Robbins Essential Pathology Genetic Diseases PDF

CHAPTER 6 Genetic Diseases 97 Table 6.4 Subg...

CHAPTER 6 Genetic Diseases 97 Table 6.4 Subgroups of Glycogenoses Clinicopathologic Category Specific Type Enzyme Deficiency Organs Affected Hepatic von Gierke disease (type I) Glucose-6-phosphatase Liver, kidney Myopathic McArdle syndrome (type V) Muscle phosphorylase Skeletal muscle Miscellaneous Pompe disease (type II) Lysosomal glucosidase (acid maltase) Cardiac and skeletal muscle, liver numb er  a s no an exac  mu l ple o n s c a l le d aneupod. Te NORMAL Liver ce c aus e o aneuplody s nondsjunc  on o a omologous p ar o cromos omes a  e  rs meo c dv son or a a lure o sser croma ds o s ep arae dur ng  e s e cond meo c dv son. Te l a- Glycogen er a ls o may o cc ur dur ng moss n s oma c cel ls, le adng o  e Various tissues pro duc  on o  wo aneuplod cel ls. Fa lure o p ar ng o omologous Glucose cromos omes ol lowe d by random ass or  men (anapas e l ag) a ls o Blood c an le ad o aneuplody. Wen nondsjunc  on o cc urs a  e  me o glucose meoss,  e gamees or me d ave e er an ex ra cromos ome (n + 1) or one less cromos ome (n − 1). Fer   lza on o suc gamees by Glycolysis Glucose nor ma l gamees may resu l n  wo  yp es o zygoes,  r s omc, w   Muscle Energy an ex ra cromos ome (2n + 1), or monos omc (2n − 1). Monos omy Glycogen nvolv ng an auos ome s a a l dur ng e a l de velopmen, w ere as  r s omes o cer  an auos omes and a monos omy nvolv ng s ex cromos omes are comp a ble w   le. Mos ac sm s a er m us e d o des cr b e  e pres ence o  wo or more p opu l a ons o cel ls w   GLYCOGEN STORAGE DISEASE—HEPATIC TYPE d eren complemens o cromos omes n  e s ame ndv du a l. One  yp e o mos acsm s c aus e d by mo c nondsjunc  on dur ng e arly embr yogeness, resu l ng n  e pro duc  on o  r s omc and mono - Glycogen s omc d aug er cel ls, w os e des cend ans  en pro duce a mos ac. Mos acsm a e c  ng s ex cromos omes s common, w ere as auos o- Glucose ma l mos acsm s no. Low blood glucose Structural Abnormalities Srucural canges n e cromosomes ypcally resul rom cromo- somal breakage ollowed by loss or rearrangemen o maeral. Suc GLYCOGEN STORAGE DISEASE—MYOPATHIC TYPE canges usually are desgnaed usng a cyogenec sorand n wc p denoes e sor arm o a cromosome and q e long arm. Eac Glycolysis arm s en dvded no numbered regons (1, 2, 3, and so on) rom e Glucose cenromere ouward, and wn eac regon e bands are numercally Low ordered. energy Glycogen output e man ypes o srucural cromosomal abnormales (Fg. 6.9) are e ollowng:    Transocaton mples ranser o a par o one cromosome o Fig. 6.8 Top, A simplified scheme of normal glycogen metabolism in anoer cromosome. e process s usually recprocal (.e., rag- the liver and skeletal muscles. Middle, The effects of an inherited defi- mens are excanged beween wo cromosomes). In genec sor- ciency of hepatic enzymes involved in glycogen metabolism. Bottom, and, ranslocaons are ndcaed by  ollowed by e nvolved The consequences of a genetic deficiency in the enzymes that metabo- cromosomes n numercal order, or example, 46,X X,(2;5) lize glycogen in skeletal muscles. (q31;p14). s noaon ndcaes a recprocal ranslocaon nvolv- ng e long arm (q) o cromosome 2 a regon 3, band 1, and e compex mugenc dsease a as mporan neracons w sor arm o cromosome 5, regon 1, band 4. Wen e broken oer acors, because afeced persons oten exb clncal man- ragmens are evenly excanged, e resulng baanced recproca esaons o dsease only ater weg gan. In s nsance, e transocaton s no armul o e carrer, wo as e normal genec rsk or dabees s “unmasked” by obesy. number o cromosomes and e ull complemen o genec mae- ral. However, durng gameogeness, abnormal (unbalanced) gam- CYTOGENETIC DISORDERS ees are ormed, resulng n abnormal zygoes. A specal paern o ranslocaon nvolvng wo acrocenrc cromosomes s called It is estimated that 50% of rst-trimester spontaneous abortions centrc fuson type, or robertsonan, transocaton. e breaks yp- are caused by chromosome abnormalities and that 1 in every 200 cally occur close o e cenromere, afecng e sor arms o bo newborns has a chromosome aberration. cromosomes. Transer o e segmens leads o one ver y large Cyogenec dsorders are dened by e presence o numercal or cromosome and one exremely small one. e sor ragmens are srucural aleraons o auosomes or sex cromosomes. los, and e afeced ndvdual as 45 cromosomes. Because e sor arms o all acrocenrc cromosomes carr y gly redundan Numerical Abnormalities genes (e.g., rbosomal RNA genes), suc loss s compable w In umans,  e nor ma l cromos ome coun s 46 (.e., 2n = 46). Any sur vval. However, dicues agan arse durng gameogeness, exac  mu l ple o  e aplod numb er (n) s c a l le d eupod. Any  CHAPTER 6 Genetic Diseases 97.e1 A B Supplemental eFig. 6.2 Pompe disease (glycogen storage disease type II). (A) Normal myocardium with abundant eosinophilic cytoplasm. (B) Patient with Pompe disease (same magnification showing the myocar- dial fibers full of glycogen seen as clear spaces.) (From Kumar V, Abbas A, Aster J: Robbins and Cotran Patho- logic Basis of Disease, 9th ed., Philadelphia, Elsevier, 2015, Fig. 5.16; Courtesy Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical Center, Dallas.) 98 CHAPTER 6 Genetic Diseases Trisomy 21 (Down Syndrome) resung n e ormaon o unbaanced gamees a may ead o abnorma zygoes. Down syndrome is the most common chromosome disorder and    Isocromosomes are ormed wen e cenromere dvdes orzon- is most frequently caused by meiotic nondisjunction in the ova of ay raer an vercay. One o e wo arms o e cromo- older mothers. some s en os, and e remanng arm s dupcaed, resung n a cromosome w ony wo sor arms or wo ong arms. e Pathogeness. Down syndrome as wo major causes, rsomy 21 and mos common socromosome presen n lve brs nvolves e robersonan ransocaon. long arm o e X cromosome and s desgnaed (Xq). Wen    About 95% of patents wt Down syndrome ave trsomy 21; er erlzaon occurs by a gamee a conans a normal X cro- parens ave a norma kar yoype. s orm o Down syndrome s mosome, e resul s monosomy or genes on Xp and rsomy or srongly lnked o maernal age: Is ncdence s 1 n 1550 lve brs genes on Xq. n women younger an 20 years bu rses o 1 n 25 lve brs n    D eeton nvolves loss o a poron o a cromosome. A sngle women older an 45 years. In 95% o cases, e exra cromosome break may delee a ermnal segmen. Two nersal breaks, w s o maernal orgn. e reason or e ncreased suscepbly o reunon o e proxmal and dsal segmens, resuls n e removal e agng ovum o nondsjuncon s no undersood. o an nernal segmen. e removed ragmen, wc lacks a cen-    About 4% of persons wt Down syndrome carry a robertsonan romere, s almos never reaned, and e genes encoded by s transocaton a nvolves e long arm o cromosome 21 and regon are los. cromosome 22 or cromosome 14. e ranslocaed segmen o    Inversons o cc ur w en  ere are  wo  ne rs   a l bre a ks n a cromosome 21 provdes e exra cromosomal maeral. e cromos ome and  e  nvolve d s eg me n reun e s a er  lpp ng parenal carrer s penoypcally normal. Oer sblngs are a around. ncreased rsk or avng Down syndrome.    A rng cromosome s a varan o a deleon. Ater loss o segmens    Rarey, persons wt a Down syndrome penotype are mosac for trsomy rom eac end o e cromosome, e arms une o orm a rng. 21. ese cases resul rom moc nondsjuncon o cromosome 21 durng an early sage o embryogeness. Clncal manesaons are Cytogenetic Disorders Involving Autosomes varable and mlder, dependng on e proporon o abnormal cells. ree auosomal rsomes (13, 18, and 21; Fg. 6.10) and wo deleon Aloug e cromosomal abnormaly n Down syndrome as syndromes (cr du cat sy ndrome, caused by deleon o cromosome been known or many years, e paogeness o e dsease remans 5p, and 22q11 deeton sy ndrome) are relavely common n lve br s elusve. Mouse models sugges a gan o a parcular regon on cro- and ave caracersc clncal eaures. Only rsomy 21 and 22q11 mosome 21 bearng loc encodng mulple proens and several mcro- deleon syndrome occur w suicen requenc y o mer bre RNAs s responsble or e obser ved penoype, bu ow ese gene consderaon. producs gve rse o e clncal eaures reman o be deermned. TRANSLOCATIONS Balanced reciprocal Centric fusion Robertsonian Lost ISOCHROMOSOMES DELETIONS Fragments INVERSIONS RING CHROMOSOMES Paracentric Fragments Pericentric Fig. 6.9 Types of chromosomal rearrangements.  CHAPTER 6 Genetic Diseases 99 Intellectual Epicanthic disability folds and flat facial profile Abundant TRISOMY 21: DOWN SYNDROME neck skin Single Incidence: 1 in 700 births palmar Karyotypes: crease Trisomy 21 type: 47,XX, +21 Translocation type: 46,XX,der(14;21)(q10;q10),+21 Mosaic type: 46,XX/47,XX, +21 Congenital heart defects Intestinal Umbilical hernia stenosis Predisposition to leukemia Prominent occiput Intellectual disability Hypotonia Micrognathia Gap between first and second toe Low set ears Short neck Overlapping fingers Congenital TRISOMY 18: EDWARDS SYNDROME heart defects Incidence: 1 in 8000 births Karyotypes: Renal malformations Trisomy 18 type: 47,XX, +18 Mosaic type: 46,XX/47,XX, +18 Limited hip abduction Microphthalmia Microcephaly and intellectual disability Polydactyly Cleft lip and palate Rocker-bottom feet Cardiac defects Umbilical Renal defects TRISOMY 13: PATAU SYNDROME hernia Incidence: 1 in 15,000 births Karyotypes: Trisomy 13 type: 47,XX, +13 Translocation type: 46,XX,+13,der(13;14)(q10;q10) Mosaic type: 46,XX/47,XX, +13 Rocker-bottom feet Fig. 6.10 Clinical features and karyotypes of the three most common autosomal trisomies: trisomy 21, Down syndrome; trisomy 18, Edwards syndrome; and trisomy 13, Patau syndrome. 100 CHAPTER 6 Genetic Diseases Clncal Features. e acal appearance o e nan—a aca proie, emaes. X nacvaon occurs eary n ea e, abou 16 days ater con- obque papebra issures, and epcanc ods (see Fg. 6.11)—s cepon. Durng s process, eer e paerna or e maerna X cro- caracersc and mmedaey suggess e dagnoss. Severe neecua mosome s randomy nacvaed n eac ce o e deveopng embryo dsaby s common; approxmaey 80% o ose alced ave an IQ and remans genecay sen n e progeny o ese ces rougou e. o 25 o 50. Mosacs w Down syndrome ave a mder penoype and Moreover,  exra X cromosomes are presen (e.g., n 48,XXXX emaes), may ave norma or near-norma negence. Down syndrome aso a bu one s nacvaed. As a resu, emaes do no ave an “exra dose” carres a g rsk o oer deveopmena and acqured dsorders: o mos o e genes ound on e X cromosome. Noe a because o    Congenta eart dsease occurs n approxmaey 40% o paens, yonzaon, norma emaes are mosacs composed o wo ce popuaons, mos commony ara sepa deecs, arovenrcuar vave maorma- one w an acve maerna X and e oer w an acve paerna X. ons, and venrcuar sepa deecs (see Caper 8). Cardac probems Penoypc canges assocaed w oss o an X cromosome, as are responsbe or a majory o e deas n nancy and eary cd- occurs n Turner syndrome, appear because severa regons on e X ood. Aresas o e esopagus and sma bowe aso are common. cromosome escape nacvaon. hus, oss o one X cromosome    Cdood acute eukema (see Caper 9) occurs a raes 10- o resus n monosomy o ose genes a are acve on bo X cro- 20-od ger an ose n unafeced cdren. mosomes. he wo dsorders resung rom gans or osses o X cro-    Neuropatoogc canges caracersc o Azemer dsease, a mosomes are Kneeer syndrome and Turner syndrome, respecvey. neurodegenerave dsease (see Caper 17), occur n vruay a Klinefelter Syndrome paens oder an age 40.    Abnorma mmune functon a predsposes o necons, parc- Klinefelter syndrome is the most common cause of hypogonad- uary o e ungs, and o yrod auommuny, s common. he ism in males and results from the presence of at least one extra X bass or s mmunoogc dsurbance s uncear. chromosome. Improved medca care as ncreased e e span o persons w r- Mos paens w Kneeer syndrome ave a 47,X XY kar yoype somy 21, and e curren medan age a dea s around 50 years. he pre- a sems rom nondsjuncon o sex cromosomes durng meoss. naa dagnoss o Down syndrome and oer rsomes s possbe usng he exra X cromosome may be o eer maerna or paerna orgn. screenng ess a rey on e anayss o ce-ree ea DNA ound n Approxmaey 15% o e paens are mosacs, suc as 46,XY/47,X XY, maerna bood, magng sudes, and (mos drecy) karyoypng o ces 47,X XY/48,X X XY. he presence o a 46,XY ne n mosacs usuay s obaned rom e concepus by amnoceness or coronc vus sampng. assocaed w a mder cnca condon. he range o manesaons s wde, and ey oten ncude e 22q11 Deletion Syndrome oowng: 22q11 deeon syndrome encompasses a specrum o penoypes a    Hypogonadsm, escuar aropy, and nfery. Sery s due o resu rom nersa deeons o band 11 on e ong arm o cromo- mpared spermaogeness. Hsoogc examnaon reveas yan- some 22 (de22q11). hese penoypes ncude: zaon o ubues, wc may ack spermaogona enrey. Ley-    Congenta eart dsease afecng e ouow racs dg ces are promnen, as a resu o yperpasa or an apparen    Abnormates of te paate, faca dysmor psm, deveopmenta deay ncrease reaed o oss o ubues. he dagnoss s oten made    hymc ypopasa and mpared T-ce mmuny durng e evauaon o nery.    Parayrod ypopasa resung n ypocacema    Increase n eng beween e soes and e pubc bone, wc creaes    S czoprena and bpoar dsorder e appearance o an eongaed body Varaon n e sze and poson o e deeons s oug o be    Eunucod body abus, marked by reduced aca, body, and pubc responsbe or dferng penoypes. Wen T-ce mmunodeicency ar and g ynecomasa and ypocacema domnae, paens are sad o ave DGeorge syn-    Mena mparmen. he degree o neecua mparmen ypcay drome, wereas ose w e so-caed veocardofaca syndrome ave s md, and n some cases, no deic s deecabe. he reducon n md mmunodeicency and pronounced dysmorpoog y and cardac negence correaes w e number o exra X cromosomes. deecs. Paens aso are a g rsk or psycoses suc as bpoar ds- Serum esoserone eves are ower an norma, and urnar y order and sczoprena, wc deveops n up o 25% o cases. he gonadoropn eves are eevaed. Paens are rarey ere, and suc paogeness o 22q11 deeon syndrome s no uy undersood, persons may be mosacs w a arge proporon o 46,XY ces. because e deeed regon encodes many genes. he dagnoss may be Kneeer syndrome s assocaed w a ger requency o severa suspeced on cnca grounds and s esabsed by deecon o e dsorders, ncudng breas cancer (20 mes more common an n deeon by uorescence n su ybrdzaon (FISH) (descrbed aer). norma maes), exragonada germ ce umors, and auommune ds- eases suc as sysemc upus er yemaosus. Cytogenetic Disorders Involving Sex Chromosomes Turner Syndrome Numerical abnor ma l i ti es i nv o lv i ng th e sex c h ro m o s o m e s , ranging from 45,X to 4 9 , XXXXY, a re compatible with l i fe and Turner syndrome, characterized by primary hypogonadism in observed in patien ts wh o o ften ex h i bi t i n f e r t i l it y a nd certain females, results from partial or complete monosomy of the short other abnormaltie s. arm of the X chromosome. Penoypcay norma maes w wo and even ree Y cromo- somes ave been denied. In conras, numerca abnormaes o X Pathogeness. Norma oogeness occurs beore yonzaon and requres cromosomes produce aypca penoypes n bo maes and emaes, bo X cromosomes o be acve. In Turner syndrome, ea ovares abe ones a are md compared w ose observed w numerca nay deveop normay eary n embr yogeness, bu e absence o abnormaes nvovng auosoma cromosomes. In arge par, e ack e second X cromosome eads o an acceeraed oss o oocyes, wc o a penoype reaed o abnormaes o sex cromosomes reaes o wo s compee by age 2 years. he ovares are reduced o aropc ibrous acors: (1) e sma amoun o genec normaon carred by e Y cro- srands, devod o ova and oces (sreak ovares). Because Turner mosome (ncudng e gene SRY a species mae sex) and (2) X nac- syndrome aso causes nongonada abnormaes, genes requred or e vaon (yonzaon), wc ends o baance gene expresson n maes and grow and deveopmen o somac ssues aso mus resde on e X  CHAPTER 6 Genetic Diseases 101 cromosome. An exampe s e sor saure omeobox gene (SHOX). s s one o e genes a are acve on bo X cromosomes. Clncal Features. e majory o paens ave complee loss o one X cromosome and a 45,X kar yoype. ese paens are e mos Short stature Low posterior hairline severely afeced and are dagnosed a br or early n cldood. Webbing of neck Typcal eaures assocaed w 45,X Turner syndrome are sown n Fg. 6.11 and nclude: Coarctation of   Growt retardaton and sor saure (below e rd percenle) aorta    Swellng o e nape o e neck due o dsended lympac cannels Broad chest (n nancy) a s seen as webbng of te neck n older cldren and widely spaced nipples    Low posteror arne    Cubtus vagus (an ncrease n e carr yng angle o e arms) Cubitus valgus    Sed-ke cest w wdely spaced npples    Hg-arced paate Streak ovaries,   Lympedema o e ands and ee infertility,   Maformatons suc as orsesoe kdney, bcuspd aorc valve, and amenorrhea coarcaon o e aora Cardovascular abnormales are e mos common cause o dea n cldood. B ecause o ovaran aropy, afeced adoles- cen grls al o develop secondar y sex caracerscs: e genala Pigmented nevi reman nanle, breas developmen s mnmal, and lle pubc ar appears. Mos paens ave prmar y amenorrea. Hypoyrodsm caused by auoanbodes occurs n as many as 50% o paens. In a sgncan mnory o paens, Turner syndrome s caused by mosacsm (n wc e ndvdual s made up o a mxure o 45,X and 46,XX cells) or by srucural abnormales o e X cromosome. e Peripheral mos common s deleon o e sor arm, resulng n paral mono- lymphedema somy o e X cromosome. Combnaons o deleons and mosacsm at birth are repored and accoun or sgncan varaons n e penoype. TURNER SYNDROME Some paens w mosacsm or paral deleons ave an almos nor- mal appearance and may presen only w prmary amenorrea. In Incidence: 1 in 3000 female births Karyotypes: adul paens, a combnaon o sor saure and prmary amenorrea Classic: 45,X sould promp srong suspcon or Turner syndrome. e dagnoss s Defective usually esablsed by karyoypng. second X chromosome: 46,X,i(Xq) 46,XXq– SINGLE-GENE DISORDERS WITH ATYPICAL 46,XXp– 46,X, r(X) PATTERNS OF INHERITANCE Mosaic type: 45,X/46,XX ree groups o genec dseases resulng rom sngle-gene muaons Fig. 6.11 Clinical features and karyotypes of Turner syndrome. do no ollow mendelan rules o nerance:    Dseases caused by rnucleode repea muaons A unque eaure o dseases caused by rnucleode repea mua-    Dseases caused by muaons n mocondral genes ons s a penomenon called antcpaton, n wc e dsease becomes    Dseases assocaed w aleraons o mprned regons o e genome more severe w eac successve generaon. s unusual eaure s relaed o e dynamc naure o rnucleode repea muaons. An Trinucleotide Repeat Mutation Diseases example can be ound n Hunngon dsease, n wc expanson o Trinucleotide repeat diseases are caused by mutations that amplify a CAG repea sequence wn e Hunngn gene (HTT) gene s a DNA sequence consisting of three base pair (trinucleotide) repeats. responsble or e dsease. Once ese repeas reac a ceran number, ey are prone o urer expansons durng spermaogeness, an aler- Pathogeness. Fragle X syndrome, Hunngon dsease, and myoonc aon a resuls n dsease a s more severe and occurs earler n le dysropy, all assocaed w neurodegeneraon, are among e more n afeced ofsprng compared o e dsease n e paren. Snce CAG promnen examples o genec dseases caused by rnucleode repea repeas encode polygluamne racs n e afeced proens, CAG expansons. e expansons may nvolve e promoer, unranslaed repea dseases are oten called ploygluamne dseases. For unclear porons o e encoded mRNA (as n  ragle X syndrome), or codng reasons, n oer rnucleode repea dseases, suc as ragle X ds- regons (as n Hunngon dsease, descrbed n Caper 16) o e ease, rple muaon repea nsably s more pronounced n develop- afeced gene. Wen muaons afec noncodng regons, RNA ng oocyes, and ence ancpaon s seen wen e abnormal alleles ranslaon s suppressed and ere s “loss o uncon. ” By conras, are passed down roug e moer. muaons nvolvng codng sequences o e gene oten gve rse o msolded proens a bo nerere w e uncon o e proen Frag le X syndrome s the prototypc trnucleotde repeat mutaton and ave a oxc “gan-o-uncon” acvy. s propery s conerred dsease. It s the second most common genetc cause o mental ds- by muaons nvolvng CAG repeas a encode polygluamne ablty (ater Down syndrome). racs, wc cause proen msoldng and aggregaon wn e I resuls rom a rple repea muaon afecng e FMR1 gene, c yoplasm, a common eaure o dseases suc as Hunngon dsease. wc encodes e amlal menal reardaon proen (FMRP). As