Goljan's Genetic and Developmental Disorders Flashcards
1
Q
What is the definition of a mutation?
A
Permanent change in DNA
2
Q
What type of mutation can be transmitted to offspring?
A
Germ cell mutations
3
Q
What type of mutations cannot be transmitted to offspring?
A
Somatic cell mutations
4
Q
What is a point mutation?
A
Change in a single nucleotide base within a gine
5
Q
What is a silent mutation?
A
Altered DNA codes for same amino acid; no phenotypic effect
6
Q
What is a missense mutation?
A
Altered DNA codes for different amino acid; change in phenotypic effect
7
Q
What type of mutation causes sickle cell disease and trait?
A
Missense mutation
8
Q
What is a nonsense mutation?
A
Altered DNA codes for a stop codon; leads to premature termination of protein synthesis
9
Q
What type of mutation causes β-thalassemia major?
A
Nonsense mutation; no synthesis of β-globin chain
10
Q
What is a frameshift mutation?
A
Insertion or deletion of 1 or more nucleotides that is not a multiple of 3
11
Q
What type of mutation causes Tay-Sachs disease?
A
4 base insertion; ↓synthesis of hexosaminidase A
12
Q
What happens if the number of base pairs deleted or added is a multiple of 3?
A
Translated protein has either gained or lost amino acids
13
Q
What type of mutation causes cystic fibrosis?
A
3-nucleotide deletion; phenylalanine lost from CFTR (degraded in Golgi)
14
Q
What is the effect of trinucleotide repeat disorders?
A
Produce DNA replication errors
15
Q
What are trinucleotide repeats?
A
Amplified sequence of 3 nucleotides; prevent normal gene expression
16
Q
What are some examples of trinucleotide repeat disorders?
A
Fragile X syndrome: CGG
17
Q
When does amplification occur?
A
Depends on sex of transmitting parent
18
Q
What determines the disease severity of trinucleotide repeat disorders?
A
Number of triplet repeats
19
Q
What disorders are caused by amplifications that occur in noncoding regions?
A
Fragile X syndrome
20
Q
What is the effect of anticipation?
A
↑disease severity in future generations
21
Q
What disorders are caused by amplifications that occur in coding regions?
A
Huntington disease
22
Q
What is the CAG codon?
A
Codes for glutamine residues; amplification produces polyglutamine disorders (neurodegenerative)
23
Q
What is the effect of misfolded protein aggregates?
A
Suppression of transcription
24
Q
What are mendelian disorders?
A
Single-gene mutations that produce large effects
25
What are the characteristics of a dominant phenotype?
Expressed when only one chromosome of a pair carries the mutant allele
26
What are the characteristics of a recessive phenotype?
Expressed when both chromosomes of a pair carry mutant alleles
27
What are the patterns of transmission in mendelian disorders?
Autosomal recessive
28
What is the most common type of mendelian disorder?
Autosomal recessive
29
What is the genotypic probability in the offspring of two heterozygotes?
Aa x Aa:
30
What are some characteristics of autosomal recessive disorders?
Complete penetrance
31
What characterizes the diseases caused by autosomal recessive disorders?
Most involve enzyme deficiencies
32
What are the physiologic consequences of an enzyme deficiency?
↑substrate proximal to block
33
What is the characteristic finding in lysosomal storage diseases?
Undigested substrates (glycosaminoglycans, sphingolipids, glycogen) accumulate in lysosomes
34
What are the underlying mechanisms that cause glycogenoses?
↑synthesis of glycogen
35
What symptoms are commonly found in glycogenoses?
Organ dysfunction
36
What is the most common autosomal recessive disorder?
Hemochromatosis
37
What are the characteristics of autosomal dominant disorders?
Heterozygotes express the disorder
38
What happens to germline homozygotes of autosomal dominant diseases?
Spontaneously aborted; means that most individuals with autosomal dominant disorders are heterozygotes at birth
39
What is the genotypic probability in the offspring of an autosomal dominant heterozygote with a homozygous normal spouse?
Aa x aa:
40
What is the origin of most new mutations?
Germ cells of elderly males (paternally inherited)
41
When do autosomal dominant disorders typically present?
Many have delayed manifestations: symptoms/signs occur later in life
42
What is the definition of complete penetrance?
All individuals with mutation express disease
43
What are the characteristics of incomplete penetrance?
Phenotypically normal; transmit disease to children
44
What is the definition of variable expressivity?
Express disease but severity varies
45
What is the most common autosomal dominant disorder?
von Willebrand disease
46
What is the typical presentation of an X-linked recessive disorder?
Male with mutant gene on X chromosome
47
What do Y chromosome disorders typically involve?
Defects in spermatogenesis
48
Why are males invariably affected by X-linked recessive disorders?
All X chromosomes in males are active
49
What characterizes the offspring of males with X-linked recessive disorders?
All daughters are asymptomatic carriers
50
Why are females unaffected by X-linked recessive disorders?
Not symptomatic because they have a paired normal allele (Xx)
51
What characterizes the offspring of female carriers of X-linked recessive disorders?
50% of sons are symptomatic
52
What do X-linked recessive diseases usually involve?
Enzyme deficiencies
53
What is the most common mendelian disorder causing mental retardation?
Fragile X syndrome
54
What is the pathogenesis of fragile X syndrome?
Genetic defect in the distal end of long arm of X chromosome (band Xq27.3)
55
What gene is located at the fragile X site?
FMR1: familial mental retardation gene
56
What occurs in females with a full fragile X mutation (>200 CGG repeats) on one of their X chromosomes?
Normal or mild ↓IQ with or without premature ovarian failure
57
What neurological findings are associated with fragile X syndrome?
Mental retardation (IQ 20-70)
58
What physical findings are associated with fragile X syndrome?
Long face
59
What distinctive physical finding develops when males with fragile X syndrome reach puberty?
Macro-orchidism
60
What is the best diagnostic test for fragile X syndrome?
DNA analysis for trinucleotide repeats
61
What is Lesch-Nyhan syndrome?
Deficiency of HGPRT; involved in salvaging purines
62
What findings are associated with Lesch-Nyhan syndrome?
Mental retardation
63
How do X-linked dominant disorders differ from X-linked recessive disorders?
Female carriers are asymptomatic
64
What is an example of an X-linked dominant disorder?
Vitamin D-resistant rickets: defect in renal/gastrointestinal reabsorption of phosphate
65
What is the chromosomal makeup of most human cells?
46 chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes
66
What is the chromosomal makeup of gametes?
Haploid: 23 chromosomes
67
What is a Barr body?
Inactivated X chromosome
68
How many Barr bodies are in each cell?
#ERROR!
69
What is the definition of nondisjunction?
Unequal separation of chromosomes in meiosis
70
What is the definition of mosaicism?
Nondisjunction in mitosis; most often involves sex chromosomes
71
What is the definition of translocation?
Transfer of chromosome parts between nonhomologous chromosomes
72
What occurs in a Robertsonian translocation?
Balanced translocation between acrocentric chromosomes (ie 14:21)
73
What term describes the loss of a portion of a chromosome?
Deletion
74
What causes Cri du chat syndrome?
Deletion of the short arm of chromosome 5
75
What are the findings in Cri du chat syndrome?
Mental retardation
76
What is the underlying mechanism of most cases of Down syndrome?
Nondisjunction?
77
What factor is associated with ↑risk for offspring with trisomy syndrome?
Advanced maternal age
78
What is the most common chromosomal abnormality causing mental retardation?
Down syndrome
79
What is the most common cause of floppy baby syndrome?
Down syndrome
80
What features of general appearance found in Down syndrome?
Muscle hypotonia
81
What is a major factor affecting early childhood survival in Down syndrome?
Congenital heart defects
82
What is the most common heart defect in Down syndrome?
Endocardial cushion defect
83
What gastrointestinal abnormalities are associated with Down syndrome?
Duodenal atresia
84
What hematologic abnormalities are associated with Down syndrome?
↑risk for leukemia:
85
What CNS abnormalities are associated with Down syndrome?
Alzheimer disease at young age
86
What immune defects are associated with Down syndrome?
Hashimoto thyroiditis
87
What fertility abnormalities are associated with Down syndrome?
Males usually infertile
88
What triple test results are diagnostic for Down syndrome?
↓serum AFP
89
What syndrome describes trisomy 18?
Edwards syndrome
90
What are the clinical findings of Edwards syndrome?
Mental retardation
91
What syndrome describes trisomy 13?
Patau syndrome
92
What are the clinical findings of Patau syndrome?
Mental retardation
93
What is the most common sex chromosome abnormality in females?
Turner syndrome; accounts for 15% of spontaneous abortions
94
What karyotype abnormalities cause Turner syndrome?
45,X
95
What complications are associated with 45,X/46,XY mosaicism?
↑risk for gonadoblastoma of ovary
96
What is the most common cause of Turner syndrome?
Mosaicism
97
What physical features is the cardinal sign of Turner syndrome
Short stature (due to loss of SHOX gene)
98
What is the function of the SHOX gene?
Critical for growth regulation
99
What physical findings are associated with Turner syndrome?
Shield chest
100
What lymphatic abnormalities are associated with Turner syndrome?
Lymphedema in the hands, feet, and neck (webbed neck)
101
What cardiovascular abnormalities are associated with Turner syndrome?
Hypoplastic left heart
102
What is a common cause of mortality in infants with Turner syndrome?
Hypoplastic left heart
103
What are streak gonads?
Ovaries devoid of oocytes; associated with risk for dysgerminoma
104
What phrase summarizes the hormonal state in Turner syndrome?
Menopause before menarche
105
What is the most common genetic cause of primary amenorrhea?
Turner syndrome
106
How does Turner syndrome cause primary amenorrhea?
↓estradiol/progesterone
107
What is a key cytologic finding of Turner syndrome?
No Barr bodies in buccal smear
108
What is the most common cause of male hypogonadism?
Klinefelter syndrome
109
What causes Klinefelter syndrome?
Nondisjunction produces 47 chromosomes (XXY)
110
What is the most common cause of Klinefelter syndrome?
Mosaicism (46,XY/47,XXY)
111
What pathophysiology underlies the finding of hypogonadism in Klinefelter syndrome?
↑FSH → ↑aromatase synthesis → ↑conversion of testosterone to estradiol in Leydig cells
112
What is the typical testicular histology in Klinefelter syndrome?
Testicular atrophy
113
What are the consequences of testicular atrophy in Klinefelter syndrome?
↓testosterone and inhibin; ↑LH and FSH, respectively
114
What genes are located on the X chromosome?
Androgen receptors
115
What determines the functional response of testosterone in the androgen receptor?
Androgen receptor contains CAG trinucleotide repeats; testosterone response depends on number of repeats
116
With which receptors does testosterone react best?
Androgen receptors containing the lowest amount of CAG repeats
117
Which happens to the androgen receptors in Klinefelter syndrome?
Androgen receptors with least amount of CAG repeats are preferentially inactivated
118
When do the physical findings of Klinefelter syndrome typically present?
Male hypogonadism and feminization begins at puberty
119
What feminization signs are associated with Klinefelter syndrome?
Female body hair distribution
120
What is the characteristic body habitus of patients with Klinefelter syndrome?
Eunuchoid proportions with disproportionately long legs
121
Which variants of Klinefelter syndrome have lower IQs?
Variants with >2X chromosomes
122
What additional abnormalities are associated with Klinefelter syndrome?
Mitral valve prolapse
123
What are the characteristics of XYY syndrome?
Paternal nondisjunction
124
What mechanism underlies multifactorial inheritance?
Interaction of genetic and environmental factors
125
What are some examples of disorders with multifactorial inheritance?
Neural tube defects
126
What does mitochondrial DNA encode?
Enzymes in oxidative phosphorylation
127
What is the inheritance pattern of mitochondrial DNA disorders?
Maternal inheritance; ova have mutant gene
128
What is genomic imprinting?
Expression of disease phenotype depends on whether mutant allele is inherited from father or mother
129
What imprinting pattern occurs in normal maternal gametogenesis?
PW gene imprinted, Angelman gene activated
130
What imprinting pattern occurs in normal paternal gametogenesis?
PW gene activated, Angelman gene imprinted
131
What causes Prader-Willi syndrome?
Microdeletion of paternal 15; complete loss of PW genes expression
132
What causes Angelman syndrome?
Microdeletion of maternal 15; complete loss of Angelman gene expression
133
What are the clinical findings in Prader-Willi syndrome?
Hypotonia
134
What are the clinical findings in Angelman syndrome?
Mental retardation
135
What gene determines male sex?
Single gene on Y chromosome
136
What is the SRY gene?
Sex-determining gene on Y chromosome
137
What effects are mediated by the SRY gene?
SRY gene produces testis-determining factor → undifferentiated gonad becomes a testis
138
What is the function of Müllerian inhibitory substance?
Causes paramesonephric duct to undergo apoptosis
139
What is the function of fetal testosterone?
Development of mesonephric duct structures → epididymis, seminal vesicles, vas deferens
140
How is the function of 5α-reductase?
Converts testosterone to DHT
141
What is the function of fetal DHT?
Development of scrotum, penis, prostate gland
142
What occurs in the absence of a Y chromosome?
Undifferentiated gonads develop into ovaries
143
What structures originate from the paramesonephric ducts?
Fallopian tubes
144
How is the vagina formed?
Sinus tubercle fuses with urogenital sinus → sinovaginal bulbs → vaginal plate → vagina
145
What are the characteristics of a true hermaphrodite?
Testis on one side, ovary on the other side
146
What are the characteristics of a pseudohermaphrodite?
Phenotype and genotype do not match
147
What are the characteristics of a male pseudohermaphrodite?
Genotype: XY
148
What is the most common cause of male pseudohermaphroditism?
Androgen insensitivity syndrome
149
What are the characteristics of a female pseudohermaphrodite?
Genotype: XX
150
What is the most common cause of female pseudohermaphroditism?
Adrenogenital syndrome
151
What is the inheritance pattern of androgen insensitivity syndrome?
X-linked recessive
152
What causes androgen insensitivity syndrome?
Loss-of-function mutation in androgen receptor gene on the X chromosome
153
What is the pathogenesis of androgen insensitivity syndrome?
Prenatal undervirilization of external genitalia; loss of pubertal male changes
154
What clinical finding is present at birth in androgen insensitivity syndrome?
Testicles in inguinal canal or abdominal cavity at birth
155
What effect does androgen insensitivity syndrome have on the internal reproductive structures?
Absence of fallopian tubes, uterus, cervix, upper vagina (functional MIS)
156
What effect does androgen insensitivity syndrome have on the external reproductive structures?
Female external genitalia with blind vaginal pouch (no fetal DHT effect)
157
How does androgen insensitivity syndrome typically present?
Primary amenorrhea as a teenager
158
Why should the testes be removed in androgen insensitivity syndrome?
Testes at risk for gonadoblastoma
159
What laboratory findings are associated with androgen insensitivity syndrome?
Normal testosterone/DHT
160
What is the definition of a congenital anomaly?
Defect recognized only at birth
161
What is the most common cause of death in children
Congenital anomalies
162
What are the major causes of congenital anomalies?
Genetic, maternal, multifactorial
163
What is the most common genetic cause of congenital anomalies?
Chromosome aberrations
164
What congenital anomalies are associated with maternal diabetes?
Macrosomia due to hyperinsulinemia, ↑muscle mass and fat
165
What congenital anomalies are associated with maternal SLE?
Congenital heart block due to anti-Ro antibodies
166
What congenital anomalies are associated with maternal hypothyroidism?
Danger of cretinism in newborn; severe mental retardation
167
What is the most common teratogen?
Alcohol: causes fetal alcohol syndrome
168
What infections are commonly associated with congenital anomalies?
TORCH syndrome:
169
What finding indicates congenital infection?
↑cord blood IgM
170
What are the mechanisms of vertical transmission?
Transplacental (most common)
171
What is the overall most common cause of congenital anomalies?
Multifactorial inheritance disorders
172
What causes congenital malformations?
Disturbance in morphogenesis in embryonic period
173
Which period in embryologic development is most susceptible to malformations?
4th-5th week
174
What are the three germ cell layers?
Ectoderm
175
What causes congenital deformations?
Extrinsic disturbance in fetal development after fetal organs have developed
176
What is the most common cause of congenital deformations?
Most often due to uterine constraint; maternal/placental factors
177
What deformation is caused by oligohydramnios?
Potter facies, club feet
178
What is the definition of a congenital disruption?
Destruction of irreplaceable normal tissue
179
What causes an amniotic band?
Rupture of amnion; encircling fibrous bands constrict fetal parts (e.g., digits)
180
What is the definition of agenesis?
Complete absence of an organ due to absence of primordial tissue
181
What is the definition of aplasia?
Primordial tissue present but no development into an organ
182
What is the definition of hypoplasia?
Incomplete development of primordial tissue; tissue histologically normal
183
What is the definition of atresia?
Incomplete formation of lumen
184
How does the timing of a teratogenic insult affect the pathogenesis of congenital anomalies?
Malformations occur during embryonic period (week 3-9)
185
What is the effect of retinoic acid on morphogenesis?
Disrupts Hox gene function
186
What are Hox genes?
Involved in patterning of craniofacial structures, vertebrae, limbs
187
What is the definition of stillbirth?
Birth of a dead child
188
What is the most common cause of stillbirth?
Abruptio placentae
189
What is the definition of spontaneous abortion?
Termination of pregnancy before 20 weeks
190
What is the most common complication of early pregnancy?
Spontaneous abortion
191
What is the most common cause of spontaneous abortion?
Trisomy 16
192
What is sudden infant death syndrome?
Sudden unexpected death of a healthy infant
193
What is the most common cause of infant death between the ages of 1 month and 1 year in the US?
Sudden infant death syndrome (majority of deaths occur before 6 months)
194
What is the pathogenesis of sudden infant death syndrome?
Multifactorial; maternal/infant risk factors
195
What is the most common autopsy finding in sudden infant death syndrome?
Petechiae: sign of tissue hypoxia
196
What CNS changes are found on autopsy in sudden infant death syndrome?
Brainstem: hypoplasia of the arcuate nucleus, astrogliosis
197
What group of newborns has the highest mortality rate?
Small for gestational age (SGA)
198
What is the most common cause of newborns that are large for gestational age (LGA)?
Maternal diabetes
199
What is the definition of prematurity?
Gestational age
200
What is the most common cause of neonatal death/morbidity?
Prematurity
201
What is the most common cause of prematurity?
Premature rupture of membranes
202
What is chrioamnionitis?
Inflammation of placental membranes
203
What is funisitis?
Inflammation of umbilical cord
204
What complications are associated with prematurity?
Respiratory distress syndrome
205
What is the pathogenesis of intrauterine growth retardation?
Maternal factors most often responsible
206
How do fetal causes of intrauterine growth retardation typically present?
Symmetrical growth retardation
207
How do placental causes of intrauterine growth restriction typically present?
Asymmetric growth retardation; brain spared
208
What amniotic finding is highly associated with intrauterine growth retardation?
Oligohydramnios
209
What is the definition of the neonatal period?
First 4 weeks of life
210
What are the common causes of death in the neonatal period?
Respiratory distress syndrome
211
What is the function of amniocentesis?
Identifies prenatal genetic defects
212
What is amniotic fluid composed of?
Primarily fetal urine; contains fetal cells
213
Where can AFP be detected?
Amniotic fluid and maternal serum
214
What is the function of chorionic villus sampling?
Detects fetal abnormalities earlier than amniocentesis
215
What is the function of ultrasonography in pregnancy?
Assessment of fetal age/sex/viability, multiple pregnancies, and fetal morphologic abnormalities
216
What are the characteristics of an open neural tube defect?
Caused by folate acid deficiency before conception; ↑AFP
217
How are AFP levels affected in Down syndrome?
↓AFP
218
How are serum hCG levels affected in Down syndrome
↑serum hCG
219
How are urine unconjucated estradiol levels affected in Down syndrome?
↓urine unconjugated estradiol
220
What tests can be used in genetic analysis?
Chromosome karyotyping
221
What mechanisms are involved in the Stochastic theories of aging?
Somatic mutation
222
What is the main hypothesis of the programmed cell death theory?
Aging is genetically determined
223
What are age-dependent changes?
Inevitably occur with age
224
What are age-related changes?
Common but not inevitable
