Chapter 6 - Genetic and Developmental Disorders Flashcards
Mutations involving germ cells can be transmitted to whom?
Mutation germ cell: transmitted to offspring
What is a mutation?
Mutation: permanent change in DNA
Mutations involving somatic cells are not transmitted to whom?
Mutation somatic cell: not transmitted to offspring
What is a point mutation?
Point mutation: change in single nucleotide base within a gene
What is a silent mutation?
Silent: altered DNA codes for same amino acid; no phenotypic effect
What is a missense mutation?
Missense: altered DNA codes for different amino acid; change in phenotypic effect
Give an example of a missense mutation.
Missense mutation: sickle cell disease/trait
What is a nonsense mutation?
Nonsense: stop codon; premature termination protein synthesis
Give an example of a nonsense mutation.
β-Thalassemia major: nonsense mutation; no synthesis β-globin chain
What is a frameshift mutation?
Frameshift: insertion/deletion 1 or more nucleotides that is not a multiple of 3
Describe the type of mutation in Tay-Sachs disease.
Tay-Sachs: 4 base insertion; ↓synthesis hexosaminidase A
Describe an insertion/deletion mutation that is not a frameshift mutation.
Number base pairs deleted/added multiple of 3, translated protein gained/lost amino acids
Give an example of an insertion/deletion mutation that is not a frameshift mutation.
CF: 3-nucleotide deletion; phenylalanine lost from CFTR; degraded in Golgi
What do trinucleotide repeat disorders produce?
TRD: produce DNA replication errors
What are trinucleotide repeats?
Trinucleotide repeats: amplified sequence of 3 nucleotides; prevent normal gene expression
Give four examples of TRDs and their triplet repeats.
FXS (CGG), myotonic dystrophy (CTG), Friedrich ataxia (GAA), HD (CAG)
Give an example of expansion of trinucleotide repeats primarily in oogenesis and an example of expansion of trinucleotide repeats primarily in spermatogenesis.
Amplification in oogenesis (FXS), spermatogenesis (HD)
What determines disease severity in TRDs?
Number triplet repeats determines disease severity
Give three examples of amplification in the noncoding region of the gene. What do these diseases have in common?
Amplification noncoding region: FXS, myotonic dystrophy, Friedrich ataxia; multisystem diseases
What is anticipation?
Anticipation: ↑disease severity future generations; ↑amplification of repeats in gametogenesis
What does CAG code for and what do CAG repeats produce?
CAG: codes for glutamine residues; produces polyglutamine disorders (neurodegenerative)
Give two examples of coding region amplification.
CAG: codes for glutamine residues; produces polyglutamine disorders (neurodegenerative)
What do misfolded protein aggregates with excess glutamine residues do?
Misfolded protein aggregates → suppress transcription, mt dysfunction, apoptosis
What are Mendelian disorders?
Single-gene mutations that produce large effects
What is the proportion of familial and new mutations in Mendelian disorders?
Majority are familial; remainder new mutations
When is the dominant phenotype expressed?
Dominant phenotype: expressed when only one chromosome of a pair carries mutant allele
When is the recessive phenotype expressed?
Recessive phenotype: expressed when both chromosomes of a pair carry mutant alleles
What are the possible locations for a mutation in Mendelian disorders?
Mutation locations: autosomes (1 to 22), sex chromosomes (X and Y)
What are the patterns of mutations in Mendelian disorders?
Patterns: autosomal recessive/dominant; X-linked recessive/dominant
What is the most common Mendelian disorder?
AR: MC mendelian disorder
Describe the offspring of two Aa parents.
Aa × Aa: 25% AA (normal), 25% (homozygous; aa), 50% heterozygous (Aa)
Describe the characteristics of AR disorders.
Characteristics: complete penetrance; Aa asymptomatic; early age; new mutations uncommon
What do most AR disorders involve?
Most AR disorders involve enzyme deficiencies
In enzyme deficiency, how are substrates proximal and distal to the enzyme block affected?
↑Substrate proximal to enzyme block; ↓substrate distal to block
What enzyme is affected in PKU and what substrates are affected?
Phenylketonuria (PKU): deficiency phenylalanine hydroxylase; ↑phenylalanine, ↓tyrosine
What occurs in LSDs?
LSD: undigested substrates (GAGS, sphingolipids, glycogen) accumulate in lysosomes
How is glycogen metabolism affected in the glycogenoses?
Glycogenoses: ↑synthesis, ↓glycogenolysis, ↑normal/abnormal glycogen in tissue
What are the clinical and lab findings in the glycogenoses?
Glycogenoses: organ dysfunction, fasting hypoglycemia, myoglobinuria (McArdle disease)
What is the most common AR disorder?
MC AR disorder: hemochromatosis
Who expresses the disorder in autosomal dominant disorders?
Heterozygotes (Aa) express the disorder
Who are spontaneously aborted in AD disorders?
Germline homozygotes (AA) are spontaneously aborted
Describe the offspring of Aa and aa parents.
Aa × aa → Aa, Aa, aa, aa; 50% have disorder (Aa); 50% normal (aa)
How are most new mutations inherited?
New mutations: paternally inherited
What is meant by delayed manifestations?
Delayed manifestations: symptoms/signs occur later in life
What is complete penetrance?
Complete penetrance: all individuals with mutation express disease
What is incomplete penetrance?
Incomplete penetrance: phenotypically normal; transmit disease to children
What is variable expressivity?
Variable expressivity: express disease but severity varies
What is the most common AD disorder?
MC AD disorder: von Willebrand disease
Where is the mutant gene located in males with XR disorder?
Males with XR disorder: mutant gene on X chromosome
Y chromosome disorders are more likely to involve what?
Y chromosome disorders involve defects in spermatogenesis
All X chromosomes in males are what?
All X chromosomes in males are active
Describe the offspring of X*Y and XX parents.
XY × XX → XX, X*X, XY, XY; all daughters asymptomatic carriers; no transmission to sons
Why are X*X heterozygous carriers not symptomatic?
X*X heterozygous carriers not symptomatic because they have a paired normal allele (X)
Describe the offspring of X*X and XY parents.
XX × XY → XX, XX, X*Y, XY; 50% sons symptomatic; 50% daughters asymptomatic carriers
XR diseases usually involve what?
XR diseases usually involve enzyme deficiencies
What is the most common Mendelian disorder causing mental retardation?
FXS: MC mendelian disorder causing mental retardation
Where is the genetic defect located in FXS?
Genetic defect distal end of long arm of X chromosome (band Xq27.3)
What gene is located at the fragile X site?
FMR1 gene located at fragile X site
Describe the clinical findings in females with the full mutation in FXS.
Females with full mutation: normal or mild ↓IQ with or without premature ovarian failure
Describe the degree of mental retardation in affected males with FXS
FXS: mental retardation (IQ 20–70)
Describe the facial changes in FXS.
FXS: long face, large mandible, everted ears, high-arched palate
Describe pubertal findings in FXS.
FXS: macro-orchidism at puberty
How is FXS diagnosed?
FXS: DNA analysis for trinucleotide repeats is best
What is Lesch-Nyhan syndrome?
Lesch-Nyhan syndrome: deficiency HGPRT; involved in salvaging purines
What are the clinical findings in Lesch-Nyhan syndrome?
Mental retardation, hyperuricemia, self-mutilation
Who is symptomatic in XD disorders?
XD inheritance: female carriers are symptomatic
What is vitamin D-resistant rickets?
Vitamin D–resistant rickets: defect in renal/gastrointestinal reabsorption of phosphate
How many human chromosomes are there?
46 chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes
What are gametes?
Gametes: products of meiosis; haploid (23 chromosomes)
What is a Barr body?
Barr body: inactivated X chromosome
What is the number of Barr bodies per cell?
Number of Barr bodies = number of X chromosomes − 1
What is nondisjunction?
Nondisjunction: unequal separation of chromosomes in meiosis
What is mosaicism?
Mosaicism: nondisjunction in mitosis; most often involves sex chromosomes
What is a translocation?
Translocation: transfer chromosome parts between nonhomologous chromosomes
What is a Robertsonian translocation? Give an example.
Robertsonian translocation: balanced translocation between acrocentric chromosomes; 14;21
What is a deletion?
Deletion: loss of portion of chromosome
What is cri du chat syndrome?
Cri du chat: short arm of chromosome 5 deleted; mental retardation, cat-like cry, VSD
Most cases of Down syndrome are due to what?
Most cases are due to nondisjunction
What does advanced maternal age increase the risk of?
Advanced maternal age: ↑risk for offspring with trisomy syndromes
What is the most common chromosomal abnormality causing mental retardation?
MC chromosomal abnormality causing mental retardation
Down syndrome
What is the most common cause of floppy baby syndrome?
MCC floppy baby syndrome
Down syndrome
Describe clinical findings in Down syndrome.
Muscle hypotonia, simian crease, flat facial profile
What is a major factor affecting survival in early childhood in Down syndrome?
Congenital heart defects: major factor affecting survival in early childhood
What is the most common heart defect in Down syndrome?
Endocardial cushion defect MC heart defect
What are the GI tract abnormalities in Down syndrome?
Gastrointestinal: duodenal atresia, Hirschsprung, tracheoesophageal fistula
What are the hematologic abnormalities in Down syndrome?
↑Risk for leukemia: acute lymphoblastic/acute megakaryocytic
Describe CNS abnormalities in Down syndrome.
Down syndrome: Alzheimer disease at young age
Describe immune defects in Down syndrome.
Immune defects: Hashimoto thyroiditis, diabetes mellitus, lung infections
Describe fertility abnormalities in Down syndrome.
Males usually infertile; females less fertile and have ↑incidence miscarriages
How is Down syndrome screened for?
Triple marker screen: ↓serum AFP, urine uE3; ↑serum hCG
What is Edward syndrome?
Edwards syndrome: trisomy 18
What are the clinical findings in Edward syndrome?
Mental retardation, clenched fist/overlapping fingers, VSD
What is Patau syndrome?
Patau syndrome: trisomy 13
What are the clinical findings in Patau syndrome?
Mental retardation, cleft lip/palate, polydactyly, VSD, cystic kidneys
What is the most common sex chromosome abnormality in females?
MC sex chromosome abnormality in females
Turner syndrome
Turner syndrome accounts for what percentage of spontaneous abortions?
Accounts for 15% of spontaneous abortions
What are the karyotype abnormalities in Turner syndrome?
Karyotype abnormalities: 45,X; structural abnormalities; mosaicism (45,X/46,XX)
The 45,X/46,XY karyotype increases the risk for what?
45,X/46,XY ↑risk for gonadoblastoma of ovary
What is the most common cause of Turner syndrome?
Mosaicism MCC Turner syndrome
What is a cardinal sign in Turner syndrome? This sign is due to what?
Short stature cardinal sign; loss of SHOX gene
The SHOX gene is critical for what?
SHOX gene critical for growth regulation
What are the clinical findings in Turner syndrome?
Shield chest, short 4th metacarpal/metatarsal, pubic hair development normal
Lymphedema hands, feet, neck (webbed neck)
What is the most common cause of mortality in infancy in Turner syndrome?
Hypoplastic left heart most common cause mortality in infancy
What are two cardiovascular abnormalities in Turner syndrome?
Preductal coarctation, bicuspid aortic valve common
What are streak gonads?
Streak gonads: devoid of oocytes, risk for dysgerminoma
Turner syndrome
The phrase “menopause before menarche” refers to what syndrome?
Turner syndrome: “menopause before menarche”
What is the most common genetic cause of primary amenorrhea? How are estradiol, progesterone, FSH, and LH affected?
MC genetic cause primary amenorrhea; ↓estradiol/progesterone; ↑FSH/LH, respectively
No Barr bodies are present in the buccal smear of patients with what karyotype?
No Barr bodies in buccal smear
45X,O
What is the most common genetic cause of male hypogonadism?
MC genetic cause male hypogonadism
Klinefelter syndrome
What is the most common cause of Klinefelter syndrome?
Nondisjunction produces 47 chromosomes (XXY)
What is the most common karyotype of Klinefelter syndrome caused by mosaicism?
Mosaicism: MC karyotype 46,XY/47,XXY
Describe the effect of increased FSH in Klinefelter syndrome.
↑FSH → ↑aromatase synthesis → ↑conversion testosterone to estradiol in Leydig cells
Why are Leydig cells prominent in Klinefelter syndrome?
Testicular atrophy; fibrosis seminiferous tubules/Sertoli cells; Leydig cells prominent
How are testosterone, inhibin, LH, and FSH affected in Klinefelter syndrome?
↓Testosterone and inhibin; ↑LH and FSH, respectively
Describe the genes carried by the X chromosome.
X chromosome genes: androgen receptors, testis function, brain development, growth
What does the androgen receptor contain?
Androgen receptor contains CAG trinucleotide repeats
Testosterone reacts best with androgen receptors containing what?
Testosterone reacts best with androgen receptors containing least # CAG repeats
Which androgen receptors are inactivated in Klinefelter syndrome?
Klinefelter syndrome: androgen receptors with least # CAG repeats preferentially inactivated
What begins at puberty in Klinefelter syndrome?
Male hypogonadism + feminization begins at puberty
List two feminization signs in Klinefelter syndrome.
Feminization signs: female body hair distribution, persistent gynecomastia
Describe Eunuchoid proportions in Klinefelter syndrome.
Eunuchoid proportions: disproportionately long legs
How is intelligence affected in Klinefelter syndrome variants with >2 X chromosomes?
Variants with >2 X chromosomes have mental retardation
What are the cardiac and endocrine abnormalities in Klinefelter syndrome?
MVP, type 2 DM, metabolic syndrome
What is the cause of XYY syndrome? What are the clinical findings?
XYY syndrome: paternal nondisjunction; aggressive behavior, normal gonadal function
Inheritance in multifactorial (complex) inheritance is due to what?
Multifactorial (complex) inheritance: interaction of genetic and environmental factors
Multifactorial inheritance is more common than what?
More common than mendelian and chromosomal disorders
Give four examples of multifactorial inheritance.
Neural tube defects, mental disease, cleft lip/palate, coronary artery disease
What does mtDNA code for?
mtDNA codes for enzymes in oxidative phosphorylation
How is mtDNA inherited?
Maternal inheritance; ova have mutant gene
What is genomic imprinting?
Expression of disease phenotype depends on whether mutant allele is inherited from father or mother
Describe genomic imprinting of chromosome 15 in normal maternal gametogenesis.
Normal maternal gametogenesis: PW gene imprinted, Angelman gene activated
Describe genomic imprinting of chromosome 15 in normal paternal gametogenesis.
Normal paternal gametogenesis: PW gene activated, Angelman gene imprinted
Describe the cause of PW syndrome.
PW syndrome: microdeletion paternal 15; complete loss PW genes expression
Describe the cause of Angelman syndrome.
Angelman syndrome: microdeletion maternal 15; complete loss Angelman gene expression
What are the clinical findings of PW syndrome?
Hypotonia, genital hypoplasia, mental retardation, obesity
What are the clinical findings of Angelman syndrome?
Mental retardation, wide-based gait, inappropriate laughter (happy puppet)
What determines the male sex?
Y chromosome: single Y gene determines male sex
What is the Y chromosome sex determining gene?
SRY gene on Y chromosome sex-determining gene
What does the SRY gene produce?
SRY gene produces testis-determining factor → undifferentiated gonad becomes a testis
What does the MIS do?
MIS causes paramesonephric duct to undergo apoptosis
What is the function of fetal testosterone?
Testosterone develops mesonephric duct structures → epididymis, seminal vesicles, vas deferens
What does 5α-Reductase do?
5α-Reductase converts testosterone to DHT
What are the functions of fetal DHT?
DHT develops scrotum, penis, prostate gland
What results from the absence of the Y chromosome?
Absence Y chromosome: undifferentiated gonads develop into ovaries
What develops from the paramesonephric ducts?
Paramesonephric ducts: fallopian tubes, uterus, upper vagina
What does the sinus tubercle fuse with? This fused structure then develops into what?
Sinus tubercle fuses with urogenital sinus → sinovaginal bulbs → vaginal plate → vagina
What is a true hermaphrodite?
True hermaphrodite: testis on one side, ovary on other side
What is a pseudohermaphrodite?
Pseudohermaphrodite: phenotype and genotype do not match
What is a male pseudohermaphrodite?
Male pseudohermaphrodite: genotype XY; phenotype ambiguous or completely female
What is the most common cause of male pseudohermaphroditism?
AIS MCC male pseudohermaphroditism
What is a female pseudohermaphrodite?
Female pseudohermaphrodite: genotypically female; phenotypically ambiguous or virilized
What is the most common cause of female pseudohermaphroditism?
Adrenogenital syndrome: MCC female pseudohermaphroditism
Describe the epidemiology of AIS.
XR disorder; male pseudohermaphroditism
What mutation causes AIS?
Loss-of-function mutation in androgen receptor gene on X chromosome
The mutation in AIS results in what?
Prenatal undervirilization of external genitalia; loss of pubertal male changes
Where are the gonads located at birth in AIS?
Testicles in inguinal canal at birth or abdominal cavity
How are the paramesonephric duct structures affected in AIS?
Absence of fallopian tubes, uterus, cervix, upper vagina; MIS is functional
How are the mesonephric duct structures affected in AIS?
Absence of epididymis, seminal vesicles, vas deferens, prostate; no fetal testosterone effect
How do the external genitalia appear in AIS?
Female external genitalia, blind vaginal pouch; no fetal DHT effect
How do AIS patients present as teenagers?
Present with primary amenorrhea as teenager
What is there risk for in AIS?
Testes at risk for gonadoblastoma
What are the lab findings in AIS?
Normal testosterone/DHT; slight ↑serum LH, estradiol
How are the majority of AIS individuals reared?
Majority reared female
Define congenital.
Congenital: defect recognized only at birth
What is the most common cause of death in children < 1 year old?
Congenital anomalies: MCC death children <1 year old
What are the major causes of congenital anomalies?
Major causes—genetic, maternal, multifactorial
What is the most common genetic cause of congenital anomalies?
Chromosome aberrations MC genetic cause of congenital anomalies
How does maternal diabetes affect the fetus?
Maternal diabetes: macrosomia; hyperinsulinemia ↑muscle mass and fat
How may maternal SLE affect the newborn?
Maternal SLE: congenital heart block due to anti-Ro antibodies
How may maternal hypothyroidism affect the newborn?
Maternal hypothyroidism: danger of cretinism in newborn; severe mental retardation
What is the most common teratogen and what does it cause?
Alcohol: MC teratogen (fetal alcohol syndrome)
What is TORCH syndrome?
TORCH syndrome = toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex virus
What does an increase in cord blood IgM indicate?
↑Cord blood IgM indicates congenital infection
What is the most common congenital infection?
CMV MC congenital infection
What are the routes of transmission in vertical transmission?
Vertical transmission: transplacental (MC), birth canal, breast-feeding
What is the most common cause of congenital anomalies?
Multifactorial inheritance disorders overall MCC congenital anomalies
What are malformations?
Malformations: disturbance in morphogenesis in embryonic period
What is the most susceptible period for malformations?
4th to 5th week most susceptible period for malformations
What are the germ cell layers?
Germ cell layers: ectoderm, endoderm, mesoderm
What are deformations?
Deformations: extrinsic disturbance in fetal development after fetal organs developed
Deformations are most often due to what?
Most often due to uterine constraint; maternal/placental factors
What is disruption?
Disruption: destruction of irreplaceable normal fetal tissue
An amniotic band is due to what?
Amniotic band: rupture of amnion; encircling fibrous bands constrict fetal parts (e.g., digits)
What is agenesis?
Agenesis: complete absence of organ; absence of primordial tissue
What is aplasia?
Aplasia: primordial tissue present but no development into an organ
What is hypoplasia?
Hypoplasia: incomplete development primordial tissue; tissue histologically normal
What is atresia?
Atresia: incomplete formation of lumen
What is important in the pathogenesis of congenital anomalies?
Congenital anomalies: timing of teratogenic insult important
How does retinoic acid result in congenital anomalies?
Retinoic acid: disrupts Hox gene function; craniofacial, CNS, cardiovascular defects
What are the Hox genes involved in?
Hox genes: involved in patterning of craniofacial structures, vertebrae, limbs
What is stillbirth?
Stillbirth: birth of a dead child
What is the most common cause of stillbirth?
Abruptio placentae MCC stillbirth
What is a spontaneous abortion?
Spontaneous abortion: termination of pregnancy before 20 weeks
What is the most common complication of early pregnancy?
MC complication early pregnancy
Spontaneous abortion
Spontaneous abortion is most commonly caused by what?
Spontaneous abortion: most commonly caused by trisomy 16
What is SIDS?
SIDS: sudden, unexpected death of healthy infant <1 year old
What is the most common cause of infant death in the U.S.?
In U.S, MCC infant death between 1 month and 1 year of age
SIDS
In SIDS, when do the majority of deaths occur?
Majority of deaths before age 6 months
Describe the pathogenesis of SIDS.
Multifactorial; maternal/infant risk factors
What is the most common finding at autopsy in SIDS?
Petechiae MC finding at autopsy; sign of tissue hypoxia
What are brainstem and cerebellum findings at autopsy in SIDS?
Brainstem (hypoplasia arcuate nucleus; astrogliosis); cerebellum (astrogliosis)
Which group based on weight and gestational age has the highest mortality rate?
SGA: group with highest mortality rate
LGA is most often due to what?
LGA: most often due to maternal DM
Define prematurity.
Prematurity: gestation age <2500 g
What is the most common cause of neonatal death and morbidity?
Prematurity MCC neonatal death/morbidity
What is the most common cause of prematurity?
Premature rupture of membranes MCC prematurity
What is chorioamnionitis?
Chorioamnionitis: inflammation of placental membranes
What is funisitis?
Funisitis: inflammation of umbilical cord
What are the complications of prematurity?
Complications: RDS, necrotizing enterocolitis, intraventricular hemorrhage
What is most often responsible for IUGR?
IUGR: maternal factors most often responsible
Describe the nature of growth retardation if a fetal cause is responsible for IUGR.
Fetal causes IUGR: symmetrical growth retardation
Describe the nature of growth retardation if a placental cause is responsible for IUGR.
Placental causes IUGR: asymmetric growth retardation; brain spared
What do the majority of IUGR infants have?
IUGR: majority have oligohydramnios
When is the neonatal period?
Neonatal period: first 4 weeks of life
What are the common causes of death in the neonatal period?
Neonatal period: common causes of death are RDS/congenital anomalies
Amniocentesis is used to do what?
Identifies prenatal genetic defects
Describe the composition of amniotic fluid.
AF is primarily fetal urine; contains fetal cells
Where can AFP be measured?
AFP measured in AF and maternal serum
What is chorionic villus sampling used for?
Chorionic villus sampling detects fetal abnormalities earlier than amniocentesis
Ultrasound is important for what in pregnancy?
US: assessment fetal age/sex/viability, multiple pregnancies, fetal morphologic abnormalities
How is the AFP level affected in open neural tube defects? What is it related to?
Open neural tube defect: folic acid deficiency before conception; ↑AFP
How is the AFP level affected in Down syndrome?
Down syndrome: ↓AFP
How is the serum hCG level affected in Down syndrome?
Down syndrome: ↑serum hCG
How is the urine unconjugated estriol level affected in Down syndrome?
Down syndrome: ↓urine unconjugated estradiol
How is genetic analysis performed?
Genetic analysis: chromosome karyotyping, DNA molecular assays
What are the Stochastic theories?
Stochastic theories: somatic mutation, DNA repair defects, cross-linking defects, FR injury
What does the programmed cell death theory propose?
Programmed cell death theory: aging genetically determined
Give two examples of age-dependent changes.
Age-dependent: inevitable with age; e.g., ↓GFR, prostate hyperplasia
Define age-related changes. Give two examples.
Age-related: common but not inevitable; e.g., Alzheimer disease, systolic hypertension
