Robbins Essential Pathology PDF, Genetic Diseases, Chapters 6 (Pages 113-118)

92 CHAPTER 6 Genetic Diseases NORMAL CYSTIC FIBR...

92 CHAPTER 6 Genetic Diseases NORMAL CYSTIC FIBROSIS LUMEN OF SWEAT DUCT LUMEN OF SWEAT DUCT + Cl Na + Cl Na CFTR ENaC NORMAL CYSTIC FIBROSIS AIRWAY AIRWAY Nor mal Dehydrated mucus mucus + + + + Cl Na H O Cl Na H O Cl Na H O Cl Na H O 2 2 2 2 Fig. 6.2 Top, In cystic fibrosis (CF), a chloride channel defect in the sweat duct causes increased chloride and sodium concentration in sweat. Bottom, Patients with CF have decreased chloride secretion and increased sodium and water reabsorption in the airways, leading to dehydration of the mucous layer coating epithelial cells, defective mucociliary action, and mucous plugging. CFTR, Cystic fibrosis transmembrane conductance regulator; ENaC, epithelial sodium channel responsible for intracellular sodium conduction. (see Fg. 6.2, bottom). s causes ncreased lumnal sodum absorpon cronc bronc s and bronc  e c  as s. D e vel opme n o lung roug epelal sodum cannels. Increased nracellular sodum and abs cess es s common. clorde drves waer reabsorpon rom e lumen, deydrang e    Pancreatc abnormates are presen n 85% o 90% o paens. In layer o mucus coang e underlyng epelal cells. In e lungs, s severe cases, e pancreac ducs are obsruced by mucous plugs, deydraon leads o deecve mucoclary acon and e accumulaon causng aropy o e exocrne glands and progressve bross (Fg. o vscd secreons a obsruc ar passages and predspose o recur- 6.4). e loss o pancreac exocrne secreon mpars a absorp- ren pulmonary necons. Vscd secreons also may obsruc pancre- on, leadng o vamn A decency, wc may conrbue o ac ducs and e vas deerens, leadng o pancreac nsuicency and squamous meaplasa o e pancreac duc epelum. mae nery, respecvey. In addon, CFTR reguaes e ranspor o    Meconum eus, a ype o bowel obsrucon, may occur n e bcarbonae ons n e epea ces o e exocrne pancreas, and s small nesne o nans because o e presence o ck plugs dysuncon causes e acdcaon o pancreac secreons. s resuls o mucus. n precpaon o mucn and mpars e acvy o dgesve enzymes    Lver nvovement may lead o mucus pluggng o ble canalcul, suc as rypsn a uncon bes under alkalne condons, bo o accompaned by ducular proleraon and pora nammaon. wc exacerbae pancreac nsuicency. Hepac seaoss s common. Over me, crross may deveop, resung n dfuse epac noduary. Suc severe epac nvovemen s encounered n ewer an 10% o paens. Morphology. Lesons var y n dsrbuon and severy dependng    Azoosperma and nfertty are ound n 95% o e afeced on genoype. maes wo sur vve o aduood; baera absence of e vas def-    P umonar y d s eas e semmng  rom ob s r uc   on and  n e c   on erens s a requen indng. o  e ar p ass ages s  e mos s e r  ous e aure (Fg. 6.3). Te broncoles o en are d send e d w     ck muc us ass o c  ae d w   marke d yp er pl as  a and y p er  ropy o  e muc us -s e - Clncal Features. e clncal manesaons o CF are proean. Sgns cre ng cel ls. Sup e r  mp os e d  n e c   ons g ve r s e o s e ve re and sympoms vary rom mld o severe, may presen a br or years  CHAPTER 6 Genetic Diseases 93 Fig. 6.4 Pathologic changes of cystic fibrosis in the pancreas. The ducts are dilated and plugged with eosinophilic mucin, and the parenchymal glands are atrophic and replaced by fibrous tissue. Diseases Caused by Mutations in Genes Encoding Enzyme Proteins Phenylketonuria Fig. 6.3 Lungs of a patient who died of cystic fibrosis. Extensive Phenylketonuria is caused by mutations that disable the enzyme mucous plugging and dilation of the tracheobronchial tree are apparent. phenylalanine hydroxylase. The pulmonary parenchyma is consolidated by a combination of both secretions and pneumonia; the greenish discoloration is the product Pathogeness. Penylkeonura (PKU) s an nborn error o meabolsm of Pseudomonas infection. (Courtesy of Dr. Eduardo Yunis, Children’s a afecs 1 n 10,000 lve-born Caucasan nans. e mos common Hospital of Pittsburgh, PA.) (classc) orm s relavely common n persons o Scandnavan descen and uncommon n Jews populaons and n persons o Arcan descen. aer, and may be reaed o e nvovemen o one organ or many. s auosomal recessve dsorder s caused by a severe decency Approxmaey 5% o 10% o e cases come o aenon a br or o penyaanne ydroxyase (PAH), wc blocks e converson o soon ater because o meconum leus Exocrne pancreac nsuicency penylalanne o yrosne and leads o yperpenylalannema. Afeced occurs n a majory (85% o 90%) o paens w CF and s assocaed nans are normal a br bu wn a ew weeks exb a rsng plasma w nerance o wo “severe” CFTR muaons (e.g., ΔF508/ΔF508), penylalanne level, wc mpars bran developmen. As penylalanne wereas paens carryng a eas one “md” CFTR muaon oten rean levels rse, normally mnor meabolc paways become more acve, pancreac exocrne uncon. Pancreac nsuicency s assocaed w yeldng nermedaes a are excreed n large amouns n e urne maabsorpon o proen and a. e auly a absorpon may nduce and n e swea, mparng a srong musy or “mousy” odor o afeced decency saes o e a-soluble vamns A, D, and K. Hypoproenema nans. Afeced nans’ pale coloraon s due o e deecve syness may be severe enoug o cause generalzed edema. Perssen darrea o yrosne, wc s requred or melann syness. resuls n recal prolapse n as many as 10% o cldren w CF. e pancreas-suicen penoype usuay s no assocaed w Clncal Features. I unreaed, by 6 mons o le PKU produces severe oer gasronesna compcaons and, n genera, ese paens menal dsably (nellgence quoen less an 60). Abou one rd demonsrae exceen grow and deveopmen. o ese cldren never walk and wo rds canno alk. Sezures, oer Cardorespraor y compcaons, suc as perssen ung nec- neurologc abnormales, decreased pgmenaon o ar and skn, and ons, obsrucve pumonar y dsease, and cor pumonae, are e mos eczema are also seen. ese complcaons can be avoded by lmng common cause o dea (approxmaey 80% o aaes n e Uned penylalanne nake early n le; ereore, nans are screened or Saes). By 18 years o age, paens w severe CF oten are colonzed PKU mmedaely ater br. Deary reamen s dsconnued ater w paogens suc as Pseudomonas aerugnosa and Burkodera adulood; owever, women o cldbearng age wo ave PKU mus go cepaca. Sgncan lver dsease occurs lae n e course and s ore- on a low penylalanne de pror o concepon because o e eraogenc sadowed by pulmonar y and pancreac nvolvemen; w mproved efecs o penylalanne and s meaboles on e eus. sur vval, lver dsease s now e rd mos common cause o dea Lysosomal Storage Diseases n paens w CF (ater cardopulmonar y and ransplan-relaed complcaons). Lysosomal storage diseases stem from mutations that lead to de e dagnoss s usually suspeced based on perssenly elevaed ciencies of enzymes required for the degradation of various metab- swea elecrolye concenraons, caracersc clncal ndngs (pulmo- olites and certain organelles. nary dsease and gasronesnal manesaons), and amly sory, and s esablsed by sequencng e CFTR gene. e use o anbocs and Pathogeness. Lysosomes, e dgesve sysem o cells, conan a pancreac enzyme replacemen erapy, as well as blaeral lung rans- number o ydrolyc enzymes a are nvolved n e breakdown o planaon, as mproved oucomes n paens w severe CF. New drug complex subsraes no soluble end producs. ese subsraes may be erapes also are now avalable a mprove e oldng, membrane derved rom nracellular organelles a are undergong auopag y or expresson, and uncon o muaed CFTR molecules. ese advances may be aken up no e cell by pagocyoss. I an enzyme requred ave exended e medan le expecancy o 40 years, cangng a leal or e caabolsm o a subsrae s mssng, parally degraded nsoluble dsease o cldood no a cronc dsease o aduls. meaboles accumulae wn e lysosomes (Fg. 6.5). In addon, 94 CHAPTER 6 Genetic Diseases Complex substrate Tay-Sachs Dsease (G Ganglosdoss: Deicency n Hexosam M2 ndase A) Tay-Sachs disease, the most common gangliosidosis, is caused by loss of function mutations affecting expression of the enzyme Normal lysosomal Lysosomal enzyme hexosaminidase A. degradation deficiency Pathogeness. In Tay-Sacs dsease, glycolpds called gangosdes A A accumulae n many ssues, bu damage s mosly conned o neurons and glal cells rougou e CNS. e molecular bass or neuronal njur y s no undersood. In many cases e muan proen msolds, and s may nduce e unolded proen response (see Caper 1), Small B B wc can lead o apopoc cell dea. diffusible end products Morphology. Afeced cells appear swollen and somemes oamy. Elecron mcroscopy reveals worled, onon skn–lke layers o C membranes wn e lysosomes (Fg. 6.6). ese canges are ound rougou e CNS, perperal nerves, and auonomc nervous sysem. e rena usually s nvolved, were e pallor produced by swollen ganglon cells n e perperal rena resuls n a conrasng “cerry red” spo n e relavely unafeced cenral macula. Clncal Features. In e mos common varan o Tay-Sacs dsease, PRIMARY Stored nonmetabolized nans appear normal a br, bu moor weakness begns a 3 o 6 STORAGE products mons o age, ollowed by neurologc mparmen, blndness, and progressvely more severe neurologc dysuncons. Dea occurs wn 2 or 3 years. Tay-Sacs dsease, lke oer lpdoses, s mos Defective fusion of autophagosome with lysosome common among Askenaz Jews, among wom e requency o eerozygous carrers s esmaed o be 1 n 30. Defective degradation of intracellular organelles Niemann-Pick Disease Types A and B Type A and type B Niemann-Pick disease is caused by loss of func- Accumulation tion mutations that affect the enzyme acid sphingomyelinase. Accumulation of SECONDARY of aberrant toxic proteins STORAGE mitochondria Pathogeness. e dsease s caused by a decency o spngo- myenase, more severe n ype A an n ype B, resulng n mpared breakdown o spngomyeln no ceramde and posporylcolne. Induction of Generation of CELL DEATH cell damage free radicals Morphology. In ype A, excess spngomyeln accumulaes n pagocyes and neurons. e macropages become sufed w Fig. 6.5 Pathogenesis of lysosomal storage diseases. In this example, droples or parcles o e complex lpd, mparng a ne vacuolaon a complex substrate is normally degraded by a series of lysosomal or oamness o e cyoplasm (Supplemenal eFg. 6.1). Wen enzymes (A, B, and C) into soluble end products. If there is a deficiency or malfunction of one of the enzymes (e.g., B), catabolism is incomplete, and insoluble intermediates accumulate in the lysosomes. In addition to this primary storage defect, secondary storage and toxic effects result from defective autophagy, leading to the accumulation of dysfunctional mitochondria and accumulation of toxic wastes. ysosome dysuncon nereres w cearance o deecve organees suc as mocondra, wc may generae desrucve ree radcas. s combnaon o deecs ulmaely leads o cell dea. Lysosomal sorage dsorders are subdvded based on e bocem- cal naure o e subsraes and e accumulaed meaboles (Table 6.3). Ceran eaures are common o mos dseases n s group:    Autosoma recessve transmsson    Onset of dsease n nfancy or eary cdood    Hepatospenomegay, due o accumulaon o parally dgesed meaboles n pagocyes    Frequent CNS nvovement w assocaed neuronal damage    Ceuar dysfuncton, caused no only by accumulaon o und- gesed maeral bu also by a cascade o secondar y evens rggered, Fig. 6.6 Ganglion cells in Tay-Sachs disease. A portion of a neuron or example, by macropage acvaon and release o cyoknes under the electron microscope shows prominent lysosomes with Mos lysosome sorage dsorders are ver y rare; only a ew o e whorled configurations. Part of the nucleus is shown above. (Courtesy more common condons are consdered ere. Dr. Joe Rutledge, Children’s Regional Medical Center, Seattle.)  CHAPTER 6 Genetic Diseases 95 Table 6.3 Selected Lysosomal Storage Disorders Disease Deficient Enzyme or Protein Accumulating Metabolite(s) Clinical Features Tay-Sachs disease Hexosaminidase GM2 ganglioside CNS disease Gaucher disease Glucocerebrosidase Glucocerebroside Mild forms: organomegaly, bone marrow failure Severe forms: CNS disease Niemann-Pick disease, Sphingomyelinase Sphingomyelin Type A: early-onset CNS disease, types A and B organomegaly Type B: early-onset organomegaly, late-onset CNS disease Niemann-Pick disease, NPC1 or NPC2; part of a Cholesterol, gangliosides Neurologic symptoms, including ataxia, type C lipid transport complex dementia; variable organomegaly MPS Type I (Hurler α-L-Iduronidase Heparin and dermatan sulfate Organomegaly, cardiovascular disease, syndrome) CNS disease MPS Type II (Hunter L-iduronate sulfatase Heparin and dermatan sulfate Similar to Hurler syndrome, but milder syndrome) phenotype Glycogenosis type 2, Lysosomal glucosidase (acid Glycogen Cardiac failure Pompe disease maltase) Morphology. Pagocyes sufed w glucocerebrosde— vewed by eecron mcroscopy, e vacuoes are engorged secondary so-called Gaucer ces—become markedly enlarged and acqure a ysosomes a oten conan membranous cyoplasmc bodes paognomonc cyoplasmc appearance caracerzed as “wrnkled resemblng concenrc lamellaed myeln gures. Because o er ssue paper” (Fg. 6.7). Splenomegaly may be massve, and e g conen o pagocyes, e mos severely afeced organs are marrow may be largely replaced by sees o Gaucer cells. e spleen, lver, bone marrow, lymp nodes, and lungs. e splenc enlargemen may be srkng. Neurons rougou e CNS also accumulae spngomyeln, wc resuls n neuronal enlargemen and vacuolzaon. Type B s assocaed w less severe spngomyelnase Clncal Features. One varan, ype 1, accouns or 99% o cases o Gaucer decency and e manesaons are mlder. dsease. I s assocaed w bone lesons, epaosplenomegaly, and e absence o CNS nvolvemen. Type 1 s mos common n Askenaz Clncal Features. Type A presens n nancy w massve Jews and s compable w long le. Types 2 and 3 are caracerzed by organomegaly and severe neurologc deeroraon Dea usually neurologc sgns and sympoms, wc may appear durng nancy (ype 2) occurs wn e rs 3 years o le. In comparson, paens w e or laer n le (ype 3). Aloug e lver and spleen also are nvolved, e ype B varan ave organomegaly bu no neurologc manesaons. clncal eaures n ypes 2 and 3 are domnaed by neurologc dsurbances, ncludng convulsons and progressve menal deeroraon. O neres, Niemann-Pick Disease Type C eerozygous carrers o Gaucer dsease are a ncreased rsk o Parknson Type C Niemann-Pick disease is caused by defects in lipid trans- dsease, or reasons a are unceran. port, leading to lipid accumulation in cells. Curren erapy s amed a reducng e burden o glucocerebro- Nemann-Pck dsease ype C resuls rom muaons n wo relaed sdes by nuson o recombnan glucocerebrosdase and w drugs genes, NPC1 and NPC2, wc encode proens a orm a complex a a nb glucocerebrosde synase. s nvolved n nracellular raickng o coesero and oer pds. Deec- Mucopolysaccharidoses ve pd ranspor resus n e nraceuar accumuaon o coesero Mucopolysaccharidoses are characterized by defective degrada- and gangosdes suc as GM1 and GM2. Afeced cldren exb aaxa, tion and excessive accumulation of mucopolysaccharides in var- vsual dsurbances, dysona, dysarra, and psycomoor regresson. ious tissues. Gaucher Disease Gaucher disease is caused by loss of function mutations in glucoce- Pathogeness. Mucopolysaccardes are syneszed by connecve rebrosidase that result in the accumulation of glucocerebrosides in ssue broblass and are par o e exracellular marx. Turnover or phagocytes and more variable accumulations in neurons. remodelng o mucopolysaccarde s medaed by upake no pagocyes and enzymac degradaon wn lysosomes. I any o ese enzymes are Pathogeness. Gaucer dsease s an auosomal recessve dsorder deecve, mucopolysaccardes, manly eparan sulae and dermaan w varable expressvy due o muaons o dferng severy. sulae, accumulae wn e lysosomes o pagocyes and oer cells. Gucocerebrosdase normally cleaves a glucose resdue rom ceramde. Is dec leads o an accumulaon o glucocerebrosde n macropages, Clncal and Morpholog c Features. Hepaosplenomegaly, skeleal parcularly n e spleen, lver, and bone marrow. s s because muc deormes, subendoelal areral deposs (parcularly n e o e glucocerebrosde s derved rom senescen red cells, wc coronar y areres), and lesons n ear valves and n e bran are are normally removed rom e crculaon by macropages n ese common o all o e mucopolysaccardoses (MPSs). Coronar y ssues. e macropages are acvaed wle aempng o dges subendoelal lesons oten lead o myocardal scema, and e glucocerebrosde and release a number o cyoknes. ese are myocardal narcon and cardac decompensaon are mporan suspeced o alerng bone meabolsm and may explan e assocaon causes o dea Mos cases are assocaed w coarse acal eaures, o Gaucer dsease w varable degrees o oseopena, oseopoross, cloudng o e cornea, jon sfness, and menal dsably Urnar y oseolyc lesons, and occasonally oseonecross. excreon o mucopolysaccardes oten s ncreased.  CHAPTER 6 Genetic Diseases 95.e1 Supplemental eFig. 6.1 Niemann-Pick disease in liver. The hepato- cytes and Kupffer cells have a foamy, vacuolated appearance resulting from deposition of lipids. (From Kumar V, Abbas A, Aster J: Robbins Basic Pathology, 10th ed., St. Louis, Elsevier, 2018, Fig. 7.10; Courtesy Dr. Arthur Weinberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas.) 96 CHAPTER 6 Genetic Diseases A B Fig. 6.7 Gaucher disease involving the bone marrow. (A) Gaucher cells with abundant lipid-laden granular cytoplasm. (B) Electron micrograph of Gaucher cells with elongated distended lysosomes. (Courtesy Dr. Mat- thew Fries, Department of Pathology, University of Texas Southwestern Medical Center, Dallas.) Severa cnca varans o MPS exs, eac resung rom e de- acc umu l a on o g lycogen n mus cle s and mus cle we a k ness due cency o a dferen enzyme. Only wo well-caracerzed syndromes o mp are d energ y pro du c   on. Myop a c or ms o g lyc ogen mer bre dscusson. sorage ds e as es are marke d by mus cl e c ramps a er e xerc s e,    M PS ty pe I, a ls o k nown as Hurer sy ndrome, s an auos oma l re ces- mus cle njur y le adng o myog lob nur  a, and  a lure o exerc s e sve ds order caus e d by a decenc y o α-L-durondas e. Afe c e d o nduce an ele va  on n bl o o d l ac  ae le vels b e c aus e o a bl o ck c ldren ave a le exp e c  anc y o 6 o 10 ye ars, and de a  s oten n g lycolyss. Mc Arde d s eas e ( yp e V g lycogenos s ) , resu l  ng due o cardac complca ons. Mucop olys accar des acc umu lae  rom a de cenc y o mus cl e pospor y l as e, s  e proo yp e o n macropages, broblass, endo elum and smo o  mus cle myop a c g lycogenos es. cel ls o  e vas c u lar wa l l, and o er cel ls. e afe c e d cel ls are    Pompe dsease (ype II glycogenoss) s caused by a decenc y o swol len and ave cle ar c yoplasm, resu l ng  rom  e acc umu la- lysosomal glucosdase (acd malase), wc s requred or gly-  on o engorge d, vac uolae d lys os omes. Acc umu la on n neu- cogen breakdown rougou e body (Supplemenal eFg. 6.2). rons accouns or  e men a l ds ab l y. However, e mos afeced cell ype s e cardac myoc ye. Car-    MPS type II, or Hunter syndrome, dfers rom Hurler syndrome domegaly s promnen, and mos paens de wn 2 years o n s mode o nerance (X-lnked) and e absence o corneal dsease onse owng o cardorespraor y alure. erapy w e cloudng. I also oten as a more prolonged, mlder clncal course. mssng enzyme can reverse cardac muscle damage and ncrease Unlke Hurler syndrome,  resuls rom a decency o L-duro- longevy. nae sulaase (a dferen enzyme an α-L-durondase). Despe e dferen enzyme decency, dencal subsraes accumu- lae because breakdown o eparan sulae and dermaan sulae COMPLEX MULTIGENIC DISORDERS requres e uncon o bo enzymes. Complex multigenic disorders are caused by interactions between Glycogen Storage Diseases (Glycogenoses) multiple gene variants and environmental factors. The various glycogen storage diseases are caused by inherited de Genec varans are reerred o as polymorpsms  ey ave an ciencies of enzymes involved in glycogen metabolism and result allele requency n e populaon o a leas 1%. Accordng o e com- in excessive accumulation of glycogen or some abnormal form of mon dsease–common varan ypoess, complex mulgenc dsorders glycogen in tissues. occur wen several polymorpsms, eac w a modes efec and low penerance, are conered. Many common dseases are oug o all Pathogeness. In glycogen sorage dseases, e specc enzyme n s group, ncludng auommune and allergc dseases, dabees, decency dcaes e ype o glycogen a accumulaes, s nracellular yperenson, and scemc ear dsease, bu  s oten no possble o locaon, and s ssue dsrbuon. Glycogen may accumulae wn pnpon a specc causave polymorpsm. Wen consderng complex e cyoplasm and somemes wn e nucle o afeced cells. Mos mulgenc dsorders, several oer prncples sould be kep n mnd: glycogenoses are nered as auosomal recessve dseases.    Aloug complex dsorders resul rom e collecve nerance Approxmaely a dozen glycogenoses ave been descrbed. On e o several polymorpsms, ceran polymorpsms may ave a bass o paopysologc ndngs, ey all no ree groups (Table 6.4): domnan nuence. For exampe, aoug varans n 20 o 30    Hepatc type. e lver syneszes glycogen and also breaks  genes are mpcaed n ype 1 dabees, a ew HLA aees conrbue down no ree glucose. Glycogenoses caused by deecs n epac more an 50% o e rsk. enzymes nvolved n glycogen meabolsm ave wo major efecs:    S ome poymorpsms are assocaed w mupe dseases, usuay lver enlargemen due o accumulaon o normal or abnormal o e same ype (e.g., auommune dsorders), wereas oers are orms o glycogen, and ypoglycema due o a alure o glucose dsease-specic. producon (Fg. 6.8). Von Gerke dsease (ype I glycogenoss),    Many genec varans nked o dsease a n e noncodng reg- resulng rom a lack o glucose-6-pospaase, s e mos mpor- uaor y regons o e genome and us are key assocaed w a an epac orm o glycogenoss. quanave varaon n gene expresson, raer an a srucura    Myopatc type. Glycogen s an mp or  an e nerg y s ource n s r  - cange n e encoded proen. ae d mus cle. Glyco gen sorage ds e as es c aus e d by d ee c  s n    Envronmena acors pay a sgnican roe n e expresson o enzy mes  a are re qu re d or g lycogen bre a kdow n lead o  e compex mugenc dsorders. Type 2 dabees s an exampe o a