

RareTelethonin-opathyItalian(?)LGMD2GTCAP

17q12TelethoninResearchonlyUnknownLGMD2HManitobaHutteritesLGMD2HTRIM32

9q31-

q34.1Zinc-fingerproteinHT2AUnknownLGMD2IUnknownLGMD2IFKRP

19q13.3Fukutin-relatedproteinClinical

Table1.AR遺傳型LGMD:MolecularGeneticsDisease

NamePresentationOtherFindingsAgeSymptomsWeaknessCalf

MuscleContractures

/ScoliosisOnset(Average)WheelchairBoundSarcoglycan-

opathyCompletedeficiency:difficultyrun,walkProximalHypertrophyLate3-15yrs(8.5yrs)~15yrsPartialdeficiency:cramps,exerciseintoleranceAdolescent-youngadulthoodCalpain-

opathyDifficultyrun,walk,toewalk;stiffback(rare)Proximal(normalhipextensorsandadductors),scapularwingingAtrophyEarly2-40yrs(8-15yrs)11-28yrsafteronsetDysferlin-

opathyInabilitytotiptoe;difficultyrun,walkDistaland/orpelvic-femoral(noscapularwinging)Transienthypertrophy(rare)17-23yrsTelethonin-

opathy(LGMD2G)Difficultyrun,walk;footdropProximalanddistallowerlimb;proximalupperlimbEarlyteens~18yrsafteronsetLGMD2HWeaknessoffacialmuscleswith"flat"smile;waddlinggait,difficultywithstairsProximallowerlimb;neckMusclewastingNotreported1-9yrsLateinlifeLGMD2IDifficultyrun,walkProximal;upper>lowerlimbHypertrophyRare,late1.5-27yrs(11.5yrs)23-26yrsafteronsetTable2.AR遺傳型

LGMD:ClinicalFindings

DiseaseNameLocus

NameGene

SymbolLocusProtein

ProductMolecular

Genetic

Test

AvailabilityLGMD1ATTID

5q31MyotilinResearchonlyLGMD1BLMNA

1q21.2LaminA/CClinical

CaveolinopathyLGMD1CCAV3

3p25Caveolin-3ResearchonlyLGMD1D

Unknown7qUnknownLGMD1E

UnknownUnknownTable3.AD遺傳型

LGMD:MolecularGeneticsNameOnsetPresentationLateFindingsSymptomsSignsLGMD1A18-35yearsProximalweaknessTightAchillestendonsDysarthriaDistalweaknessLGMD1B4-38years(~1/2onsetinchildhood)ProximallowerlimbweaknessContracturesofelbowsArrhythmiaandothercardiaccomplications(25-45years)SuddendeathLGMD1D<25yearsDilatedcardiomyopathyCardiacconductiondefectProximalmuscleweaknessAllindividualsremainambulatoryLGMD1E9-49years(30)ProximallowerandupperlimbweaknessPelger-HuetanomalyContracturesDysphagiaCaveolinopathyLGMD1C~5yearsCrampingMild-moderateproximalweaknessCalfhypertrophyTable4.AD遺傳型LGMD:ClinicalFindings

TypeCKMuscleBiopsyTestAvailabilityProteinstudyAutosomal

RecessiveSarcoglycanopathyMildlytogreatlyelevatedSarcoglycanantibodies;absentDGC(testshowspoorspecificity)Clinical

Calpainopathy>10timesnormalResearchonlyDysferlinopathyOftenmassivelyelevated>100timesnormalAbsenceofdysferlinonimmunoblottingClinical

Telethoninopathy3-17timesnormalAbsenceoftelethoninonimmunohistochemistry(specificityunknown)NotavailableLGMD2H4-30timesnormalNotreportedNotavailableLGMD2INormaltogreatlyelevatedVariableexpressionofalphadystroglycan,slightreductionoflamininalpha2(testshowspoorspecificity)NotavailableAutosomal

DominantLGMD1ANormalormildlyelevatedNormalmyotilinonimmunohistochemistryorimmunoblottingNotavailableLGMD1BNormalormildlyelevatedNotavailableLGMD1D2-4timesnormalNotavailableLGMD1E1-3timesnormalNotavailableCaveolinopathy4-25timesnormalCaveolin3reducedonimmunofluorescenceandWestern

blottingResearchonlyTable5.LGMD亞型分型試驗

Absenceofcalpain3onimmunoblotting(testshowspoorspecificity)LGMD的診斷：病史體征家族史實驗室檢查：血清CK，肌肉活檢（病理學、免疫組化特異蛋白染色---除dysferlinimmunoblotting

較特異和敏感外，其它蛋白的檢測特異性較差，因此蛋白的檢測是為進一步突變檢測作基礎SarcoglycanopathiesDystrophin免疫組化染色四種sarcoglycan免疫組化染色Westernblotting基因突變檢測LGMD遺傳咨詢目前準確的診斷仍有困難—遺傳咨詢有一定難度基因攜帶者檢出：CAPN3,DYSF,FKRP,SGCA,SGCB,SGCD,andSGCG，前提是先證者發(fā)現(xiàn)了基因突變產(chǎn)前診斷：羊水細胞或絨毛膜細胞，前提是先證者發(fā)現(xiàn)了基因突變LGMD臨床表現(xiàn)

肌肉無力萎縮限于肢體近端（肩帶肌、骨盆帶肌）極少累積心肌和咽喉肌肉，個別亞型除外家族內(nèi)成員的起病、無力萎縮肌肉的分布和疾病的進展也可有明顯不同不同亞型臨床表現(xiàn)有一些差異

面肩肱型FSHDAR型遺傳

Gene定位在chromosome4q發(fā)病率20,000分之一男和女均可發(fā)病任何年齡均可發(fā)病，但多數(shù)在10歲左右發(fā)病

FSHD

主要為肩帶肌和面肌受累后期可累及軀干和骨盆帶肌在同一家系內(nèi)患病者的表現(xiàn)可有很大的不同許多患者表現(xiàn)不典型（如面肌受累較輕）或很輕疾病隱襲進展，可有靜止期壽命正常FSHD---1.肌病面容可在嬰兒期出現(xiàn)不能蹙額、皺眉閉眼無力（“睡眠時眼睛不能閉攏）不能吹口哨、噘嘴—“金魚嘴”疾病進展嚴重時，發(fā)音可能含混不清FSHD---2.肩帶受累

肩帶肌無力、萎縮，翼狀肩胛胸鎖關節(jié)向前突出胸肌萎陷肱二頭肌和肱三頭肌可以萎縮，而前臂肌肉正常FSHD---3.其它征象常伴感音神經(jīng)性耳聾視網(wǎng)膜血管病脊柱側突或后側突較輕，發(fā)生也較晚無心肌受累脛前肌若早期受累可伴腓腸肌肥大遺傳早現(xiàn)FSHDFSHD---診斷和產(chǎn)前診斷與基因相關聯(lián)的限制酶DNA片段分析

：正常人大于35kb，患者小于35kb這種差異用于診斷和產(chǎn)前診斷片段越短，可能發(fā)病越早，病情越重強直性肌營養(yǎng)不良DM1（最常見）

Myotoninproteinkinase(DMPK);Chromosome19q13.3;AD遺傳DM2(PROMM)

Zincfingerprotein9(ZNF9);Chromosome3q21;AD遺傳DM3

Chromosome15q21-q24;AD遺傳DM1的分子遺傳學在DMPK基因3’末端非翻譯區(qū)內(nèi)出現(xiàn)CTG三核苷酸串聯(lián)重復序列數(shù)目不穩(wěn)定地異常重復擴展。正常：3to37CTGrepeatcopies患者：50to4,000輕者：50to150repeats一般：100to1,000repeats重者：Upto4,000repeats強直性肌營養(yǎng)不良DM1的臨床特征肌營養(yǎng)不良肌病面容（斧形臉）頸細伴胸鎖乳突肌萎縮、頭前傾（鵝頸）構音障礙、吞咽困難肌強直累及面肌、頸肌、四肢遠端肌，后期也可累及近端肌遇冷加重，反復活動后可以減輕叩擊肌肉可以誘發(fā)肌強直現(xiàn)象強直性肌營養(yǎng)不良DM1多系統(tǒng)損害

眼—白內(nèi)障內(nèi)分泌—睪丸萎縮、月經(jīng)失調(diào)、不育、流產(chǎn)、糖尿病、高胰島素血癥禿額胃腸道癥狀—吞咽困難、巨結腸、便秘心臟傳導異常呼吸通氣不足DM避免使用的藥物：阿米替林、地高辛、普魯卡因酰胺、心得安、奎寧、鎮(zhèn)靜藥（肌松劑）預后：壽命減低，50-60歲死亡死亡原因肺炎或呼吸功能衰竭(>30%)心律失常(猝死)(30%):心臟傳導阻滯;室性心動過速DM1---先天性強直性肌營養(yǎng)不良CTG重復可達730to4,300repeats發(fā)生率：10%to15%ofDM1患強直性肌營養(yǎng)不良的母親后代中的25%

產(chǎn)科問題：羊水過多，胎動少，臀先露，早產(chǎn)

臨床表現(xiàn)：全身肌張力低下、智能低下、呼吸功能不全、喂養(yǎng)困難。典型的面部表現(xiàn):小下巴、高腭弓、眉弓突出關節(jié)屈曲

嬰兒期無肌強直，6歲后可逐步表現(xiàn)出肌強直先天性強直性肌營養(yǎng)不良的實驗室特點EMG:NomyotoniaCK:UsuallynormalMusclebiopsy: