USMLE Step 1 Web Prep Genetic Disorders

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CHAPTER 6: GENETIC DISORDERS

Disorders involving an Extra Autosome

Trisomies General Mental retardation Chromosomal nondis un!tion

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DOWN SYNDROME
General #ar$ot$%e& '7(( or () *+1 Most !ommon mental retardation ,is- in!reases .ith maternal age /athogenesis 0ondis un!tion ,o1ertsonian translo!ation Clini!al Mental retardation 2Mongoloid3 4a!ies 5rush4ield s%ots 5road short ne!

6imian !rease
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DOWN SYNDROME CONT

Clini!al !on7t Congenital heart de4e!ts& Endo!ardial !ushion de4e!t Duodenal atresia 8irs!hs%rung7s disease A99

Al:heimer7s disease
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EDWARDS SYNDROME (TRISOMY 18)

General #ar$ot$%e& '7 (( or () *1; <n!reases .ith maternal age

0ondis un!tion

Clini!al M, 9o. set ears * mi!rognathia =verla%%ing 4lexed 4ingers ,o!-er&1ottom 4eet Diagnosis #ar$ot$%e
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PATA S SYNDROME (TRISOMY 13)

General #ar$ot$%e& '7 (( or () *13 ,is- in!reases .ith maternal age 0ondis un!tion Clini!al M, Cle4t li% *>or %alate ?6D ,enal a1normalities Mi!ro!e%hal$ /ol$da!t$l$
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CRI D

CHAT SYNDROME

General #ar$ot$%e& '@ (( or ()A "%& Deletion o4 the short arm o4 !hromosome " Clini!al 2Cat&li-e3 !r$ M, Congenital heart disease Mi!ro!e%hal$
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DISORDERS IN"OL"ING SE# CHROMOSOMES

#line4elter7s s$ndrome General #ar$ot$%e& '7 (() Male h$%ogonadism 0ondis un!tion

9a1s

9o. testosterone

Clini!al Testi!ular atro%h$ <n4ertilit$ Bemale hair distri1ution 8igh&%it!hed voi!e G$ne!omastia
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DISORDERS IN"OL"ING SE# CHROMOSOMES

Turner7s s$ndrome General #ar$ot$%e& '" (= Bemale h$%ogonadism Clini!al 6hort stature 26trea-ed3 ovaries <n4ertilit$ /rimar$ amenorrhea C$sti! h$groma * .e11ed ne! /redu!tal Coar!tation o4 the aorta
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DISORDERS IN"OL"ING SE# CHROMOSOMES

Determination o4 sex #ar$ot$%e Cgeneti!D sex ) !hromosome testi!ular develo%ment Gonadal sex =varian or testi!ular tissue Du!tal sex Mullerian or Eol44ian du!ts /henot$%e CgenitalD sex External genital a%%earan!e
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DISORDERS IN"OL"ING SE# CHROMOSOMES

True herma%hrodite De4inition

/resen!e o4 1oth testi!ular * ovarian tissue

Geneti! sex '@ ((A '@ ()A '" (>() Cmosai!sD Gonadal sex =var$ * testes =votestes Du!tal sex Mixed /henot$%i! sex Am1iguous
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DISORDERS IN"OL"ING SE# CHROMOSOMES CONT

Bemale %seudoherma%hroditism Geneti! sex '@ (( Gonadal * du!tal sex normal 4emale /henot$%i! sex virili:ed or am1iguous genitalia Ex%osure o4 4emale 4etus to androgens in utero CA8 Androgen&%rodu!ing tumors Exogenous androgens
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DISORDERS IN"OL"ING SE# CHROMOSOMES CONT

Male %seudoherma%hroditism Geneti! sex '@ () /henot$%i! sex Bemale genitalia Gonadal * du!tal sex Fndes!ended testes Testi!ular 4emini:ation Mutation o4 androgen re!e%tor

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MENDELIAN DISORDERS
De4inition 6ingle gene mutation Mutations /oint mutation 6$non$mous Missense 0onsense Brameshi4t /atterns o4 inheritan!e Autosomal dominant Autosomal re!essive (&lin-ed
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MENDELIAN DISORDERS CONT

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A TOSOMAL RECESSO"E DISORDERS

C$sti! 4i1rosis General Mutation o4 CBT, Chromosome 7 B"0; /athogenesis De4e!tive !hloride !hannel
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o1stru!tion o4 du!ts
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CYSTIC &I'ROSIS CONT

Distri1ution 9ungs

/ulmonar$ in4e!tions& /seudomonas Chroni! 1ron!hitis /an!reas o <nsu44i!ien!$G Mala1sor%tion steatorrhea Male re%rodu!tive s$stem o <n4ertilit$ 9iver o /lugging 1iliar$ !irrhosis G< tra!t
o o o

Me!onium ileus
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CYSTIC &I'ROSIS CONT

Diagnosis 6.eat test D0A %ro1e /rognosis 30 $ears Death due to %ulmonar$ in4e!tions& /seudomonas
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PHENYL(ETON RIA
En:$me de4e!t /hen$lalanine h$drox$lase /resentation 0ormal at 1irth 9ight s-in * hair Mous$ odor Diagnosis 6!reened at 1irth Treatment Dietar$ restri!tion o4 %hen$lalanine
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M, 1$ @ months

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AL(APTON RIA
En:$me de4e!t 8omogentisi! oxidase Beatures

5la!- urine * !artilage Earl$ onset arthritis

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GLYCOGEN STORAGE DISEASES

De4inition De4i!ien!ies in en:$mes ne!essar$ 4or gl$!ogen meta1olism T$%e <

Glu!ose&@&%hos%hatase de4G 8e%atomegal$ * h$%ogl$!emia

T$%e << 9$sosomal glu!osidase de4G Cardiomegal$& Death 1$ age + T$%e ? Mus!le %hos%hor$lase de4G Exer!ise&indu!ed mus!le !ram%s
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TAY)SACHS DISEASE
De4e!t

8examinidase A de4G

a!!umG o4 GM+ ganglioside

Distri1ution ,etina& !herr$&red s%ot C06 /resentation Mental deterioration * motor in!oordination Death 1$ +&3 Ash-ena:i He.s EM

Distended l$sosomes

Diagnosis En:$me assa$s * D0A %ro1es

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NEIMANN)PIC( DISEASE
De4e!t

6%hingom$elinase de4G

a!!umG o4 s%hingom$elin

Distri1ution C06

,etina& !herr$&red s%ot ,E6 Ash-ena:i He.s

/resentation Mental * motor mani4estations 6%lenomegal$ * l$m%hadeno%ath$ 0ormal at 1irth s$m%toms 1$ @ months EM

death 1$ age +

2:e1ra 1odies3

Diagnosis 5io!hemi!al assa$ * D0A %ro1es

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GA CHER DISEASE
De4e!t

Glu!o!ere1rosidase de4 glu!o!ere1roside

a!!umG o4

/resentation T$%e < 8e%atos%lenomegal$ /an!$to%enia 9$m%hadeno%ath$ 5M involvement Mi!ro

Gau!her7s !ells

Diagnosis 5io!hemi!al assa$

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M COPOLYSACCHARIDOSIS
De4inition De4i!ien!ies in l$sosomal en:$mes 4or degradation o4 M/6 M/6 <& 8urler7s De4i!ien!$ o4 &iduronidase 6evere M/6 <<& 8unter7s (&lin-ed re!essive Mild
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A TOSOMAL DOMINANT DISORDERS

Bamilial h$%er!holesterolemia E%idemiolog$ Most !ommon inherited disorder De4e!t

9D9 re!e%tor mutation& !hromosome 19 in!reased !ir!ulating !holesterol 9oss o4 4eed1a!- inhi1ition o4 8MG CoA redu!tase

/resentation Elevated serum !holesterol 6-in xanthomas (anthelasma

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A TOSOMAL DOMINANT DISORDERS CONT

Mar4an7s s$ndrome De4e!t

Mutation o4 4i1rillin gene& !hromosome 1"

Distri1ution 6-eletal o Ara!hnoda!tal$ 6u1luxation o4 lens Cardiovas!ular o C$sti! medial ne!rosis o A< * M?/
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disse!ting aorti! aneur$sm

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A TOSOMAL DOMINANT DISORDERS CONT

Ehlers&Danlos s$ndrome De4e!t

De4e!t in !ollagen s$nthesis or stru!ture

Clini!al 8$%erextensi1le s-in * oints ?ariants T$%e 3& most !ommon T$%e '& T$%e <<< !ollagen& ru%ture o4 arteries * !olon T$%e 9& (9, de4e!t in !o%%er meta1olism Com%li!ations Hoint dislo!ations

Dia%hragmati! hernias ,etinal Deta!hment

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A TOSOMAL DOMINANT DISORDERS CONT

0euro4i1romatosis T*+, I& 90I Geneti!s T6G& 0B&1 Chromosome 17 Clini!al Multi%le neuro4i1romas 2!a4J&au&lait s%ots3 9is!h nodules

<n!reased meningiomas * %heo!hromo!$toma

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NE RO&I'ROMATOSIS CONT
T*+, 2& 10I Geneti!s T6G& 0B&+ Chromosome ++& merlin Clini!al 5ilateral a!ousti! neuromas 0euro4i1romas * !a4J&au&lait s%ots 0o 9is!h nodules
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A TOSOMAL DOMINANT DISORDERS CONT

?on 8i%%el&9indau disease Geneti!s T6G& v89 Chromosome 3% Clini!al 8emangio1lastomas C$sts o4 liverA %an!reas * -idne$s KMulti%le 1ilateral renal !ell !ar!inomas
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TRIPLET REPEAT M TATIONS

Bragile ( Geneti!s CGG re%eat mutations BM,&1 gene on ( !hromosome Clini!al M, 5ig a. 5ig ears Ma!roor!hidism Diagnosis D0A %ro1e
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TRIPLET REPEAT M TATIONS

8untington7s disease Geneti!s CAG tri%let re%eat mutation /atholog$ Atro%h$ o4 !audate nu!leus Clini!al Earl$&onset dementia 8untington7s !horea