Unit II Diseases Flashcards
1
Q
What is the pattern of inheritance for Duchenne Muscular Dystrophy?
A
X-linked recessive disease
Affects 1/3000 males
2
Q
What is the pattern of inheritance for HNPP (Hereditary Neuropathy with Liability to Pressure Palsies)?
A
Autosomal Dominant
3
Q
What is the pattern of inheritance for Osteogenesis Imperfecta Type 1?
A
Autosomal Dominant
4
Q
What is the pattern of inheritance for Charcot-Marie-Tooth Type 1A?
A
Autosomal Dominant
5
Q
What is the pattern of inheritance for Osteogenesis Imperfecta Types II, III, IV?
A
Autosomal Dominant
6
Q
What is the pattern of inheritance for Huntington’s Disease?
A
Autosomal Dominant (also can be auto recessive or X-linked as well)
7
Q
What is the pattern of inheritance for Myotonic Dystrophy 1?
A
Autosomal Dominant
8
Q
What is the pattern of inheritance for PKU (Phenylketouria)?
A
Autosomal Recessive
Over 400 mutant alleles=high allelic heterogeneity= more likely to have compound heterozygotes and varied severity
9
Q
What is the pattern of inheritance for ATD (alpha1-Antitrypsin Deficiency)?
A
Autosomal Recessive
More common in N. Europeans, 1/2500 affected, 1/25 carriers
10
Q
What is the pattern of inheritance for Tay-Sachs Disease?
A
Autosomal Recessive
1/360,000 general
1/3,600 Ashkenazi Jew (100x more likely)
Also more likely in French- Canadian of Quebec, Amish in Pennsylvania, and Cajun of Louisiana
11
Q
What is the pattern of inheritance for Sandhoff Disease?
A
Autosomal Recessive
12
Q
What is the pattern of inheritance for AB-Variant of Tay-Sachs?
A
Autosomal Recessive
13
Q
What is the pattern of inheritance for Cystic Fibrosis?
A
Autosomal Recessive
14
Q
What is the pattern of inheritance for Hereditary Hemochromatosis?
A
Autosomal Recessive
15
Q
What is the pattern of inheritance for Achondroplasia?
A
Autosomal Dominant
1/40,000
Incomplete Dominance
16
Q
What is the pattern of inheritance for Neurofibromatosis Type 1?
A
Autosomal Dominant
17
Q
What is the pattern of inheritance for Marfan Syndrome?
A
Autosomal Dominant (1/5000)
18
Q
What is the pattern of inheritance for AD Polycystic Kidney Disease?
A
Autosomal Dominant (1/1000)
19
Q
What is the pattern of inheritance for Familial Hypercholesterolemia?
A
Autosomal Dominant (1/500)
20
Q
What is the pattern of inheritance for Fragile X Syndrome?
A
X-linked Dominant
21
Q
What is the pattern of inheritance for Hemophilia A
A
X-linked Recessive
22
Q
What is the pattern of inheritance for Turner Syndrome?
A
Sex Chromosome Disorder (45X)
Affects 1/2000-5000 liveborns
23
Q
What is the pattern of inheritance for Klinefelter Syndrome?
A
Sex Chromosome Disorder (47XXY)
Affect 1/1000
24
Q
What is the pattern of inheritance for XYY Syndrome?
A
Sex Chromosome Disorder (47XYY)
Affects 1/900-1000
25
What is the pattern of inheritance for Testicular Feminization (AIS)?
X-linked recessive
26
What is the pattern of inheritance for Congenital Adrenal Hyperplasia?
Autosomal recessive
| 1/25,000 births
27
What is the pattern of inheritance for Dosage Sensitive Sex Reversal (DSS)?
X-linked recessive
28
What is the pattern of inheritance for 5alpha Reductase Deficiency?
Autosomal recessive
29
What is the pattern of inheritance for Leydig cell hypoplasia?
Autosomal recessive
30
What is the pattern of inheritance for Smith-Lemli-Opitz Syndrome?
Autosomal Recessive
31
What is the pattern of inheritance for Kallman Syndrome?
Autosomal and X-linked forms
32
What is the pattern of inheritance for Nonsydromic Deafness?
Autosomal Dominant (progressive childhood deafness) or Autosomal Recessive (congenital deafness)
33
What is the pattern of inheritance for Syndromic Deafness?
Deafness with associated syndromes
34
What is the pattern of inheritance for Fabry Disease?
X-linked Recessive
35
What is the pattern of inheritance for Down's Syndrome?
Chromosomal Abnormality
(Trisomy 21)
Affects 1/900
36
What is the pattern of inheritance for Patau's Syndrome?
Chromosomal Abnormality
| Trisomy 13
37
What is the pattern of inheritance for Edward's Syndrome?
Chromosomal Abnormality
| Trisomy 18
38
What is the pattern of inheritance for Cri-du-chat?
Autosomal contiguous gene syndrome
39
What is the pattern of inheritance for Prader-Willi Syndrome?
Autosomal contiguous gene syndrome
40
What is the pattern of inheritance for Angelman Syndrome?
Autosomal contiguous gene syndrome
41
What is the pattern of inheritance for WAGR Syndrome?
Autosomal contiguous gene syndrome
42
What is the pattern of inheritance for DiGeorge Syndrome?
Autosomal contiguous gene syndrome
43
What is the pattern of inheritance for Acute Lymphomatic Leukemia (ALL)?
Hyper-diploidy (<50 chromosomes) in bone marrow
44
What is the pattern of inheritance for Chronic Myelogenous Leukemia (CML)?
Translocation (in bone marrow)
45
What is the pattern of inheritance for Acute Promyeloid Leukemia (APL/PML)?
Translocation (in bone marrow)
46
What is the pattern of inheritance for Maternally Inherited Interstitial Duplication?
Interstitial duplication in chromosome 15
47
What is the pattern of inheritance for IDIC 15?
Inverted duplicated isochromosome 15
48
What is the pattern of inheritance for Gaucher Disease?
Autosomal recessive
1/50,000 general
1/450 Ashkenazi Jews
49
What is the pattern of inheritance for Pompe Disease?
Autosomal Recessive
50
What is the pattern of inheritance for Progeria?
De novo dominant trait
51
What are the Autosomal Dominant Diseases?
```
HNPP
Osteogenesis Imperfecta Charcot-Marie-Tooth Type 1A
Huntington’s Disease
Myotonic Dystrophy 1
Achondroplasia
Neurofibromatosis
Marfan Syndrome
Polycystic Kidney Disease
```
52
How do Autosomal Dominant Diseases look on a Pedigree?
Males and females affected equally, Child of affected parent has 50% chance of getting disease, (Note that some indviduals may have reduced penetrance, meaning they don't exhibit the phenotype (not on pedigree), but they are still able to pass on the disease allele)
53
What are the Autosomal Recessive Diseases?
```
PKU
ATD
Tay-Sachs Disease
Sandhoff Disease
AB-Variant of Tay Sachs
Cystic Fibrosis
Hereditary Hemochromatosis
Congenital Adrenal Hyperplasia
5-alpha reductase deficiency
Leydig cell hypoplasia
Smith-Lemli-Opitz Syndrome
Pompe Disease
Sickle Cell
```
54
How do Autosomal Recessive Diseases look on a pedigree?
Males and females affected equally, All children of affected parent will be carriers
55
How do X-linked Dominant Diseases look on a pedigree?
Males and females affected equally, If mother is affected, both female and male children have 50% chance of being affected, If father is affected, all daughters will be affected but NO sons will be affected
56
What are the X-linked Dominant Diseases?
Fragile X Syndrome
57
How do X-linked Recessive Diseases look on a pedigree?
Only affects males, If mother is affected, females have 50% chance of being a carrier while males have a 50% chance of being affected, If father is affected, all daughters will be carriers but NO sons will be affected
58
What are the X-linked Recessive Diseases?
```
Duchenne Muscular Dystrophy
Hemophilia A
Testicular Feminization
Dosage Sensitive Sex Reversal
Fabry Disease
```
59
How do Mito Diseases look on a pedigree?
mtDNA inherited from mother only, Males and females are equally likely to be affected OR asymptomatic carriers (mutated mtDNA has to exceed normal mtDNA to cause disease)
60
What are the Mito Diseases?
Examples: Kearns-Sayre Syndrome, MELAS, MERRF
61
What are the chromosomal abnormality diseases?
```
Turner Syndrome
Klinefelter
XYY Syndrome
Down’s
Trisomy 13
Trisomy 18
```
62
What are the Autosomal Contiguous Gene Syndromes?
```
Cri-du-Chat
Prader-Willi
Angelman
DiGeorge
WAGR
```
63
What are the Clinical Presentations of Duchenne Muscular Dystrophy?
Onset around 2 yrs, lose motor function, in wheelchair by 18 yrs, median age at death is 18 yrs.
Progressive myopathy, characterized by large calves (adipose tissue overcomes muscle tissue); Gowers Maneuver; median age of death 18 yrs; abnormal gait; progressive myopathy; high creatine kinase levels (shows evidence of muscle damage)
64
What are the Clinical Presentations of HNPP (Hereditary Neuropathy with Liability to Pressure Palsies)?
Temporary (usually reversible) neuropathy when pressure is applied to various nerves; limbs can ‘go to sleep’ for longer periods of time (hours, days, to months)
First attack in 20-30 yrs old (usually recovery is complete, there is mild disability if not)
65
What are the Clinical Presentations of Osteogenesis Imperfecta Type 1?
Brittle bones, increased fractures, blue sclerae, normal stature, progressive hearing loss in adults
66
What are the Clinical Presentations of Charcot-Marie-Tooth Type 1A?
Demyelinating motor and sensory neuropathy; lower extremity weakness and muscle atrophy and mild sensory loss; foot deformity known as hammertoes
Note: all versions of CMT affect peripheral nervous system, type 1A is dominant
67
What are the Clinical Presentations of Osteogenesis Imperfecta Types II, III, IV?
Brittle bones, increased fractures, blue sclerae (Type II much more severe, usually lethal in perinatal period)
68
What are the Clinical Presentations of Huntington's Disease?
```
Progressive neurodegenerative disorder with adult onset; chorea (child-like dance movement); death within 15 yrs of onset;
Gene anticipation (earlier onset in offspring and subsequent generations) most commonly occurs with paternal repeats
```
69
What are the Clinical Presentations of Myotonic Dystrophy 1?
Droopy eyes, intellectual difficulty, hypotonia
70
What are the Clinical Presentations of PKU (Phenylketouria)?
Epilepsy, mental retardation, hyperactivity
Newborn screen used to be Guthrie test (high phenylalanine overrides bacterial inhibitio, leading to bacterial growth), now by Tandem Mass Spectrometry
Screening timing is important because PAH is normal at birth because mom’s PAH is still in fetus, so test a few days later but still early enough to avoid CNS damage
71
What are the Clinical Presentations of ATD (alpha1-Antitrypsin Deficiency)?
Late onset: increased risk of developing emphysema, liver cirrhosis/cancer (risks increase with smokers)
Screen with sequence specific oligonucleotide probes for Z and S alleles
72
What are the Clinical Presentations of Tay-Sachs Disease?
Progressive neurodegeneration of CNS. Onset at 3-6 months, with muscle weakness, decreased attentiveness, and increased startle response appear.
Later on: seizures, vision and hearing loss, diminishing mental function, and paralysis. An eye abnormality called “cherry-red spot” is a characteristic of T-S. Children of T-S usually live only till 3-4 years of age
Screen enzyme activity (at low temp, both enzymes active, at high temp HexA degrades and B still functions) test and DNA test (three mutant alleles account for 95% of cases)
Can screen carriers (have less HexA in blood)
73
What are the Clinical Presentations of Sandhoff Disease?
Symptoms similar to Tay-Sachs
| Screening enzyme activity shows that both HexA and HexB are inactive (just Hex A in Tay-Sachs)
74
What are the Clinical Presentations of AB-Variant of Tay-Sachs?
Resemble Tay-Sachs disease
75
What are the Clinical Presentations of Cystic Fibrosis?
Salty skin, poor growth and poor weight gain despite a normal food intake, accumulation of thick, sticky mucus, frequent chest infections, and coughing or shortness of breath
76
What are the Clinical Presentations of Hereditary Hemochromatosis?
Hepatic cirrhosis in combination with hypopituitarism, cardiomyopathy, diabetes, arthritis, or hyperpigmentation.
77
What are the Clinical Presentations of Achondroplasia?
Short stature, rhizomelic limb shortening (proximal limb shorter than distal limbs), large head with frontal bossing (prominent forehead); megalencephaly; “trident” hand; spinal cord compression (small cranial foramina); between 3-7% die suddenly in during first year
78
What are the Clinical Presentations of Neurofibromatosis Type 1?
Cafe au Lait spots, axillary and inguinal freckling; multiple neurofibromas; Lisch nodules (spots/bumbs on eye)
100% penetrance, variable expressivity
79
What are the Clinical Presentations of Marfan Syndrome?
Connective tissue disorder; ocular, skeletal and cardiovascular manifestations; risk of aortic aneurysm; appear tall and skinny (long-limbed); hypermobile joint, pectus excatum/carnatum
80
What are the Clinical Presentations of AD Polycystic Kidney Disease?
Enlarged kidneys with multiple cysts, end stage renal disease, extra-renal cysts (i.e. in pancreas), intracranial aneurysms
81
What are the Clinical Presentations of Familial Hypercholesterolemia?
High cholesterol levels, deposition of cholesterol throughout body, premature coronary artery disease
82
What are the Clinical Presentations of Fragile X syndrome?
Onset at childhood, mental deficiency, dysmorphic facies, male postpubertal macroorchidism (enlarged testicles); speech/language delay, autism-like syndromes, large ears/prominent jaws
Fragile X-associated tremor/ataxia syndrome (FXTAS): from premutation, Parkinsonian-like features, adult onset, ataxia, tremor, memory loss, peripheral neuropathy
Premature Ovarian failure in women (20% of women with permutation)
83
What are the Clinical Presentations of Hemophilia A?
Bleed complications (decreased clotting)
84
What are the Clinical Presentations of Turner Syndrome?
Gonadal dysgenesis, short stature, heart defects, fused kidneys, webbed neck, brown nevi, widely spaced nipple, infertility, social difficulty etc.
85
What are the Clinical Presentations of Klinefelter Syndrome?
Gonadal dysgenesis/hypogonadism, infertility, tall stature, gynecomastea, high frequency of sterility, language impairment
86
What are the Clinical Presentations of XYY Syndrome?
Indistinguishable physically or mentally from normal males and are usually fertile (a little taller); increased risk of behavioral and educational problems, delayed speech and language skills
NOT associated with criminal behavior
87
What are the Clinical Presentations of Testicular Feminization (AIS)?
Feminine features (due to end-organ unresponsiveness to testosterone)
88
What are the Clinical Presentations of Congenital adrenal hyperplasia?
Ambiguous genitalia, masculization of females
89
What are the Clinical Presentations of Dosage Sensitive Sex Reversal (DSS)?
Leads to development of ovaries even in the presence of expressed SRY
90
What are the Clinical Presentations of 5α reductase deficiency?
Incomplete phallic development, severe hypospadias (pseudovaginal perineal hypospadius); ambigous external genitalia in 46 XY males
91
What are the Clinical Presentations of Leydig cell hypoplasia?
Male psuedohermaphriditism
92
What are the Clinical Presentations of Smith-Lemli-Opitz Syndrome?
Feminization of males
93
What are the Clinical Presentations of Kallman Syndrome?
Gonadotropin deficiency, hypogenitalism in males
94
What are the Clinical Presentations of Nonsyndromic
| Deafness?
1/500-1000 are deaf (further broken down into syndromic, nonsyndromic, etc)
½ of children with clinical presentation are genetic/congenial (recessive); of those, ¾ are non syndromic (occur in isolation)
Congenital Deafness in recessive form
Progressive Childhood Deafness in dominant form
95
What are the Clinical Presentations of Syndromic Deafness?
General: Intellectual
96
What are the Clinical Presentations of Fabry Disease?
Neurologic pain crises in childhood; reduced sweating, risk of heat stroke; progressive renal failure (cause of death prior to renal transplanation); risk of heart attacks and stroke; hypertrophy of cardiac tissue also seen
97
What are the Clinical Presentations of Down’s Syndrome?
```
Mid-face hypoplasia, short stature, hypotonia, moderate intellectual disability
Congenital malformations (endocardial cushion defects, duodenal atresia, GI anomalies, Hirschprung disease)
```
98
What are the Clinical Presentations of Patau’s Syndrome?
```
Characteristic facies, severe intellectual disabilities
Congenital malformations (fusion of brain lobes, facial clefts, polydactyly, renal defects)
```
99
What are the Clinical Presentations of Edward’s Syndrome?
```
Intrauterine growth retardation, characteristic facies, severe intellectual disabilities, characteristic hand positioning, hypertonicity
Congenital malformations (valvular heart disease, posterior fossa CNS maldevelopment, diaphragmatic hernias, renal defects, seizures)
```
100
What are the Clinical Presentations of Cri-du-chat?
Microcephaly
Characteristic cry
Seizures, intellectual disability
101
What are the Clinical Presentations of Prader-Willi Syndrome?
Hypotonia, hypopigmentation, hypogenitalism, obesity, excessive eating, short stature, small hands and feet, hypogonadism, intellectual disabilities
102
What are the Clinical Presentations of Angelman Syndrome?
Seizures, intellectual disability, unusual facial appearance, short stature, severe intellectual disabilities, prominent chin
103
What are the Clinical Presentations of WAGR Syndrome?
Wilms tumor
Aniridia
Genitourinary anomalies
Intellectual disability
104
What are the Clinical Presentations of DiGeorge Syndrome?
Absent or hypoplastic thymus and parathyroid’s, congenital heart disease
105
What are the Clinical Presentations of Acute Lymphomatic Leukemia (ALL)?
Down’s patients 20-100x more likely to develop condition
Enlarged spleen, joint and/or hip pain, low-grade fever, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising
106
What are the Clinical Presentations of Chronic Myelogenous Leukemia (CML)?
Enlarged spleen causing pain on the left side, malaise, joint and/or hip pain, low-grade fever, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising
107
What are the Clinical Presentations of Acute Promyeloid Leukemia (APL/PML)?
Enlarged spleen causing pain on the left side, malaise, joint and/or hip pain, low-grade fever, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising
108
What are the Clinical Presentations of Maternally Inherited Interstitial Duplication?
Hypotonic as infants, present with autism and seizures as older children
NOTE: Patients with paternally derived inherited interstitial duplications are normal
109
What are the Clinical Presentations of IDIC 15?
Similar to maternally inherited interstitial duplication; hypotonic as infants, present with autism and seizures as older children
110
What are the Clinical Presentations of Gaucher Disease?
```
Hepatosplenomegaly, thrombocytopenia, anemia, join pain, CNS issues
Three types (Type 1 most common, does not have CNS issues, affects 6-80 yrs, GCase activity <30%)
```
111
What are the Clinical Presentations of Pompe Disease?
Progressive muscle failure, cardiomegaly, hypotonia, cardiomyopathy, respiratory distress, muscle weakness, feeding difficulties, and failure to thrive (used to die by 1 yr)
112
What are the Clinical Presentations of Progeria?
Premature aging syndrome
113
What are the Mechanisms of Duchenne Muscular Dystrophy?
Loss of Function: Large deletions in many exons in Xp21.2 (dystrophin gene); nonsense frameshift
High new mutation rate (alleles have 0 fitness because sons not living to reproduce)
Sometimes carrier females will demonstrate milder symptoms later in life (8%);
In-frame deletion or missense leads to milder Becker dystrophy
114
What are the Mechanisms of HNPP (Hereditary Neuropathy with Liability to Pressure Palsies)?
Loss of Function:
| Deletion of PMP22 gene due to unequal crossing over (PMP22 is integral glycoprotein in nerves)
115
What are the Mechanisms of Osteogenesis Imperfecta Type 1?
Loss of Function: nonsense frameshift in COL1A1
| Causes unstable mRNA that's degraded, reducing COL1A1, which is important for collagen strength
116
What are the Mechanisms of Charcot-Marie-Tooth Type 1A?
Gain of Function: duplication of of PMP22 gene, 17p11.2
| PMP22 is integral glycoprotein in nerves
117
What are the Mechanisms of Osteogenesis Imperfecta Types II, III, IV?
Novel Property Mutation: the COL1A2 protein has new property due to new/different folding, forming collagen trimers (much worse than Type I)
Classified as problem of assembly of monomers into homodimer
118
What are the Mechanisms of Huntington's Disease?
Polyglutamate disease; increased CAG repeats (>40 penetrant, <27 is normal, some traits in between) in huntington gene (number of repeats correlates with disease onset and severity) due to slipped mispairing
Parental transmission bias—trinucleotide expansion more likely to come from father
Larger the repeat number, the greater the clinical severity in terms of age-of-onset and progression
119
What are the Mechanisms of Myotonic Dystrophy 1?
Increased CTG repeats (in 3’ UTR) of DMPK gene
120
What are the Mechanisms of PKU (Phenylketouria)?
Defect in PAH-phenylalanine hydroxylase enzyme (common) or BH4 cofactor (rare, also have high neurotransmitter imbalance because BH4 involved is involved in neurotransmitter synthesis)
High phenylalanine in blood, toxic to CNS
Side note: pregnant mothers advised to keep a low phenylalanine diet, irrespective of child genotype, because reduces risk of miscarriage and congenital malformations)
121
What are the Mechanisms of ATD (alpha1-Antitrypsin Deficiency)?
Defective alpha1-AT protein (normally protease inhibitor of elastase; elastase recruited by neutrophil) → increased elastase activity→ decreased elastin in lungs→ emphysema and lung damage
Smoking accelerates disease b/c causes lung damage, increasing neutrophil expression and thus elastase
Z allele (Glu342Lys) expresses misfolded protein that aggregates in the endoplasmic reticulum of liver cells, causing damage to the liver in addition to the lung. Is more common
S allele (Glu264Val) expresses an unstable protein that is less effective.
(M allele is wild-type)
122
What are the Mechanisms of Tay-Sachs Disease?
Lysosomal storage disease; from defect in alpha subunit of HEXA (has alpha and beta subunits), which degrades GM2 ganglioside
Inability to degrade GM2 ganglioside, which aggregates in lysosomes in CNS neurons;
Over 100 HEXA mutations are known; most common mutant allele (~80%) in the Ashkenazi Jewish population is a 4 bp insertion in exon 11 of HEXA, causing a frameshift and a premature stop codon (null allele)
123
What are the Mechanisms of Sandhoff Disease?
Defects in both HexA (αβ) and HexB (homodimer of ββ) caused by a defective β subunit
124
What are the Mechanisms of AB-Variant of Tay-Sachs?
Rare form where HexA and HexB are normal but GM2 accumulates due to defect in the GM2 activator protein (GM2AP), which facilitates interaction between the lipid substrate and the HexA enzyme within the cell
125
What are the Mechanisms of Cystic Fibrosis?
Mutation of CFTR gene; CFTR protein needed to regulate components of sweat, digestive juices, and mucus by regulating movement of chloride and sodium ion across epithelial membranes
126
What are the Mechanisms of Hereditary Hemochromatosis?
Mutation in HFE gene on Chr. 6, important in iron regulation; defect causes iron overload
127
What are the Mechanisms of Achondroplasia?
Gain of Function:Gly380Arg mutation in FGFR3 Gene (hot spot for mutation)
Receptor normally inhibits bone growth; defective receptor always on, causing shortening of limbs
De novo mutations occur almost exclusively in father’s germline and increase with paternal age
Homozygous state is lethal! Only see phenotype in heterozygotes (this is incomplete dominance)
128
What are the Mechanisms of Neurofibromatosis Type 1?
Mutation on chr. 17 on NF1 gene (codes for neurofibroma protein)
129
What are the Mechanisms of Marfan Syndrome?
Mutation in FBN1 mutations (codes for fibrillin)
130
What are the Mechanisms of AD Polycystic Kidney Disease?
Mutation in ADPKD-1 (85%; chr. 16) or ADPKD-1 (14.5%; chr. 4); Locus heterogeneity (mutation in more than one locus can the same clinical condition)
131
What are the Mechanisms of Familial Hypercholesterolemia?
Mutations in gene encoding LDL receptor (can't clear LDL from bloodstream)
132
What are the Mechanisms of Fragile X syndrome?
Trinucleotide CGG expansion (>200 penetrant, 6-45 normal, grey zone/premutation in between) in 5’ UTR causing hypermethylation, and thus silencing of gene at fragile site of X chromosome
Maternal gene anticipation
Premutation is 59<200 (aren’t hypermethylated, in fact they make more RNA, which contributes to primary ovarian insufficiency and FXTAS)
Haplotype effect: AGG repeats within CGG repeats reduce risk (haplotype is combination of alleles at adjacent locations that transmit together)
5’UTR: Fragile X and FTAXS (CGG)
Intron: Friedrich ataxia (GAA), myotonic dystrophy 2 (CCTG)
Exon: Huntington (CAG)
3’UTR: myotonic dystrophy 1 (CTG, maternal)
133
What are the Mechanisms of Hemophilia A?
Factor VIII deficiency
| Note: Hemophilia B is Factor IX
134
What are the Mechanisms of Turner Syndrome?
Meiotic nondisjunction (greater chance in M1 because more abnormal gametes)
135
What are the Mechanisms of Klinefelter Syndrome?
Meiotic Nondisjunction
| Half of cases due to failure of pseudoautosomal recombination (15% are result of mosaicism)
136
What are the Mechanisms of XYY Syndrome?
Meiotic Nondisjunction
| Results from errors in paternal meiosis II, producing YY sperm.
137
What are the Mechanisms of Testicular Feminization (AIS)?
Absence or abnormality of cytosolic androgen receptor protein; similar to androgen insensitivity syndrome, mutations androgen receptor gene.
138
What are the Mechanisms of Congenital adrenal hyperplasia?
ACTH secretion increased (b/c lack of negative feedback via cortisol to pituitary), such that adrenals are hyperplastic, overproducing androgens
139
What are the Mechanisms of Dosage Sensitive Sex Reversal (DSS)?
Duplication of a gene DAX1
| DAX1 is a member of the nuclear hormone receptor superfamily
140
What are the Mechanisms of 5α reductase deficiency?
Failure of end organs to activate testosterone to dihydrotestosterone (DHT) in 46, XY individuals; 5-alpha reductase needed to covert tetosterone to active DHT
141
What are the Mechanisms of Leydig cell hypoplasia?
Homozygous mutations in the LHR the gene for luteinizing hormone receptor (LHR) receptor, leading to lack of testosterone production
142
What are the Mechanisms of Smith-Lemli-Opitz Syndrome?
Cholesterol synthesis disorder, decreasing testosterone production
143
What are the Mechanisms of Kallman Syndrome?
Maldevelopment of hypothalamus
144
What are the Mechanisms of Nonsyndromic
| Deafness?
Allelic heterogeneity
| GJB2 most commonly mutated (DFBN1 protein); responsible for 50% of nonsyndromic deafness
145
What are the Mechanisms of Fabry Disease?
Due to deficiency of alpha-galactosidase (protein misfolding); Accumulation of glycosphingolipids causes widespread microvascular damage
One particular mutation (25% of disease)
146
What are the Mechanisms of Down’s Syndrome?
95% of Trisomy 21 cases are result of non-disjunction in maternal meiosis I
3-4% Robertsonian Translocation (usually extra 21 is fused with chromosome 14, resulting in 45 chromosomes)
1-2% of Mosaic Down’s Syndrome (47,XX+21/46XX)
147
What are the Mechanisms of Patau’s Syndrome?
Trisomy 13
148
What are the Mechanisms of Edward’s Syndrome?
Trisomy 18
| Usually due to translocation der(14, 18)
149
What are the Mechanisms of Cri-du-chat?
Del(5p15.2)
150
What are the Mechanisms of Prader-Willi Syndrome?
```
Paternal Del(15q11-q13) accounts for 70% of cases
Uniparental disomy and imprinting error account for remaining cases
```
151
What are the Mechanisms of Angelman Syndrome?
```
Maternal Del(15q11-q13)
Increased incidence in infertile couples using advanced reproductive therapy to conceive (may be related to imprinting erasure and resetting malfunctions)
```
152
What are the Mechanisms of WAGR Syndrome?
Del(11p13)
| Interstitial deletion of 11p13 (large enough to see at chromosome level)
153
What are the Mechanisms of DiGeorge Syndrome?
Del(22q11.2)
154
What are the Mechanisms of Acute Lymphomatic Leukemia
| (ALL)?
Hyper-diploidy (<50 chromosomes) in bone marrow, sometimes peripheral blood
155
What are the Mechanisms of Chronic Myelogenous Leukemia (CML)?
Bcr-Abl translocation (9;22) is diagnostic
156
What are the Mechanisms of Acute Promyeloid Leukemia (APL/PML)?
PML-RARA translocation (15;17) is diagnostic
| Viewing Auer rods (cytosolic precipitation) is diagnostic
157
What are the Mechanisms of Maternally Inherited Interstitial Duplication?
Maternally derived proximal 15q11-q13 chromosome anomalies are most frequent cytogenetic abnormalities in patients with autism (related to GABA-A)
There is linkage disequilibrium between patients with autism and polymorphisms in GABAA –b3 locus on chromosome 15q have been reported. GABAA is an important neurotransmitter in the CNS.
158
What are the Mechanisms of IDIC 15?
Inverted duplicated isochromosome 15
| These patients have extra chromosome, known as marker chromosome that was maternally inherited
159
What are the Mechanisms of Gaucher Disease?
Build up of glucocereborsides in macrophage lysosomes due to lack of glucocerebrosidase function – these are Gaucher cells and they get stuck in liver and spleen
160
What are the Mechanisms of Pompe Disease?
Accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme
161
What are the Mechanisms of Progeria?
Point mutation in LMNA/C gene yielding abnormal progerin protein
Progerin targeted to nuclear membrane by Farnesyl group→ pathological effects at membrane
