5 genetic and developmental disorders

8/11/2019 5 Genetic and Developmental Disorders

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5 Genetic and Developmental DisordersMutations

Mutations are a permanent change in DNA.

Mutations Mutations are a permanent change in DNA.

Pointmutations

In both sickle cell trait and sickle cell disease, a missense mutationoccurs when adenine replaces thymidine, causing valine to replaceglutamic acid in the sixth position o the !"globin chain. As a result,#$%s spontaneously sickle in the peripheral blood i the amount osickle hemoglobin is greater than &'(.

Mutation involving a change in a single nucleotide base within a gene

). *ilent mutationo Altered DNA codes or the same amino acid without changing the

phenotypic e ect+. Missense mutation

o Altered DNA codes or a different amino acid, which changes thephenotypic e ect

. Nonsense mutation

o Altered DNA codes or a stop codon that causes prematuretermination o protein synthesis

In !"thalassemia ma-or, a nonsense mutation produces a stopcodon that causes premature termination o DNA transcription o the!"globin chain. %onse uently, there is a marked decrease in thesynthesis o hemoglobin A /0 +! +1, resulting in a microcytic anemia.

2rameshi t mutation

). Insertion or deletion o one or more nucleotides shi ts the reading rame o theDNA strand

+. 3xample"in 4ay"*achs disease, a our"base insertion results in the synthesiso a de ective lysosomal en5yme /hexosaminidase1.

4rinucleotide repeat disorderspage 67

page 6&

). 3rrors in DNA replicationo %ause ampli ication o a se uence o three nucleotides /e.g., %A81,which disrupts gene unction


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+. Associated with anticipation

a. Increasing severity o clinical disease in each successive generationb. %aused by the addition o more trinucleotide se uences during

gametogenesisc. 2emale carriers may be symptomatic

9ccurs i they have more paternally /than maternally1 derived: chromosomes with trinucleotide repeats

d. 3xamples" ragile : syndrome, ;untington


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oxidase degenerative arthritis

8alactosemia 8alactose )"phosphate"uridyltrans erase/8AB41

8alactose )"phosphate

Mental retardation, cirrhosis,hypoglycemia

Avoid dairy products

;ereditaryructose

intolerance

Aldolase $ 2ructose )"phosphate %irrhosis, hypoglycemia, renaldisease

Avoid ructose, sucrose, honey

;omocystinuria %ystathioninesynthase

;omocysteine andmethionine

Mental retardation, vesselthrombosis

Maple syrup urinedisease

$ranched chain 0"ketoaciddehydrogenase

Beucine, valine,isoleucine, and theirketoacids

Mental retardation, sei5ures,eeding problems, sweet"

smelling urine

McArdle


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b. ;omo5ygotes are symptomatic early in li e.c. ;etero5ygous individuals /Aa1 are asymptomatic carriers.

4he dominant gene /A1 overrides the mutant recessive gene/a1.

d. $oth parents must be hetero5ygous to transmit the disorder.3xample"Aa ? Aa AA, Aa, Aa, aa /+7( without disorder7'( asymptomatic carriers +7( with disorder1

+. A# protein de ects. Inborn errors o metabolism

a. Most metabolic disorders are due to an en5yme de iciency.b. *ubstrate and intermediates proximal to the en5yme block increase.c. Intermediates and the end product distal to the en5yme block

decrease.d. 8lycogenoses

ii PathogenesisIncrease in glycogen synthesis /e.g., von 8ierke


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i. *ymptoms and signs may not occur early in li e.ii. 3xample"in adult polycystic kidney disease, cysts are not

present at birth.iii. Penetrance

i. %omplete penetrance

All individuals with the mutant gene expressthe disorder /e.g., amilial polyposis1.ii. #educed penetrance

Individuals with the mutant gene arephenotypically normal.4hey transmit the disorder to their o spring/e.g., Mar an syndrome1.

iv. Cariable expressivity

All individuals with the mutant gene express thedisorder but at di erent levels o severity.

+. 9ther AD disorders

o ;untington


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i. Mental retardationMost common mendelian disorder that causesmental retardation7'( o emale carriers may develop mentalretardation.

ii. Phenotypic changesBong ace, large mandible, everted earsiii. Macro"orchidism /enlarged testes1 at puberty

c. Diagnosisi. DNA analysis to identi y trinucleotide repeats /best test1ii. 2ragile : chromosome study

2. Besch"Nyhan syndrome

a. De iciency o hypoxanthine"guanine phosphoribosyltrans erase /;8P#41i. Normally involved in salvaging the purines hypoxanthine and

guanineb. %linical indings

i. Mental retardation, hyperuricemia, sel "mutilation2. 9ther :# disorders

a. 4esticular emini5ation, chronic granulomatous disease, $ruton


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c. Inactivation accounts or the parental derivation o the :chromosomes in emales.

7'( o : chromosomes are paternal and 7'( arematernal

8eneral considerations

). Most human cells are diploid /@& chromosomes1.a. Autosomes ++ pairsb. *ex chromosomes /:: in emales and :H in males1 ) pair

+. 8ametes, the products o meiosis, are haploid /+ chromosomes1.. Byon hypothesis

a. In emales, one o the two : chromosomes is randomly inactivated.Inactivation occurs in the embryonic period o development.

b. 4he inactivated : chromosome is called a $arr body.

ii It is attached to the nuclear membrane o cells.iii 4hey are visible in s uamous cells obtained by scraping the

buccal mucosa.b. Normal emales have one $arr body, and normal males have none.c. Inactivation accounts or the parental derivation o the :

chromosomes in emales.

7'( o : chromosomes are paternal and 7'( arematernal.

%hromosomal alterationspage J+

page J

In a orm o Down syndrome, the mother o an a ected child has @7/not @&1 chromosomes because o a robertsonian translocationbetween the long arms o chromosomes +) and )@, producing onelong chromosome /)@ +)1. 4he mother also has one chromosome)@ and one chromosome +). 4he ather has the normal @&chromosomes. 4he a ected child has @& chromosomes with three

unctional +) chromosomes including chromosome /)@ +)1 andchromosome +) rom the mother and chromosome )@ and

chromosome +) rom the ather

Numeric or structural abnormalities o autosomes or sex chromosomes

). Nondis-unctiona. =ne ual separation o chromosomes in the irst phase o meiosisb. #esults in ++ or +@ chromosomes in the egg or spermc. 3xamples"4urner


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c. Most o ten involves sex chromosomes /e.g., 4urner


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i. Mental retardationii. %le t lip and palateiii. Polydactyly, C*D, cystic kidneysiv. 3arly death

Disorders involving sex chromosomespage JF

). 4urner


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v. Decreased testosterone Aromatase converts testosterone to estradiolestradiol causes emini5ation.Increased B; /loss o negative eedback withtestosterone1

vi. 9ne $arr body. :HH syndrome

a. %aused by paternal nondis-unctionb. Associated with aggressive /sometimes criminal1 behavior

c. Normal gonadal unction

,ther Patterns of !nheritance

Multi actorial /polygenic1 inheritance

). %ombination o multiple minor gene mutations plus environmental actors+. 3xamples o multi actorial inheritance

a. 9pen neural tube de ects Associated with decreased maternal olate levels

b. 4ype + diabetes mellitus

Associated with obesity, which down"regulates insulinreceptor synthesis

Multi actorial /polygenic1 inheritance

). %ombination o multiple minor gene mutations plus environmental actors+. 3xamples o multi actorial inheritance

a. 9pen neural tube de ects Associated with decreased maternal olate levels

b. 4ype + diabetes mellitus

Associated with obesity, which down"regulates insulinreceptor synthesis

Mitochondrial DNA disorders). 2unction o mitochondrial DNA

o %odes or en5ymes involved in mitochondrial oxidativephosphorylation reactions

+. Inheritance pattern

a. A ected emales transmit the mutant gene to all their children.9va contain mitochondria with the mutant gene.

b. A ected males do not transmit the mutant gene to any o theirchildren.

*perm lose their mitochondria during ertili5ation.+. 3xamples"Beber


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8enomic imprinting). Inheritance pattern

a. Inheritance depends on whether the mutant gene is o maternal orpaternal origin.

b. 3xamples"Prader"Gilli syndrome and Angelman syndrome

+. Pathogenesisa. Normal changes in maternal chromosome )7 during gametogenesisi. Prader"Gilli gene is inactivated by methylation /imprinted1.ii. Angelman gene is demethylated /activated1.

b. Normal changes in paternal chromosome )7 during gametogenesisi. Prader"Gilli gene is demethylated /activated1.ii. Angelman gene is imprinted /inactivated1.

c. Microdeletion o the entire gene site on paternal chromosome )7i. %auses Prader"Gilli syndromeii. %omplete loss o Prader"Gilli gene activity

Boss o activated Prader"Gilli gene on paternalchromosome )7Inactivated Prader"Gilli gene on maternalchromosome )7

d. Microdeletion o the entire gene site on maternal chromosome )7i. %auses Angelman syndromeii. %omplete loss o Angelman gene activity

Boss o activated Angelman gene on maternalchromosome )7Inactivated Angelman gene on paternal chromosome)7

. %linical indings in Prader"Gilli syndromea. Mental retardation, short stature, hypotonia at birthb. 9besity /tendency to overeat1, hypogonadism

@. %linical indings in Angelman syndromea. Mental retardationb. Gide"based gait /resembles a marionette1c. Inappropriate laughter / happy puppet syndrome1

Disorders of Se Differentiation

Normal sex di erentiation

). Absence o the H chromosomea. 8erminal tissue di erentiates into ovaries.b. Gol ian /mesonephric1 duct structures undergo apoptosis.

+. Presence o the H chromosomea. 8erminal tissue di erentiates into testes.b. MOllerian inhibitory actor /MI21 causes mOllerian tissue to undergo

apoptosis.MI2 is synthesi5ed in the *ertoli cells.

c. 2unction o etal testosterone

ii Develops the wol ian duct structuresiii 3pididymis, seminal vesicles, vas de erens

b. 70"#eductase converts testosterone to dihydrotestosterone /D;41.c. 2unctions o etal D;4

ii Develops the prostate glandiii

Develops the external male genitalia

8enitalia is phenotypically emale be ore D;4 is


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produced.

Normal sex di erentiation

). Absence o the H chromosomea. 8erminal tissue di erentiates into ovaries.b. Gol ian /mesonephric1 duct structures undergo apoptosis.

+. Presence o the H chromosomea. 8erminal tissue di erentiates into testes.b. MOllerian inhibitory actor /MI21 causes mOllerian tissue to undergo

apoptosis.MI2 is synthesi5ed in the *ertoli cells.

c. 2unction o etal testosterone

ii Develops the wol ian duct structuresiii 3pididymis, seminal vesicles, vas de erens

b. 70"#eductase converts testosterone to dihydrotestosterone /D;41.c. 2unctions o etal D;4

ii Develops the prostate glandiii Develops the external male genitalia

8enitalia is phenotypically emale be ore D;4 isproduced.

4rue hermaphrodite

). 2etus has both male and emale gonads.

+. Earyotype is usually @&,::

Pseudohermaphrodite

). Phenotype and genotype do not match.+. Male pseudohermaphrodite

a. 8enotypic male /:H with testes1b. Phenotypic emalec. 3xample"testicular emini5ation

. 2emale pseudohermaphroditea. 8enotypic emale /:: with ovaries1b. Phenotypic male

c. 3xample"virili5ation in adrenogenital syndrome

4esticular emini5ation). :# disorder with a de iciency o androgen receptors

o 2etal D;4 and testosterone are unable to unction without a receptor.+. %linical and laboratory indings

a. 4esticles are present in the inguinal canal or abdominal cavity.b. MOllerian structures are absent because MI2 is present.


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Absence o allopian tubes, uterus, cervix, upper vaginac. Male accessory structures are absent

No testosterone e ect on the wol ian duct structuresd. 3xternal genitalia remain emale

ii No D;4 e ectiii Cagina ends as a blind pouch.

b. ;ormone levelsii Normal male levels o testosterone and D;4

iii 3strogen activity is unopposed, because estrogen receptorsare present.

+. Ma-ority o patients are reared emale.

'on*enital Anomalies De ects present at birth that may or may not have a genetic basis.

4ypes o errors in morphogenesispage )')

page )'+

9ligohydramnios /decreased amniotic luid1 rom decreasedproduction o etal urine /e.g., renal agenesis, cystic disease o thekidneys1 restricts etal movement in the uterine cavity. As a result,newborns have lat acial eatures /Potter


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&. Atresiaa. Incomplete ormation o a lumen

b. 3xample"duodenal atresia

%auses o congenital anomalies

Table 5- . Terato*ens Associated with 'on*enital Defects

Terato*en Defect Alcohol Mental retardation, microcephaly, atrial septal de ect

%ocaine Microcephaly, renal agenes is, congeni tal hear t disease

Diethylstilbestrol Caginal or cervical clear cell carcinoma, mOllerian de ects

Phenytoin Nail and distal phalanx hypoplasia, cle t lip and>or palate

#etinoic acid %ranio acial, central nervous system, and cardiovascular de ects

4halidomide Amelia /absent limbs1, phocomelia /seal"like limbs1

4obacco Intrauterine growth retardation, low bi rth weight

Calproate Neural tube de ects

Gar arin Nasal hypoplasia, agenesis corpus callosum

Table 5-5. 'on*enital !nfections Associated with 'on*enital Defects

!nfection Transmission 'linical +indin*s%ytomegalovirus 4ransplacental Dea ness, I=8#, %N* calci ication /periventricular1

%ulture urine /best luid to culture1 urine cytologic testshows intranuclear inclusions

;erpes simplextype +

$irth canal I=8#

#ubella 4ransplacental Dea ness, patent ductus arteriosus

*yphilis 4ransplacental 9ccurs a ter +' weeks< gestation;epatitis, saddle nose, blindness, peg teeth

4oxoplasmosis 4ransplacental $lindness, %N* calci ication /basal ganglia1Pregnant woman should avoid cat litter

Caricella 4ransplacental Bimb de ects, mental retardation, blindness

%N*, central nervous system I=8#, intrauterine growth retardation.page )'

page )'@

). Ma-ority are unknown+. Multi actorial

o %ombination o genetic and environmental actors. 3nvironmental actors

a. Maternal disordersi. Diabetes mellitus

Increased risk o neural tube de ects and congenitalheart diseaseMaternal hyperglycemia causes etal macrosomia.

;yperinsulinemia in the etus increases

muscle mass and stores o at in the adiposetissue.ii. *ystemic lupus erythematosus


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Newborn may develop congenital heart block i themother has anti"#o antibodies.

iii. ;ypothyroidismNewborn may develop cretinism.

b. Drugs and chemicalsc. %ongenital in ections

i. Newborn has an increase in cord blood IgM.IgM normally is not synthesi5ed in the etus unlessthere is a congenital in ection.

ii. Certical transmission routes o transmission4ransplacental /most common route1

$irth canal

Pathogenesis o congenital anomaliesPregnant women should not be treated or acne with retinoic acid.#etinoic acid disrupts the unction o the HOX gene, leading tocranio acial, central nervous system, and cardiovascular de ects.

). 4iming o teratogenic insulta. Mal ormations occur during the embryonic period /between third and

ninth weeks1.b. De ormations occur during the etal period /ninth week to term1.

+. Alterations during key steps in morphogenesisa. Mutations may occur in genes normally involved in morphogenesis.

3xample"mutations o the HOX gene alters development ocranio acial structures.

b. Alterations in cell proli eration, migration, and apoptosis

Selected Perinatal and !nfant Disorders

*tillbirth

). $irth o a dead child+. Most o ten caused by an abruptio placentae

o Premature separation o the placenta because o a retroplacentalblood clot

*tillbirth

). $irth o a dead child+. Most o ten caused by an abruptio placentae

o Premature separation o the placenta because o a retroplacentalblood clot


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*pontaneous abortionpage )'@

page )'7

). 4ermination o a pregnancy be ore +' weeks+. %aused by a etal karyotypic abnormality

o =sually trisomy )& in 7'( o cases. Predisposing actors

a. Advanced maternal ageb. In ections /e.g., Streptococcus agalactiae, Listeria monocytogenes 1

c. 4obacco, alcohol use

*udden in ant death syndrome /*ID*1 *udden and unexpected death o an in ant be ore ) year o age whose death

remains unexplained a ter autopsy

). 3pidemiologya. Most common cause o death o an in ant younger than ) year old in

developed countriesb. Most deaths occur between + and @ months o age.

J'( occur in in ants under & monthsc. Death usually occurs during sleep.

+. Pathogenesisa. No single causeb. Maternal actors

3xamples"smoking, young agec. In ant actors

3xamples"prematurity, sleeping prone, neural developmentaldelay, inborn error o oxidation o atty acids

. Autopsy indings

o Nonspeci ic signs o tissue hypoxia are present.

a. 4hickened pulmonary arteriesb. Petechiae on the pleura and epicardium

c. Microscopic changes o hypoxia in the brainstem /e.g., arcuatenucleus1

5 genetic and developmental disorders

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