Robbins Essential Pathology Genetic Diseases PDF

102 CHAPTER 6 Genetic Diseases w a X-nked dseases, rage X syndrome afecs predomnanly and e paen develops Angelman syndrome. e precse way...

102 CHAPTER 6 Genetic Diseases w a X-nked dseases, rage X syndrome afecs predomnanly and e paen develops Angelman syndrome. e precse way a e males. Afeced males ave a long ace and large mandble. Large es- afeced genes conrbue o ese syndromes s no undersood. cles are presen n 90% o cases. In unafeced males, ere are around 30 CGG repeas n e FMR1 gene, wereas n afeced males ere DIAGNOSIS OF GENETIC DISORDERS are 200 o 4000 repeas. ese “ull” muaons arse rom premua- ons w 52 o 200 repeas. e premuaons are convered o ull Once a penoype s recognzed a suggess a parcular genec dsor- muaons by urer amplcaon durng oogeness. FMRP regulaes der, pedgree analyss may be used o urer evaluae e possbly a a e ranslaon o synapc proens, and s absence n afeced males genec dsease s segregang wn a amly. e absence o oer afeced causes marked menal dsably. amly members, owever, does no exclude a genec dsorder, as many muaons arse de novo. An addonal conoundng acor s nonpaerny, Diseases Caused by Mutations in Mitochondrial Genes esmaed o nvolve 2% o 5% o brs. Conrmaon o a suspeced genec dsorder reles on specc ess, wc also ave mporan roles n evalu- Mitochondria in the fertilized zygote are entirely derived from the ang euses a are deemed o be a ncreased rsk or genec dsorders. ovum; thus, only mothers transmit mitochondrial genes and their e eld o esng or genec dsorders s evolvng a a rapdly accel- defects to their offspring. erang pace. A bre revew o curren esng modales and er use or s unusual paern o ransmance s reerred o as materna e dagnoss o genec dsorders s ofered below and s summarzed n nertance. Dseases caused by muaons n mocondral genes are Table 6.5. rare. One class o mocondral genes a s muaed n mocon- dral dsorders encode enzymes nvolved n oxdave pospor yla- Genetic Test Modalities and Applications on, and as mg be expeced, e ssues a are mos afeced n Tess a are used o conrm e dagnoss o varous genec dsorders ese dsorders are ose a are mos dependen on oxdave pos- are desgned o deny e causave genec abnormaly or, n some por ylaon, a s, skeleal muscle, e ear, and e bran. nsances, e efec o e abnormaly on proens encoded by muaed genes. ese ess can be broadly dvded no several caegores: Diseases Caused by Alterations of Imprinted Regions: 1. Tests tat detect structura abnormates of cromosomes. Hsorcally, Prader-Willi and Angelman Syndromes ese were dened solely by karyotype anayss, n wc mea- Certain genes are normally subject to differential “silencing” pase cromosomes prepared rom culured cells (usually perperal through epigenetic modications in male and female gametes, blood lympocyes) are saned w a dye a produces a unque and disturbances in this process (termed imprinting) can lead to paern o alernang lg and dark bands on eac cromosome. abnormal gene expression and developmental abnormalities. Increasngly, kar yoypng s beng replaced by array-based compar- atve genomc ybrdzaton (CGH), n wc DNA rom a paen Pathogeness. Aloug all umans ner wo copes o eac auosomal and a normal conrol are labeled w wo dferen uorescen dyes. gene, carred on omologous maernal and paernal cromosomes, he DNAs are mxed and ybrdzed o an array o probes dspayed e acves o e male and emale alleles o some genes dfer. ese as dsnc spos on a sde a span e genome. Over- or underrep- dferences arse rom an epgenec process called genomc mprnng. resenaon o paen DNA correspondng o a parcuar genomc Maernal mprnng reers o ranscrponal slencng o e maernal regon s scored as a cange n e rao o uorescen ag 1 o uo- allele n e ovum, wereas paernal mprnng reers o ranscrponal rescen ag 2. Array CGH as severa advanages over kar yoypng: I slencng o e paernal allele n e sperm. Imprnng occurs n e does no requre ce cuure, s easy o nerpre, and aso as muc ovum or sperm and s en sably ransmed o all somac cells greaer resouon, wc s med ony by e number o dscree derved rom e zygoe. probes a are presen n e array. Fuorescence n stu ybrdza- Two uncommon genec dsorders are caused by deecs nvolvng ton (FISH) s used o deny cromosoma abnormaes afec- an mprned genomc regon, Prader-Wll syndrome and Angelman ng specic genomc regons. Fuorescen probes conanng DNA syndrome (Fg. 6.12). sequences o neres are apped o meapase spreads or nerpase    Prader-W syndrome s caracerzed by nellecual dsably, nuce. he probe ybrdzes o s compemenar y sequence on e sor saure, ypoona, obesy, small ands and ee, and ypo- cromosome, wc s en vsuazed w a uorescence mcro- gonadsm. Afeced paens ave deleons o band q12 n e long scope. FISH can deec cromosoma gans, osses, or ransocaons arm o cromosome 15 (15q12), and n all cases e deleon s o parcuar genomc regons (Fg. 6.13). Moecuar ess aso ave ound n e paernally derved cromosome 15. been deveoped a use ce ree ea DNA ound n maerna bood    Angeman syndrome s assocaed w nellecual dsably, as (a so-caed qud bopsy) o assess woe-cromosome numbers n well as aaxc ga, sezures, and napproprae lauger, a peno- e deveopng eus. Curren appcaons ncude denicaon o ype que dsnc rom Prader-Wll syndrome. Afeced paens ea sex and e deecon o copy number canges n sex cromo- also ave deleons nvolvng cromosome 15q12, bu e deleon somes and auosomes, ncudng rsomes 13, 18, and 21. occurs n e maernally derved cromosome 15 raer an e 2. Tests tat detect mutatons n snge genes. I a muaon n a parc- paernally derved cromosome. uar gene s suspeced, a regon can be ampied by poymerase e molecular bass o ese wo syndromes s complex bu can can reacton (PCR), sequenced, and compared w a norma be undersood n e conex o mprnng. A se o genes on maer- reerence sequence. I s becomng easer o sequence many genes, nal cromosome 15q12 s mprned (and ence slenced), suc a even e enre genome, by capurng DNA regons by ybrdzng all gene uncon depends on e paernal allele. I e paernal genes o a known se o nuceode sequences and sequencng a o ese. are deleed, gene uncon s compleely los and e paen develops hs meod, caed next generaton sequencng (NGS), s becomng Prader-Wll syndrome. A dferen gene a also maps o cromo- ncreasngy afordabe and s beng used wdey, bu nerpreaon some 15q12 s mprned on e paernal cromosome, suc a e o e resus s compex and requres specay raned ndvduas. uncon o s gene depends on e maernal allele. I s gene s 3. Tests tat detect bocemca abnormates assocated wt partcuar deleed rom e maernal allele, gene uncon agan s compleely los genotypes. In many nsances nvovng snge-gene dsorders,  s  CHAPTER 6 Genetic Diseases 103 MATERNAL PATERNAL (M) (P) Imprinted Prader-Willi Active Prader-Willi genes genes Active Angelman Imprinted Angelman gene gene Deletion in mater nal Deletion in pater nal chromosome chromosome (M) (P) (M) (P) Active Prader-Willi Imprinted Prader-Willi genes genes Site of deletion Site of deletion Imprinted Angelman Active Angelman gene gene ANGELMAN SYNDROME PRADER-WILLI SYNDROME Fig. 6.12 Genetics of Angelman and Prader-Willi syndromes. Table 6.5 Testing Modalities for Genetic Disorders Test Type Applications and Examples Biochemical Assays Quantitative assays for metabolites or electrolytes Detection of abnormal metabolite levels in metabolic disorders (e.g., phenylketonuria); detection of high sodium levels in sweat (cystic fibrosis) Assay of enzyme activity Detection of enzyme deficiencies (e.g., acid maltose in Pompe disease; G6PD defi- ciency) Hemoglobin electrophoresis Detection of abnormal hemoglobins (e.g., sickle hemoglobin) Cytogenetic Assays Karyotyping Grossly evident structural changes in chromosomes (e.g., trisomy 21 in Down syn- drome) Fluorescence in situ hybridization (FISH) Subtle/submicroscopic structural changes in chromosomes (e.g., del(5) in cri du chat syndrome) “Molecular” Cytogenetic Assays Multiplex ligation-dependent probe amplification Small deletions and insertions (e.g., partial deletion of BRCA1 in familial breast cancer) Array-based genomic hybridization Copy number changes (e.g., trisomy 21 in Down syndrome) NextGeneration sequencing Copy number changes, translocations (mainly used clinically to identify somatic copy number changes and translocations in cancer cells) Genetic Assays Allele-specific PCR and related techniques Specific base pair changes (single, e.g., sickle hemoglobin mutation, or multiple, e.g., CFTR mutations in cystic fibrosis) Sanger DNA sequencing Mutations in individual genes (e.g., glucose-6-phosphatase mutations in von Gierke disease) NextGeneration sequencing Mutations in many genes and/or in noncoding regions (used clinically to identify somatic mutations in cancer cells and in research to discover mutations responsible for unusual phenotypes) 104 CHAPTER 6 Genetic Diseases A B Fig. 6.13 Fluorescence in situ hybridization (FISH). (A) Interphase nucleus from a male patient with suspected trisomy 18. Three different fluorescent probes have been used: a green probe specific for the X chromosome centromere (one copy), a red probe specific for the Y chromosome centromere (one copy), and an aqua probe specific for the centromere of chromosome 18 (three copies). (B) A metaphase spread in which two fluores- cent probes have been used, one hybridizing to chromosome region 22q13 (green) and the other hybridizing to chromosome region 22q11.2 (red). There are two 22q13 signals. One of the two chromosomes does not stain with the probe for 22q11.2, indicating a microdeletion in this region. This abnormality gives rise to the deletion 22q11.2 syndrome. (Courtesy Dr. Nancy R. Schneider and Jeff Doolittle, Cytogenetics Laboratory, University of Texas Southwestern Medical Center, Dallas.) easer, ceaper, or aser o es or aeraons n muaed proens    Advanced materna age (beyond 34 years), wc s assocaed w or er uncons an o deny e underyng DNA muaon greaer rsk o rsomes drecy. Exampes abound and ncude swea esng n cysc bro-    Conirmed carrer saus or a balanced recprocal ranslocaon, ss; dencaon o g serum penylalanne levels n penylke- robersonan ranslocaon, or nverson onura; dencaon o sckle emoglobn n red cells n sckle cell    A cromosoma abnormay afecng a prevous cld dsease; and dencaon o enzyme decences n a wde varey    D eermnaon of fea sex wen e paen or parner s a con- o dsorders. rmed carrer o an X-lnked genec dsorder Posnaa genec anayss usually s perormed on perperal blood Indications for Genetic Analysis lympocyes because o ease o samplng. Indcaons are as ollows: e precedng dscusson descrbed some o e ecnques avalable    Mupe congena anomaes or e dagnoss o genec dseases. For judcous applcaon o ese    Unexpaned neecua dsaby and/or developmenal delay meods,  s mporan o recognze wc persons requre genec    Suspeced aneupody (e.g., eaures o Down syndrome) esng and e bes ecnque or deecon o e suspeced genec    Suspeced unbaanced auosome (e.g., Prader-Wll syndrome) dsorder. Genec esng can be dvded no prenaal and posnaal    Suspeced sex cromosome abnormay (e.g., Turner syndrome) esng, eac w s own se o ndcaons.    Suspeced frage X syndrome Prenata genetc anayss sould be ofered o all paens wo are a    Infery (o rule ou a sex cromosome abnormaly) rsk o avng cyogenecally abnormal progeny. I may be perormed    Mupe sponaneous aborons (o rule ou a balanced ranslocaon on cells obaned by amnoceness, on coronc vllus bopsy mae- n a paren) ral, or cell ree eal DNA obaned rom maernal blood. Indcaons nclude e ollowng:  7 Diseases of Blood Vessels O U T L I N E Mechanisms of Vascular Diseases, 105 Kawasaki Disease, 114 Congenital Vascular Anomalies, 105 Thromboangiitis Obliterans (Buerger Disease), 114 Hypertension, 106 Small-Vessel Vasculitides, 114 Atherosclerosis, 107 Infectious Vasculitis, 114 Aneurysms and Dissections, 110 Disorders of Veins, 114 Aortic Aneurysms, 110 Varicose Veins, 114 Aortic Dissections, 111 Thrombophlebitis, 115 Vasculitis, 112 Tumors of Blood Vessels and Lymphatics, 115 Giant Cell (Temporal) Arteritis, 112 Hemangiomas, 115 Takayasu Arteritis, 113 Kaposi Sarcoma, 115 Polyarteritis Nodosa, 113 Angiosarcomas, 116 Despe advances n medca and surgca ner venons, vascuar ds- nersum (see Caper 3). As we w dscuss, dsurbances o endo- ease remans a eadng cause o moray n e Uned Saes. he ea uncon are common n vascuar dsease. Aso mporan are arges o s aken by compcaons reaed o aerosceross, many dsurbances o bood low, because a ranson rom norma amnar because  compromses bood low and as serous deeerous efecs low o sass or o urbuen low can aer endoea uncon and on e ear, bran, and oer va organs. In addon, yperenson se e sage or severa ypes o vascuar dsease. and venous romboss aso are common causes o cncay sgn- W s as a bre prmer, we now urn o specc dseases o bood can dsease. Aoug e oowng dscusson separaes dseases o vesses. vesses rom dseases o e ear, e crcuaor y sysem and e ear uncon as a un, and  soud be recognzed a prmar y deecs CONGENITAL VASCULAR ANOMALIES n one componen oten ave mporan mpacs on anoer. hese neracons w be gged rougou e oowng caper and Anaomc varans o bood vesses are common bu are argey o con- n Caper 8 cern ony o surgeons and ner venona cardoogss, or wom ey presen cnca caenges. Severa may cause dsease, owever, and deser ve bre menon: MECHANISMS OF VASCULAR DISEASES    Berry aneurysms are n-waed arera oupoucngs n cerebra Common orms o vascuar dsease deveop roug wo prncpa vesses, mos commony ound a branc pons around e crce o mecansms: Ws; ey may rupure sponaneousy, causng aa nracerebra    Narrowng or compete obstructon of vesse umens, occurrng emorrage (see Caper 17). eer progressvey (e.g., by aerosceross) or acuey (e.g., by    Arterovenous stuas are abnorma connecons beween areres romboss or embosm) and vens wou an ner venng capar y bed. hey may be deve-    Weakenng o vesse was, causng daon and/or rupure opmena deecs or may orm ater rupure o arera aneur ysms Anaomcay, e vascuaure can be subdvded no g-pres- no adjacen vens, oowng njures a perce areres and vens, sure arera vesses, wc suppy bood; capar y beds, were d- or rom nlammaor y necross o adjacen vesses, as may occur uson o gases (O and CO ) and soues appens; and ow-pressure w necons and oer orms o vascus. Arerovenous suas 2 2 venous vesses, wc reurn bood o e ear. Arera vesses ave can cause g-oupu cardac aure by sunng arge voumes o ck muscuar was rc n smoo musce ces and pay a key roe n bood rom e arera o e venous crcuaon. bood pressure reguaon, wereas venous vesses ave nner was    Fbromuscuar dyspasa s a oca rreguar ckenng o e was and g bood voume capacy, owng o er dsensby. he o medum- and arge-szed muscuar areres. he wa ckenng umna surace o a vesses s covered by a ayer o endoea ces, produces umna senoss or can be assocaed w abnorma ves- wc under norma crcumsances nbs coaguaon and nlam- se spasm a reduces vascuar low. In e rena areres,  can ead maon and manans lud baances beween e vascuaure and e o renovascuar ypertenson. 105 106 CHAPTER 7 Diseases of Blood Vessels HUMORAL FACTORS BLOOD VOLUME Sodium Constrictors Dilators Mineralocor ticoids Angiotensin II Prostaglandins Atrial natriuretic peptide Catecholamines Kinins Thromboxane NO Leukotrienes Endothelin LOCAL FACTORS BLOOD CARDIAC PERIPHERAL Autoregulation PRESSURE OUTPUT RESISTANCE pH, hypoxia Constrictors Dilators CARDIAC FACTORS α-adrenergic β-adrenergic Hear t rate Contractility NEURAL FACTORS Fig. 7.1 Blood pressure regulation. NO, nitric oxide. ave b een mpcaed n e rsk o de veopng yp er enson, bu n HYPERTENSION 95% o cas es e sp ecc caus e s unknown (ence  s caed essen- Sustained high blood pressure (hypertension) causes vessel and ta y per tenson). Mos o e remanng cas es o yp er enson o cc ur end-organ damage and is a major risk factor for atherosclerosis. s econdar y o rena ds eas e or ormone-s ecreng adrena umors Bood pressure mus be mananed wn a narrow range o (e.g., umors s ecreng adoserone, norepneprne, or epneprne). ensure dever y o O and nurens o ssues and remova o CO and R arey, yp er enson s caus ed by muaons n ndvdua genes a 2 2 meaboc wases. Low pressure (ypotenson) resus n nadequae ncreas e adoserone pro duc on or reabs or pon o s o dum by e peruson, organ dysuncon, and  severe and sysemc, sock and kdne y, empaszng e mp or ance o es e mecansms o bo o d somemes dea (see Caper 3). Muc more common s ypertenson, pressure conro. an nsdous bu mporan cause o morbdy and moray. Morphology. Hyp er enson acceeraes a e rogenes s and c aus es Pathogeness. Resng bood pressure s a uncon o cardac oupu degenera ve canges n  e w a  s o  arge- and me d u m -s ze d and ressance o low, wc s dcaed by e muscuar one o are- ar er es  a can ead o aor c dssecon and cerebrovascuar roes (Fg. 7.1). A o ese acors are subjec o reguaon and coun- emorrage (descrbed aer and n Caper 17). Areroes can erreguaon by ormones produced by e kdney and e ear (Fg. aso be afeced by ese canges. 7.2), as we as by neura npus rom e sympaec ner vous sysem,    Hyane arteroosceross s marked by ckenng o e arer- as oows: oar was by pnk, amorpous, yane maera and narrowng    Renn s a ormone a s produced n e kdney by ces a sense o vesse umens (Fg. 7.3A). he ckenng s caused by pasma rena peruson. Decreased peruson smuaes producon o proens and pds a eak across njured endoea ces no renn, a proease a ceaves crcuang angoensnogen o ango- vesse was and by ncreased producon o exraceuar marx ensn I. proens by smoo musce ces.    he acve orm o angotensn s a ormone w wo mporan    Hyper pastc arteroosceross s more ypca o severe yperen- acves: (1)  ncreases vascuar smoo musce one and ress- son. Vesses exb “onon skn, ” concenrc, amnaed ck- ance o low and (2)  smuaes e reease o adosterone rom e enng o areroar was due o proeraon o smoo musce adrena gand, eadng o ncreased reenon o sodum by e kd- ces and deposon o basemen membrane maera, eadng ney and ncreased bood voume, wc n urn enances cardac o umna narrowng (Fg. 7.3B). In ver y severe yperenson, ng, sroke voume, and cardac oupu. B o o ese aeraons brnod necross o vesse was may occur. rase bood pressure. he acve orm o angoensn s creaed by successve ceavages o angoensnogen by renn oowed by ango- ensn-converng enzyme, an mporan arge o drugs used o Clncal Features. Uness severe, yperenson may be asympomac rea yperenson. or many years un cardovascuar compcaons (e.g., sroke, myo-    he ear conans ces a respond o ncreased srec due carda narcon, aorc aneur ysm) deveop. Less dramac presena- o ara daon by reeasng atra natruretc ormone, wc ons ncude sowy progressve rena aure due o narrowng o rena ncreases rena excreon o sodum and waer and ereby owers areroes. hese compcaons can be prevened by medcaons a bood voume and bood pressure. enance rena sodum excreon or nb angoensn producon    Supermposed on ese ormona reguaors are npus rom e (e.g., angoensn-converng enzyme nbors). hereore, screenng sympatetc nervous system, wc ac o ncrease vascuar one and paens or yperenson s one o e mos efecve and mporan cardac oupu. aces o prevenve medcne. Severe yperenson (sysoc pressures Hyp er enson s dened, s ome wa arbrary, as a resng sys- > 200 mm Hg) occurs ess commony and s assocaed w eadace oc pressure o 130 mm Hg or greaer or a dasoc pressure o 80 and aered sensorum. hs varan, ermed magnant ypertenson, mm Hg or greaer. B o genec and envronmena ac ors (sress, can ead o rena emorrages, rena aure, cerebra edema, and ob esy, smokng, pysca nac vy, and g sa consumpon) dea and s a medca emergency a requres mmedae reamen.  CHAPTER 7 Diseases of Blood Vessels 107 Atrial natriuretic peptide Cardiac volume sensors + Excretes Na and water Vasodilation Blood volume BLOOD PRESSURE Normotension BLOOD PRESSURE Blood Vaso- volume constriction (Low volume or low resistance; renal ar ter y stenosis) + Resorbs Na and water Aldosterone Low renal pressure Low renal sodium Adrenal Liver Renin Angiotensin II Angio- Angiotensin I tensinogen Angiotensin-conver ting enzyme Endothelium in many tissues Fig. 7.2 Interplay of renin, angiotensin, aldosterone, and atrial natriuretic peptide in blood pressure regulation. o  es e a re ox  d  z e d  ow - d e n s  y  p opro e  n ( L DL ) and co- ATHEROSCLEROSIS  e s  e ro  cr ys a s. Snce  es e a re n o n or m a   y pre s e n ,  e y a re Atherosclerosis underlies the pathogenesis of coronary, cerebral, re c o g n  z e d as  ore  g n sub s anc e s (so-caed “d a n g e r s  g n a  s” ) and peripheral vascular disease, and causes more morbidity and by ce s suc as m a c rop  a g e s ,  r  g ge r  ng an  n   a m m a or y mortality in the western world than any other disorder. re s p on s e Orgnay conned many o ger-ncome counres, aerosce-    Vesse wa nlammaton resus n e accumuaon o nlam- ross s ncreasngy prevaen n ower-ncome counres as Wesern maor y ces, ncudng macropages and T ces, wc reease des and esyes spread. Lesons n e nma caed ateromas or c yoknes a nduce smoo musce ce proeraon and e ateromatous paques mpnge on vesse umens and resrc bood syness and deposon o exraceuar marx componens suc low. More mporany, aeromaous paques can beed or racure; as coagen. hs nlammaon conrbues o e naon, pro- e aer oten provokes romboss, causng rapd occuson o vesses gresson, and compcaons o aerosceroc esons. and scema and narcon o downsream ssues. Inlammaon sec- Hypercoeseroema and emodynamc acors (yperenson ondar y o aeromas can weaken vesse was, eadng o aneur ysma and urbuen bood low) are beeved o be e major naors o daon and sgncan cnca consequences. endoea damage. In genera, a condons assocaed w g LDL eves or oer orms o dyspdema are aso assocaed w Pathogeness. Atheroscleross appears to be the consequence o an ncreased rsk o cncay sgncan aerosceross. Rsk acors chronc, repettve endothelal njury leadng to inlammaion and are mupcave. Facors assocaed w ncreased rsk ncude e vesse wa damage oowng: he evens a cumnae n ormaon o an aeroma pay ou    Hy percoesteroema. he cenra roe o coesero, and more over decades (Fg. 7.4) and are no enrey undersood, bu e oow- speccay LDL, s gged by e acceeraed aeroscero- ng scenaro s avored: ss seen n fama y percoesteroema (see Caper 6), wc    Endotea njury eads o ncreased vascuar permeaby and eu- s caracerzed by eevaed ser um LDL eves due o nered kocye adeson, and aers endoea gene expresson, avorng deecs n e LDL recepor. LDL (“bad” coesero) devers co- nlammaon and romboss. esero o perpera ssues ncudng e vesse wa, wereas    Ac c umu  at  on of p o prote n s an d a s s o c  ate d p  d s o cc urs n  e g-densy poproen (HDL) coesero (“good” coesero) ve ss e wa b e c au s e o e n d o  e   a  d amage. Te mos  mp or  a n mobzes coesero rom e perper y and ranspors  o e