Goljan - Genetic and Developmental Disorders Chapter Flashcards
(154 cards)
1
Q
Sickle cell disease
A
Sickle hemoglobin; autosomal recessive
2
Q
Cystic fibrosis
A
Cystic fibrosis transmembrane regulator (CFTR); autosomal recessive
3
Q
Familial hypercholesterolemia
A
Low-density lipoprotein (LDL) receptor; autosomal dominant
4
Q
Neurofibromatosis
A
Neurofibromin; autosomal dominant
5
Q
Hemophilia A
A
Factor VIII; X-linked recessive
6
Q
Deficient enzyme in alkaptonuria
A
Homogentisate oxidase
7
Q
Clinical findings in alkaptonuria
A
- Black urine (undergoes oxidation when exposed to light)
- Black pigmentation of nose, ears, cheeks
- Black cartilage in joints and intervertebral discs, producing degenerative arthritis
8
Q
Biochemical findings in alkaptonuria
A
- Increased homogentisate (black pigment), which binds to collagen in connective tissue, tendons, cartilage
- Decreased maleylacetoacetate
9
Q
Deficient enzyme in galactosemia
A
Galactose-1-phosphate uridyltransferase (GALT)
10
Q
Biochemical findings in galactosemia
A
- Increased galactose-1-phosphate –> toxic to liver and CNS
- Increased galactose in urine
- Increased galactitol –> sugar alcohol that produces osmotic damage in lens
- Decreased glucose-1-phosphate
- Decreased glucose-6-phosphate
- Decreased blood glucose in fasting state
11
Q
Clinical findings in galactosemia
A
- Mental retardation
- Cirrhosis
- Fasting hypoglycemia (due to decrease in gluconeogenic substrates distal to block)
- Cataracts (due to osmotic damage)
12
Q
Treatment for galactosemia
A
Avoid dairy products (galactose derives from lactose)
13
Q
Deficient enzyme in hereditary fructose intolerance
A
Aldolase B
14
Q
Biochemical findings in hereditary fructose intolerance
A
- Increase in fructose-1-phosphate –> toxic substrate
- Decreased glyceraldehyde-3-phosphate
- Decreased dihydroxyacetone phosphate (DHAP)
- Decreased glucose in the fasting state
15
Q
Clinical findings in hereditary fructose intolerance
A
- Cirrhosis
- Hypoglycemia (due to decrease in gluconeogenic substrates)
- Hypophosphatemia (used up in phosphorylating fructose)
16
Q
Treatment for hereditary fructose intolerance
A
Avoid fructose (e.g., in honey) and sucrose (glucose + fructose)
17
Q
Deficient enzyme in homocystinuria
A
Cystathionine synthase
18
Q
Biochemical findings in homocystinuria
A
- Increased homocysteine and methionine levels
2. Decreased cystathionine
19
Q
Clinical findings in homocystinuria
A
- Mental retardation
- Vessel thrombosis (due to homocysteine accumulation)
- Lens dislocation and arachnodactyly (similar to Marfan syndrome)
20
Q
Deficient enzyme in maple syrup urine disease
A
Branched chain alpha-ketoacid dehydrogenase
21
Q
Biochemical findings in maple syrup urine disease
A
- Increased isoleucine –> decreased acetyl CoA + decreased succinyl CoA
- Increased leucine –> decreased acetyl CoA + acetoacetate
- Increased valine –> decreased succinyl CoA
22
Q
Clinical findings in maple syrup urine disease
A
- Mental retardation
- Seizures
- Feeding problems
- Sweet-smelling urine
23
Q
Deficient enzyme in phenylketonuria
A
Phenylalanine hydroxylase
24
Q
Biochemical findings in phenylketonuria
A
- Increased levels of phenylalanine and neurotoxic byproducts
- Decreased levels of tyrosine
25
Clinical findings in phenylketonuria
1. Mental retardation
2. Microcephaly
3. Mousy odor (due to conversion of phenylalanine into phenylacids)
4. Decreased skin pigmentation (melanin derives from tyrosine, the levels of which are reduced)
26
Treatment for phenylketonuria
1. Restrict phenylalanine; avoid sweeteners containing phenylalanine (e.g., NutraSweet)
2. Add tyrosine to diet
27
Pregnant women with PKU must be on a...or their newborns will be...at birth.
Phenylalanine-free diet; mentally retarded
28
Hereditary angioedema
C1 esterase inhibitor deficiency; autosomal dominant
29
Deficient enzyme in "malignant" phenylketonuria
Dihydropterin reductase
30
Accumulated substrates in "malignant" phenylketonuria
Phenylalanine and neurotoxic byproducts
31
Treatment for "malignant" phenylketonuria
1. Restrict phenylalanine in diet
2. Administer L-dopa and 5-hydroxytryptophan to replace neurotransmitters
3. Administer BH4 (i.e., tetrahydrobiopterin)
32
Patients with "malignant" phenylketonuria are unable to metabolize...or..., resulting in decreased synthesis of...and..., respectively.
Tryptophan; tyrosine; serotonin; dopamine
Note: Metabolism of both tryptophan and tyrosine requires BH4.
33
Deficient enzyme in McArdle disease
Muscle glycogen phosphorylase
34
Biochemical findings in McArdle disease
1. Increased glycogen
| 2. Decreased glucose
35
Clinical findings in McArdle disease
1. Glycogenosis with muscle fatigue
2. Propensity for rhabdomyolysis with myoglobinuria
3. No lactic acid increase with exercise due to lack of glucose in muscle and a corresponding lack of anaerobic glycolysis
36
Deficient enzyme in Pompe disease
Alpha-1,4-glucosidase (lysosomal enzyme)
37
Clinical findings in Pompe disease
1. Glycogenosis
| 2. Cardiomegaly with early death from heart failure (or, to be more specific, restrictive cardiomyopathy)
38
Accumulated substrate in patients with Pompe disease
Glycogen
39
Deficient enzyme in von Gierke disease
Glucose-6-phosphatase (gluconeogenic enzyme)
40
Biochemical findings in patients with von Gierke disease
1. Increased glucose-6-phosphate
| 2. Decreased glucose
41
Clinical findings in von Gierke disease
1. Glycogenosis
2. Enlarged liver and kidneys (both contain gluconeogenic enzymes)
3. Fasting hypoglycemia (no response to glucagon or other gluconeogenesis stimulators)
42
Deficient enzyme in Gaucher disease (type I)
Glucocerebrosidase
43
Most common lysosomal storage disease
Gaucher disease
44
Clinical findings in Gaucher disease type I
1. Hepatosplenomegaly
2. Fibrillar-appearing macrophages in liver, spleen, and bone marrow
3. Pancytopenia from marrow involvement
4. Hypersplenism from enlarged spleen
Note: There is no CNS involvement.
45
Treatment for Gaucher disease
Replacement therapy with recombinant enzyme is effective
46
Deficient enzyme in Hurler syndrome
Alpha-1-iduronidase
47
Biochemical findings in Hurler syndrome
Dermatan and heparin sulfate (mucopolysaccharides or glycosaminoglycans) accumulate in mononuclear phagocytic cells, lymphocytes, endothelial cells, intimal smooth muscle cells, and fibroblasts.
48
Describe the typical clinical course of Hurler syndrome.
Normal at birth but develop severe mental retardation and hepatosplenomegaly by 6-24 months.
49
Clinical features of Hurler syndrome
1. Coarse facial features
2. Short neck
3. Corneal clouding
4. Coronary artery disease
5. Vacuoles in circulating lymphocytes
50
A milder form of Hurler syndrome is..., which is characterized by an...inheritance pattern.
Hunter syndrome; X-linked recessive
51
Deficient disease in Niemann-Pick disease
Sphingomyelinase
52
Accumulated substrate in Niemann-Pick disease
Sphingomyelin
53
...are present in 30-50% of Niemann-Pick cases.
Cherry red macula
54
Signs and symptoms of Niemann-Pick disease begin...
At birth.
55
Niemann-Pick disease type A is very severe and involves the...
CNS, causing psychomotor dysfunction and shortened lifespan.
56
Niemann-Pick disease type B does not involve the CNS and pts...
Survive into adulthood.
57
Laboratory findings in cases of Niemann-Pick disease
Phagocytic cells affected in liver (hepatomegaly), spleen (massive splenomegaly), lymph nodes, and bone marrow. Phagocytes have a foamy appearance; zebra bodies are seen on EM.
58
Deficient enzyme in Tay-Sachs disease
Hexosaminidase A
59
Accumulated substrate in Tay-Sachs disease
GM2 ganglioside
60
Describe the typical clinical course of Tay-Sachs disease.
Normal at birth but manifest signs and symptoms by 6 months of age.
61
Clinical findings in Tay-Sachs disease
1. Muscle weakness
2. Mental deterioration
3. Whorled configurations in neurons
4. Cherry-red macula (pale ganglion cells with excess gangliosides accentuate the normal red color of the macular choroid)
62
Give four examples of autosomal recessive disorders
1. Hemochromatosis
2. 21-hydroxylase deficiency
3. Wilson disease
4. Thalassemia
63
An increase in normal glycogen in tissue would be seen in..., while an increase in structurally abnormal glycogen in tissue would be seen in...
von Gierke disease; debranching enzyme deficiency
64
Glycogen deposition in tissue produces restrictive heart disease in...and hepatorenomegaly in...
Pompe disease; von Gierke disease
65
Most common autosomal recessive disorder
Hemochromatosis
66
In adult polycystic kidney disease (AD disorder), cysts are...
Not present at birth.
67
In familial polyposis (AD disorder), polyps are...
Not present at birth.
68
Familial polyposis is characterized by...penetrance.
Complete
69
Marfan syndrome is characterized by...penetrance.
Incomplete
70
If all individuals with a mutant gene express a particular disorder but at different levels of severity, then this is known as...
Variable expressivity.
71
Give an example of an autosomal dominant disease that exhibits variable expressivity.
Neurofibromatosis; some pts may have a few cafe au lait spots (coffee-colored flat lesions), while others have numerous neurofibromas (pedunculated, pigmented lesions)
72
Male-to-male disease transmission is characteristic of...
Autosomal dominant inheritance.
73
Give some examples of diseases inherited in an autosomal dominant manner.
1. HD
2. Osteogenesis imperfecta
3. Achondroplasia
4. Tuberous sclerosis
5. Hereditary spherocytosis
6. von Willebrand disease
7. Myotonic dystrophy
8. Familial hypercholesterolemia
74
Most common autosomal dominant disorder
von Willebrand disease
75
Enzyme deficiencies are...in autosomal dominant disorders.
Relatively uncommon
76
...are the most common type of proteins affected in X-linked recessive disorders.
Enzymes
77
Fragile X syndrome (FXS) is an...trinucleotide repeat disorder.
X-linked recessive
78
Most common Mendelian disorder causing mental retardation
Fragile X syndrome
79
What is the genetic defect in FXS?
At the distal end of the long arm of the X chromosome (band Xq27.3), CGG amplification produces a constriction that gives the appearance of a fragile portion of the X chromosome; the familial mental retardation-1 (FMR1) gene is located at this site; loss of function of this gene, which is most abundantly expressed in the brain and testis, is responsible for mental retardation in FXS
80
Clinical findings in FXS
1. Affected males have mental retardation with an IQ range of 20-70
2. Females with FXS and less affected males have IQs that approach 80
3. Facial changes -- long face, large mandible, everted ears, arched palate
4. Macro-orchidism (enlarged testes) at puberty is almost universal
5. Mitral valve prolapse
6. Pectus excavatum
7. Scoliosis
8. Hyperextensible joints
81
Normal testicular volume at puberty is..., whereas in individuals with FXS, the volume is...
17 mL; >25 mL
82
Best test for diagnosis of FXS
DNA analysis (PCR) to identify trinucleotide repeats
83
Lesch-Nyhan syndrome is due to deficiency of...
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
84
HGPRT is normally involved in...
Salvaging the purines hypoxanthine and guanine.
85
Clinical findings in Lesch-Nyhan syndrome
1. Mental retardation
2. Hyperuricemia
3. Self-mutilation
86
Give some examples of X-linked recessive disorders.
1. Androgen insensitivity syndrome
2. Chronic granulomatous disease
3. Bruton agammaglobulinemia
4. Glucose-6-phosphate dehydrogenase deficiency
87
What distinguishes X-linked dominant disorders from autosomal dominant disorders?
There is no male-to-male transmission observed in X-linked dominant disorders.
88
Vitamin D-resistant rickets is an...that involves...
X-linked dominant disorder; defective renal and gastrointestinal reabsorption of phosphate
89
The...observed in patients with vitamin D-resistant rickets results in...
Hypophosphatemia; defective bone mineralization (i.e., osteomalacia), because phosphate is required to drive calcium into bone
90
What is the Lyon hypothesis?
In females, one of the two X chromosomes (X paternal, X maternal) is randomly inactivated.
91
Random X inactivation occurs on day...of embryonic development.
16
92
An inactivated X chromosome is known as a...
Barr body.
93
Barr bodies are found attached to the...of cells and can be counted in...
Nuclear membrane; squamous cells obtained by scraping the buccal mucosa
94
Unequal separation of chromosomes in meiosis
Nondisjunction
95
Examples of diseases caused by nondisjunction
1. Turner syndrome (22 + 23 = 45 chromosomes)
| 2. Down syndrome (24 + 23 = 47 chromosomes)
96
Nondisjunction of chromosomes during mitosis in the early embryonic period
Mosaicism; two chromosomally different cell lines are derived from a single fertilized egg
97
Mosaicism most often involves...
Sex chromosomes (e.g., in Turner syndrome)
98
Transfer of chromosome parts between nonhomologous chromosomes
Translocation
99
Translocation in which translocated fragment is functional
Balanced translocation
100
A balanced translocation between two acrocentric chromosomes is known as a...
Robertsonian translocation
101
In an acrocentric chromosome, the centromere is...
Near the end of the chromosome
102
Loss of the short arm of chromosome 5 causes...
Cri du chat syndrome
103
Clinical findings in cri du chat syndrome include...
1. Mental retardation
2. Cat-like cry
3. Ventricular septal defect (VSD)
104
In one type of Down syndrome, the mother of an affected child has 45 (not 46) chromosomes because of a...between the long arms of chromosomes...
Robertsonian translocation; 21 and 14
105
Causes of Down syndrome
1. Nondisjunction (95% of cases, trisomy 21)
2. Robertsonian translocation (4% of cases, 46 chromosomes)
3. Mosaicism (1% of cases)
106
Major risk factor for Down syndrome
Increased maternal age
107
Meiotic nondisjunction of chromosome 21 occurs in..., usually during
Oogenesis; meiosis I
108
Approximately...of concepti with trisomy 21 die in embryonic or fetal life.
75%
109
Some clinical findings in Down syndrome
1. Mental retardation -- pts have mild retardation (IQ 50-75; usually mosaics) or severe retardation (IQ 20-35)
2. Muscle hypotonia is present at birth
3. Upslanting of palpebral fissures
4. Epicanthic folds
5. Flat facial profile
6. Macroglossia with protuberant tongue
7. Simian crease
8. Heart defects (40-50% of pts)
9. Umbilical hernia
10. Gap between 1st and 2nd toe
11. Atlantoaxial instability (danger of spinal cord compression)
110
Most common cause of "floppy baby" syndrome
Down syndrome
111
Most common chromosomal abnormality associated with mental retardation
Down syndrome
112
What is the major factor affecting survival in early childhood in pts with Down syndrome?
Heart defects
113
Which specific heart defects are seen in pts with Down syndrome?
1. Endocardial cushion defects (43%)
2. VSD (32%)
3. ASD (10%)
4. Tetralogy of Fallot (6%)
5. Isolated patent ductus arteriosus (4%)
114
GI tract abnormalities in Down syndrome
1. Tracheoesophageal fistula -- proximal esophageal ends blindly and distal esophagus arises from trachea
2. Duodenal atresia -- atresia of the small bowel distal to where the common bile duct empties; characterized by vomiting of bile stained fluid at birth
3. Hirschsprung disease -- aganglionic segment in large bowel; problem with stooling at birth
115
Hematologic abnormalities in Down syndrome
Increased risk for developing leukemia; acute lymphoblastic leukemia (ALL) and acute megakaryocytic leukemia are the most common types of leukemia; leukemia is usually preceded by transient myeloproliferative diseases
116
CNS abnormalities in Down syndrome
Most pts develop the neuropathologic signs of Alzheimer disease by 35-40 years of age.
117
...is the major factor affecting survival in older individuals with Down syndrome.
Alzheimer disease
118
...codes for amyloid precursor protein, which is the precursor for...
Chromosome 21; ABeta protein
119
Immune abnormalities in pts with Down syndrome
Increased risk for developing:
1. Hypothyroidism secondary to Hashimoto thyroiditis
2. Lung infections
3. Diabetes mellitus
120
Males with Down syndrome are usually unable..., while females with Down syndrome exhibit decreased...and an increased...
To father children; fertility; incidence of miscarriages
121
Which laboratory findings during pregnancy suggest a mother is carrying a child with Down syndrome?
1. Decreased serum alpha-fetoprotein (AFP)
2. Decreased urine unconjugated estriol (uE3)
3. Increased serum human chorionic gonadotropin (hCG)
122
Invasive diagnostic tests for Down syndrome include:
1. Amniocentesis with chorionic villous sampling
2. Percutaneous umbilical blood sampling
3. Cytogenetic and DNA studies used to confirm the diagnosis
123
Second most common trisomy syndrome
Trisomy 18 (Edwards syndrome)
124
Clinical findings in Edwards syndrome
1. Mental retardation
2. Clenched fist with overlapping fingers
3. Rocker-bottom feet (also seen in trisomy 16)
4. VSD
5. Early death
125
Trisomy 13 is also known as...
Patau syndrome
126
Clinical findings in Patau syndrome
1. Mental retardation
2. Cleft lip and palate
3. Polydactyly
4. VSD
5. Cystic kidneys
6. Early death
127
Most common sex chromosome abnormality in females
Turner syndrome
128
Pts with Turner syndrome exhibit...
Normal intelligence
129
Karyotypic abnormalities in Turner syndrome
1. 45,X karyotype (most conceptuses are nonviable; majority are due to a paternal nondisjunction)
2. Mosaicism (most common cause of Turner syndrome) -- 45,X/46,XX karyotype is most commonly seen; 45,X/46,XY karyotype is also observed (these pts are at increased risk for developing gonadoblastoma of the ovary)
130
As many as...of spontaneous abortions are due to Turner syndrome.
15%
131
Clinical findings in Turner syndrome
1. Short stature is a cardinal finding (>95% of cases); due to deletion of a second SHOX gene located on the X chromosome
2. Carrying angle of the arms is increased (cubitus valgus)
3. Short fourth metacarpal or metatarsal bone produces the knuckle (index finger)-knuckle-dimple (short 4th metacarpal/metatarsal bone)-knuckle sign (Archibald's sign)
4. Shield chest with widely spaced nipples and underdeveloped breasts is present
5. Pubic hair development is normal
6. Lymphedema may occur in the hands, feet, and neck in infancy
132
Lab findings in Turner syndrome
1. Growth hormone and insulin-like growth factor-1 are normal
2. Estradiol and progesterone levels are decreased
3. FSH and LH levels are increased
133
What causes the webbed neck in Turner syndrome?
Dilated lymphatic channels (cystic hygroma)
134
Cardiovascular abnormalities in Turner syndrome
Congenital heart disease occurs in 20-50% of cases; a hypoplastic left heart is the major cause of mortality in early infancy; preductal coarctation commonly occurs and often presents with left-sided heart failure; bicuspid aortic valves are another common cardiac abnormality
135
Genitourinary abnormalities in Turner syndrome
1. Both ovaries are replaced by fibrous stroma (called streak gonads); results in increased risk for developing ovarian dysgerminoma
2. Ovaries are devoid of oocytes by two years of age
3. Primary amenorrhea occurs with delayed sexual maturation
4. Incidence of horseshoe kidneys in increased
136
Most common genetic cause of primary amenorrhea
Turner syndrome
137
Hypothyroidism due to...occurs in 10-30% of cases.
Hashimoto thyroiditis
138
Most common genetic cause of male hypogonadism
Klinefelter syndrome
139
Causes of Klinefelter syndrome
1. Nondisjunction is the most common cause (90% of cases); produces 47 chromosomes with an XXY karyotype; maternal and paternal nondisjunction in meiosis I occurs in roughly equal proportions
2. Mosaicism is the remaining cause of the syndrome, with the most common karyotype being 46,XY/47,XXY
140
In Klinefelter syndrome, testicular abnormalities and female secondary sex characteristics do not develop until...
Puberty.
141
In pts with Klinefelter syndrome, testicular volume at puberty is...and is due to...
Decreased (
142
Histologic exam of the testes in pts with Klinefelter syndrome reveals...
Fibrosis of seminiferous tubules with absence of spermatogenesis (azoospermia; infertility) and loss of Sertoli cells
143
Loss of Sertoli cells in Klinefelter syndrome leads to a...and a corresponding increase in...
Decrease in inhibit; FSH (due to loss of negative feedback from inhibin)
144
...in pts with Klinefelter syndrome are prominent because of atrophy of other portions of the testis.
Leydig cells
145
Increased FSH levels in Klinefelter syndrome increases synthesis of...in Leydig cells.
Aromatase
Note: Increased synthesis of aromatase very likely converts a little of the testosterone that is synthesized by the Leydig cells into estradiol. However, this does not fully explain why pts with Klinefelter syndrome have hypogonadism and feminization.
146
Primary reason for hypogonadism and feminization in Klinefelter syndrome is that...
Testosterone does not have a normal interaction with androgen receptors; the gene on the X chromosome that is responsible for androgen receptor synthesis contains CAG trinucleotide repeats; the functional response to testosterone is dependent on the number of CAG repeats in the androgen receptor; testosterone interacts better with androgen receptors that have the smallest number of CAG repeats; in Klinefelter syndrome, the X chromosome with the shortest stretch of CAG repeats is preferentially inactivated, leaving behind androgen receptors that have the longest CAG repeats; testosterone does not interact with androgen receptors with the longest CAG repeats, which, along with increased conversion of testosterone into estradiol by aromatase, causes hypogonadism and leaves estradiol unopposed by any androgen effects, causing feminization
147
Signs of male hypogonadism in Klinefelter syndrome
1. Persistent gynecomastia
2. Facial, body, and pubic hair are diminished
3. Hair distribution in the pubic region resembles that of a female (i.e., there is a lack of extension of hair from the mons pubis to the umbilicus)
4. Penis is small (micropenis) because of decreased fetal production of testosterone in utero
5. Testicular volume is decreased from testicular atrophy
148
Describe the body habitus of pts with Klinefelter syndrome.
Eunuchoid body habitus with disproportionately long legs
149
Intelligence in Klinefelter syndrome
1. Mean IQ is lower than normal
2. Minor developmental and learning disabilities are present in most cases
3. In pts that have more than two X chromosomes, the IQ is lower.
150
Cardiovascular abnormality present in 50% of adults with Klinefelter syndrome
Mitral valve prolapse
151
Endocrine abnormalities seen in pts with Klinefelter syndrome
Increased incidence of type 2 diabetes mellitus and metabolic syndrome (insulin resistance)
152
Lab findings in Klinefelter syndrome
1. Decreased serum testosterone and increased serum LH
2. Increased serum FSH and estradiol
3. Decreased serum inhibin
4. Azoospermia (no sperm)
153
Pts with Klinefelter syndrome are at increased risk for developing...
1. SLE
2. Rheumatoid arthritis
3. Sjogren syndrome
4. Breast cancer
5. Osteoporosis
154
XYY syndrome is due to...and is associated with...
Paternal nondisjunction; aggressive (sometimes criminal) behavior and normal gonadal function
