Chapter 5 Flashcards
1
Q
Most common examples of complex multigenic disorders
[those in which no single gene is necessary or sufficient to produce disease]
A
Atherosclerosis
Diabetes
Hypertension
Autoimmune disease
2
Q
2 most common cardiovascular lesions in Marfan’s syndrome
A
Mitral valve prolapse
Dilation of ascending aorta
3
Q
Most common form of GM2 gangliosidosis
A
Tay Sachs disease
4
Q
Which type of Niemann Pick disease is most common?
A
Type C
5
Q
What is the most common lysosomal storage disorder?
A
Gaucher disease (Type 1 is most common subset)
6
Q
Most common isochromosome present in live births
A
Long arm of X [i(X)(q10)]
Leads to monosomy for genes on short arm of X and trisomy for genes on long arm of X
7
Q
Differentiate missense from nonsense point mutations
A
Missense = single base substituted for another base (conservative or nonconservative)
Nonsense = single base change that changes amino acid to a premature stop codon
8
Q
Effect of mutations involving noncoding sequences
A
Point mutations in promoters or ehnacers may interfere with TF binding, leading to reduction/lack of transcription
Point mutations in introns may lead to defective splicing and thus interfere with normal processing of initial mRNA transcripts —> failure to form mature mRNA and gene product not synthesized
9
Q
2 potential effects on protein encoding associated with deletions and insertions
A
- If # of base pairs involved is in multiples of 3, the reading frame remains intact and an abnormal protein lacking or gaining 1+ amino acids will be synthesized (CF)
- If # of base pairs involved is not in multiples of 3, result is frameshift mutation, usually resulting in premature stop codon (Tay Sachs)
10
Q
Characterize mutations associated with trinucleotide repeats and give major example
A
Amplifications of a sequence of 3 nucleotides; almost all affected sequences share nucleotides G and C
Degree of amplification increases during gametogenesis
Ex: Fragile X syndrome with 250-4000 tandem repeats of CGG within FMR1 when there should only be 29
11
Q
Inheritance of marfan syndrome, ehlers-danlos syndrome (some variants), and familial hypercholesterolemia
A
Autosomal dominant
12
Q
Manifestations and chance of inheritance of autosomal dominant conditions
A
Manifested in heterozygous state, so at least one parent of an index case is usually affected
Affected+unaffected parent = 50% chance of inheritance
13
Q
Discuss concept of “new mutation” as it relates to autosomal dominant conditions
A
With every autosomal dominant disorder, some proportion of patients do not have affected parents, meaning they have a new mutation involving either egg or sperm from which they derived; siblings are not at risk; usually seen in germ cells of older fathers
14
Q
Define penetrance — what does it mean to have 50% penetrance, and what is incomplete penetrance?
A
50% penetrance = 50% of those who carry the gene express the trait
Incomplete penetrance = inherited the gene but are phenotypically normal
15
Q
Define variable expressivity
A
Trait is seen in all individuals carrying mutant gene but expressed differently in each
16
Q
Biochemical mechanisms associated with loss of function mutations
A
Those involved in regulation of complex metabolic pathways subject to feedback inhibition (familial hypercholesterolemia - loss of LDL receptors)
Key structural proteins like collagen and cytoskeletal elements of red cell membrane
17
Q
Even a single mutant in the collagen chain leads to marked deficiency in collagen, known as a ____ _____ mutant because it impairs function of the normal allele
A
Dominant negative
18
Q
Which is more common, gain of function mutations or loss of function mutations?
A
Loss of function
19
Q
Inheritance of lysosomal storage diseases, glycogen storage diseases, ehlers danlos syndrome (some variants), and alkaptonuria
A
Autosomal recessive
20
Q
Contrast autosomal recessive conditions from autosomal dominant
A
Expression of defect tends to be more uniform than in autosomal dominant
Complete penetrance is common
Onset usually early in life
21
Q
T/F: for X-linked disorders, almost all are recessive
A
True
22
Q
In terms of X-linked disorders, sons of heterozygous women have ___% chance of inheritance
A
50
23
Q
Examples of X-linked recessive conditions
A
Fragile X syndrome DMD Hemophilia A and B CGD G6PD deficiency Agammaglobulinemia Wiskott aldrich syndrome Diabetes insipidus Lesch-nyhan syndrome
24
Q
Example of x-linked dominant disorder
A
Vitamin D-resistant rickets
25
Enzyme mutations may result in synthesis of an enzyme with reduced activity or a reduced amount of normal enzyme leading to 3 potential consequences:
- Accumulation of substrate
- Metabolic block and decreased amount of end product necessary for normal function
- Failure to inactivate a tissue-damaging substrate
What are 2 conditions in which accumulation of substrate is a problem?
Galactosemia (deficiency in GIP uridyltransferase)
Lysosomal storage diseases (deficiency in degradative enzymes)
26
Enzyme mutations may result in synthesis of an enzyme with reduced activity or a reduced amount of normal enzyme leading to 3 potential consequences:
- Accumulation of substrate
- Metabolic block and decreased amount of end product necessary for normal function
- Failure to inactivate a tissue-damaging substrate
What are 2 conditions in which metabolic block leads to decreased amount of end product necessary for normal function?
Albinism = lack of tyrosinase —> melanin deficiency
Lesch-Nyhan syndrome = deficiency of end product —> overproduction of intermediates that are injurious at high concentrations
27
Enzyme mutations may result in synthesis of an enzyme with reduced activity or a reduced amount of normal enzyme leading to 3 potential consequences:
- Accumulation of substrate
- Metabolic block and decreased amount of end product necessary for normal function
- Failure to inactivate a tissue-damaging substrate
What is an example of failure to inactivate a tissue-damaging substrate?
Alpha-1-antitrypsin deficiency = destruction of elastin in walls of lung alveoli d/t inability to inactivate neutrophil elastase —> emphysema
28
How do single-gene defects affect membrane receptors in terms of familial hypercholesterolemia?
Reduced synthesis of functional LDL receptors —> defective transport of LDL into cells —> excessive cholesterol synthesis
29
How do single-gene defects affect transport systems in cystic fibrosis?
Defective Cl- transport —> injury to lungs and pancreas
30
What happens when those with G6PD deficiency are given antimalarial drugs?
Severe hemolytic anemia
D/t single-gene defect leading to enzyme defiency that is unmasked after exposure to certain drugs
31
Etiology of Marfan syndrome
Usually autosomal dominant inherited defect in fibrillin, inhibiting polymerization of fibrillin fibers (dominant negative effect)
[missense mutation in FBN1 gene encoding fibrillin-1; found on Chr 15q.21.1]
32
2 fundamental mechanisms by which loss of fibrillin leads to clinical manifestations of Marfan syndrome
Loss of structural support in microfibril rich CT — fibrils provide a scaffolding on which tropoelastin is deposited to form elastic fibers; particularly abundant in the aorta, ligaments, and ciliary zonules of lens
Excessive activation of TGF-b signaling — normal microfibrils sequester TGF-b, can lead to deleterious effects on vascular smooth muscle development and increases activity of MMPs, leading to loss of ECM
33
Skeletal abnormalities in Marfan syndrome
Unusually tall with long extremities and long, tapering fingers and toes
Lax joint ligaments
Dolichocephalic with bossing of frontal eminences and prominent supraorbital ridges
Spinal deformities
Chest is classically deformed with either pectus excavatum or carinatum
34
Ocular changes with Marfan syndrome
Ectopia lentis - bilateral subluxation or dislocation of lens
35
Cardiovascular lesions are the most life threatening complications associated with Marfans. What are some examples?
Mitral valve prolapse
Dilation of asending aorta d/t cystic medionecrosis potentially leading to aortic dissection
36
Describe effect of valve lesions in Marfan syndrome
Valve lesions + lengthening of chordae tendinae lead to mitral regurg
37
Etiology of Ehlers-Danlos syndrome
Defect in synthesis or structure of fibrillar collagen
Mode of inheritance encompasses all 3 mendelian patterns
38
Describe classic type (I/II) of Ehlers-Danlos syndrome
Skin and joint hypermobility, atrophic scars, easy bruising; complications include diaphragmatic hernia
Autosomal dominant inheritance
Gene defects: COL5A1, COL5A2 —> abnormalities in type V collagen
39
Describe kyphoscoliosis type (VI) Ehlers-Danlos syndrome
Hypotonia, joint laxity, congenital scoliosis, ocular fragility; complications include rupture of cornea and retinal detachment
Autosomal recessive
Gene defects: lysyl hydroxylase (responsible for cross-linking so collagen lacks stability)
40
Describe vascular type (IV) Ehlers-Danlos syndrome
Thin skin, arterial or uterine rupture, bruising, small joint hyperextensibility; complications include rupture of colon and large arteries
Autosomal dominant
Gene defects: COL3A1 —> abnormalities in type III collagen (heterogenous effects)
41
Etiology of familial hypercholesterolemia
Mutation in gene encoding receptor for LDL which is involved in transport and metabolism of cholesterol
42
Why do people with familial hypercholesterolemia have increased synthesis of LDL?
Because IDL, the immediate precursor of plasma LDL, also uses hepatic LDL receptors (apoprotein B-100 and E) for its transport into the liver. Impaired transport of IDL secondarily diverts a greater proportion of plasma IDL into the precursor pool for plasma LDL
43
Familial hypercholesterolemia involves a marked increase in scavenger-receptor-mediated traffic of LDL cholesterol into the cells of the mononuclear phagocyte system and possibly the vascular walls. This increase is responsible for what 2 complications of familial hypercholesterolemia?
Xanthomas
| Premature atherosclerosis
44
Different classes of mutations leading to familial hypercholesterolemia
```
Class I = no synthesis
Class II = no transport
Class III = no binding
Class IV = no clustering
Class V = no recycling
```
45
Describe class I mutations leading to familial hypercholesterolemia
No synthesis
Relatively uncommon
Complete failure of synthesis of the receptor protein (null allele)
46
Describe class II mutations leading to familial hypercholesterolemia
No transport!
Fairly common
Encode receptor proteins that accumulate in the ER because their folding defects make it impossible for them to be transported to golgi
47
Describe class III mutations leading to familial hypercholesterolemia
No binding!
Affect LDL binding domain of receptor
Encoded proteins reach the cell surface but fail to bind LDL (or do so poorly)
48
Describe class IV mutations leading to familial hypercholesterolemia
No clustering!
Encode proteins that are synthesized and transported to cell surface efficiently and bind LDL normally but fail to localize in coated pits, so LDL is not internalized
49
Describe class V mutations leading to familial hypercholesterolemia
No recycling!
Encode proteins that are expressed on cell surface, can bind LDL, and can be internalized, but pH-dependent dissociation of receptor and bound LDL fails
Such receptors are trapped in the endosome where they are degraded (not recycled)
50
Types of lysosomal storage diseases
```
Glycogenoses
Sphingolipidoses
Sulfatidoses
Mucopolysaccharidoses
Mucolipidoses
Fucosidoses
Mannosidoses
Aspartylglycosaminuria
Wolman disease
Acid phosphate deficiency
```
51
Enzyme defect in Tay Sachs disease
Mutations in alpha subunit locus on Chr15 causing severe deficiency of hexosaminidase A
[most affect protein folding, but over 100 mutations have been identified; triggers unfolded protein response leading to apoptosis]
52
Clinical presentation of Tay Sachs
Especially prevalent among Ashkenazic jews
Affected infants appear normal at birth but begin to manifest symptoms at 6 months
Relentless motor and mental deterioration, beginning with motor incoordination, mental obtundation leading to muscular flaccidity, blindness, and increasing dementia
Cherry-red spot in macula
Complete vegetative state reached within 1-2 years followed by death at age 2-3
53
Morphologic findings of Tay Sachs
GM2 gangliosides accumulate primarily in neurons of central and autonomic nervous systems as well as retina (also heart, liver, and spleen)
Cytoplasmic inclusions with whorled configurations
Cherry red spot on macula
54
Enzyme defect in types A and B of Niemann Pick disease and its genetic basis
Deficient sphingomyelinase
Sphingomyelinase = Chr11p15.4 — one of the imprinted genes that is preferentially expressed from mom’s chromosomes as a result of epigenetic silencing of paternal gene
Typically autosomal recessive inheritance
55
Defect in Type C Niemann Pick disease (most common)
Mutations in NPC1 and NPC2 d/t primary defect in nonenzymatic lipid transport. NPC1 is membrane bound while NPC is soluble; both are involved in transport of free cholesterol from lysosomes to cytoplasm
56
Clinical presentation of Type A Niemann Pick
Severe infantile form with extensive neurologic involvement, marked visceral accumulations of sphingomyelin, and progressive wasting
Infants have protruberant abdomen and HSM, followed by progressive FTT, vomiting, fever, generalized lymphadenopathy and progressive deterioration of psychomotor function
Early death within 3 years
Most common in Ashkenazi jews
57
Clinical presentation of Type B Niemann Pick
Patients have organomegaly but generally no CNS involvement
Usually survive into adulthood
Most common in Ashkenazi jews
58
Clinical presentation of Type C Niemann Pick
Clinically heterogenous
May present as hydrops fetalis, stillbirth, or neonatal hepatitis
MOST COMMONLY presents as chronic form with progressive neurological damage
Presents in childhood; marked by ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, and psychomotor regression
59
Morphologic findings in Niemann Pick disease
Sphingomyelin accumulation in lysosomes of mononuclear phagocyte system
Cells become enlarged, cytoplasm foamy, vacuoles appear as zebra bodies on electron micro — affects spleen, liver, LNs, bone marrow, tonsils, GI tract, lungs (spleen tends to be massively enlarged)
In the brain gyri are shrunken and sulci widened, retinal cherry red spot similar to Tay Sachs in 1/3 to 1/2 of patients
60
Enzyme defect in Gaucher disease (most common lysosomal storage disorder)
Cluster of autosomal recessive disorders d/t mutations in gene encoding glucocerebrosidase
[typically responsible for cleaving glucose residue from ceramide; when defective - glucocerebroside accumulates principally in phagocytes and some in CNS. Disease is d/t burden of storage material AND inflammatory cytokine release]
61
Clinical presentation of Type I Gaucher disease (most common form)
Chronic non-neuropathic form, reduced but still some enzymatic activity
Storage of glucocerebrosides is limited to mononuclear phagocytes throughout the body without involving the brain
S/s appear in adult life, dominated by splenic and skeletal involvement (pancytopenia+thrombocytopenia d/t hypersplenism; bone erosion d/t presence of gaucher cells)
Found principally in european jews
62
Clinical presentation of Type II Gaucher disease
Acute neuropathic form - infantile acute cerebral pattern, virtually no enzyme activity
NO predilection for jews in this form
Som HSM, bubt clinically dominated by progressive CNS involvement —> early death
CNS dysfunction, convulsions, and progressive mental deterioration + organ involvement (liver, spleen, LNs)
63
Clinical presentation of type III gaucher disease
Intermediate between types I and II
Systemic involvement similar to type I + progressive CNS disease beginning at young age
CNS dysfunction, convulsions, progressive mental deterioration + organ involvement (liver, spleen, LNs)
64
Morphologic findings in Gaucher disease
Distended phagocytic cells (Gaucher cells) found in spleen, liver, bone marrow, LNs, tonsils, thymus, Peyer patches, possibly in alveolar septa and lung spaces
Fibrillary type cytoplasm (crumpled tissue paper) that can be resolved as elongated, distended lysosomes containing stored lipid
Gaucher cells may appear in Virchow Robin spaces
65
Enzyme defect in mucopolysaccharidoses
Deficiencies of enzymes involved in degradation of mucopolysaccharides (glycosaminoglycans such as dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate)
66
All mucopolysaccharidoses are autosomal recessive except which one?
Hunter syndrome is X-linked recessive
67
General clinical presentation of mucopolysaccharidoses
Progressive, characterized by coarse facial features, clouding of the cornea, joint stiffness, and mental retardation
Urinary excretion of accumulated MPSs is often increased
68
Mucopolysaccharidosis characterized by deficiency of alpha-1-iduronidase causing one of the most severe types. Affected children appear normal at birth but develop the disease by 6-24 months. Growth retardation, coarse facial features, skeletal deformities followed by death at age 6-10, often d/t cardiovascular complications
Hurler syndrome (MPS I-H)
69
Mucopolysaccharidosis characterized by a milder clinical course than Hurler syndrome without corneal clouding
Hunter syndrome
70
Morphologic findings of mucopolysaccharidoses
Accumulated mucopolysaccharides typically found in mononuclear phagocytic cells, endothelial cells, intimal smooth muscle cells, and fibroblasts
Common sites of involvement = spleen, liver, bone marrow, LNs, blood vessels, heart
Some lysosomes replaced by lamellated zebra bodies similar to NP disease
HSM, skeletal deformity, valvular lesions, subendothelial arterial deposits, particularly in coronary arteries and lesions in the brain
71
Enzyme defect in Von Gierke disease vs. McArdle disease
Von Gierke disease (hepatic type) = G6P deficiency —> low BG
McArdle disease (myopathic type) = Muscle phosphorylase deficiency —> low energy
72
Enzyme defect and clinical presentation of Pompe disease type II
Lysosomal glucosidase (acid maltase) deficiency
Massive cardiomegaly, muscle hypotonia, cardiorespiratory failure within 2 years
Milder adult form only has skeletal muscle involvement - presents w/ chronic myopathy
73
Clinical presentation of Von Gierke disease
FTT, stunted growth, hepatomegaly, renomegaly
Hypoglycemia
Hyperlipidemia, hyperuricemia —> gout and skin xanthomas
Bleeding tendency d/t platelet dysfunction
74
Clinical presentation of McArdle disease
Painful cramps associated with strenuous exercise
Myoglobinuria in 50% of cases
Onset in adulthood (~20 years) and compatible with normal longevity
Muscular exercise fails to raise lactate level in venous blood
Serum creatine kinase always elevated
75
Morphologic findings in Von Gierke vs. McArdle disease
VG: hepatomegaly with intracytoplasmic accumulations of glycogen and small amounts of lipid; intranuclear glycogen; renomegaly with intracytoplasmic accumulations of glycogen in cortical tubular epithelial cells
McArdle: skeletal muscle accumulations of glycogen - predominant in subsarcolemmal location
76
Morphologic findings in pompe disease
Mild hepatomegaly - ballooning of lysosomes with glycogen, creating lacy cytoplasm
Cardiomegaly - glycogen within sarcoplasm as well as membrane bound
Skeletal muscle with changes similar to heart
77
2 usual causes of aneuploidy
Nondisjunction — gametes have either extra chromosomes (n+1) or one less (n-1), resulting in trisomic (2n+1) or monosomic (2n-1) zygotes if fertilization occurs
Anaphase lag — one homologous chromosome in meiosis or one chromatid in mitosis lags behind and is left out of the cell nucleus —> one normal cell + one cell with monosomy
78
Mitotic errors in early development give rise to 2+ populations of cells with different chromosomal complement in same individual
Can result form mitotic errors during cleavage of fertilized ovum or in somatic cells
Mosaicism
[most commonly occurs in sex chromosomes —> Turner’s syndrome, can be viable in autosomal mosaics with Down syndrome]
79
Difference between chromosomal deletion, ring chromosome, and isochromosome
Chromosomal deletion = refers to loss of portion of a chromosome — most are interstitial
Ring chromosome = form of deletion produced when break occurs at both ends —> fusion
Isochromosome = one arm is lost and remaining arm is duplicated
80
Difference between interstitial and terminal chromosomal deletions
Interstitial = occur when there are 2 breaks within a chromosome arm, followed by loss of chromosomal material between the breaks and fusion of broken ends
Terminal = result from single break in chromosome arm, producing fragment with no centromere which will be lost at next cell division
81
Reciprocal translocation vs. Robertsonian translocation
Reciprocal = single breaks in each of 2 chromosomes, with exchange of material; no loss of genetic material, so individual is likely phenotypically normal but at increased risk for producing abnormal gametes
Robertsonian = translocation between 2 acrocentric chromosomes; breaks typically occur close to centromeres; transfer of segments then leads to one very large chromosome and one extremely small one. Small product is usually lost but contained redundant genes so phenotype is normal
82
Incidence of trisomy 21
1/700 newborns in the US
Occurs in 1/1550 live births in women under age 20, in contrast to 1/25 live births for moms 45+, suggesting that meiotic nondisjunction of Chr21 occurs in ovum
83
Trisomy 21 associated karyotypes
Trisomy 21 type = 47,XX + 21
Translocation type = 46,XX, der(14;21)(q10)(q10), +21
Mosaic type = 46,XX/47,XX+21
84
Diagnostic clinical features for trisomy 21
Flat facial profile, oblique palpebral fissures, epicanthic folds
Most have IQ 25-50
40% have congenital heart disease (ostium primum, atrial septal defects, AV valve malformations, ventricular septal defects); may also have atresias of esophagus and small bowel
Increased risk for acute leukemia; past age 40 will develop neuropathologic changes similar to Alzheimer disease
Abnormal immune responses predispose to infection, particularly lungs and thyroid autoimmunity
85
Compare trisomy 13 and 18 clinically
Trisomy 13 = Patau syndrome:
Microcephaly, mental retardation, cleft lip and palate, microphthalmia, polydactyly, rocker bottom feet, cardiac defects, umbilical hernia, renal defects
Trisomy 18 = Edwards syndrome:
Prominent occiput, low set ears, short neck, micrognathia, mental retardation, overlapping fingers, rocker bottom feet, congenital heart defects, renal malformations, limited hip abduction
86
Chromosomal anomaly in DiGeorge syndrome/velocardial facial syndrome
Chromosome 22q11.2 deletion
One region affected is gene TBX1 expressed in pharyngeal mesenchyme and endodermal pouch from which facial structures, thymus, and parathyroid are derived
87
Clinical presentation/features in DiGeorge syndrome and velocardiofacial syndrome
DiGeorge:
Thymic hypoplasia — T cell immunodeficiency, parathyroid hypoplasia — hypocalcemia, cardiac malformations affecting outflow tract, mild facial anomalies
```
Velocardiofacial syndrome:
Facial dysmorphism (prominent nose, retrognathia), cleft palate, cardiovascular anomalies, learning disabilities, may also have immune deficiency
```
Both conditions carry higher risk for psychiatric disorders like schizophrenia, bipolar, ADHD
88
Lyon hypothesis
1. Only one of the X chromosomes is genetically active
2. The other X undergoes heteropyknosis and is rendered inactive
3. Inactivation of either X occurs at random among all cells of blastocyst around day 5.5 of embryonic life
4. Inactivation of the same X chromosome persists in all cells derived from each precursor cell
89
Incidence of Klinefelter syndrome
1/660 live male births
90
Karyotype of klinefelter syndrome
Classic pattern = 47,XXY d/t nondisjunction at first meiotic division
91
Clinical features of Klinefelter syndrome
Male hypogonadism is only consistent finding
Eunuchoid body with abnormally long legs, small atrophic testes with small penis, lack of deep voice/beard/and male distribution of pubic hair, gynecomastia, increased incidence of T2DM, mitral valve prolapse in 50%, increased risk of osteoporosis, breast cancer, extragonadal germ cell tumors, and autoimmune diseases like SLE
92
Karyotypic abnormalities associated with Turner’s syndrome
Approximately 57% are missing an entire X chromosome = 45,X
Most are mosaics because 45,X is thought to be inviable
93
Clinical features of Turner syndrome
Primarily hypogonadism on phenotypic females
Presents with peripheral lymphedema at birth
Short stature, webbing of neck, cubitus valgus, cardiovascular malformation, amenorrhea, lack of secondary sex characteristics, and fibrotic ovaries (streak ovaries)
Most important cause of increased mortality = cardiac abnormalities
94
Single most important cause of primary amenorrhea
Turner syndrome
95
Hermaphrodite vs. pseudohermaphrodite
Hermaphrodite = presence of both ovarian and testicular tissue
Pseudohermaphrodite = disagreement between phenotypic and gonadal sex
[female PH has ovaries but male external genitalia and vice versa]
96
Nucleotides involved in trinucleotide repeats
Causative mutations are associated with expansion of stretch of nucleotides that usually share nucleotides G and C
Usually CAG repeats —> polyglutamine diseases
97
Diseases associated with trinucleotide-repeat expansions in noncoding regions
Fragile X syndrome (CGG triplet —> transcriptional silencing —> LoF)
Friedrich Ataxia (GAA triplet —> transcriptional silencing —> LoF)
Myotonic dystrophy
98
Disorders associated with trinucleotide repeats in coding regions
Spinobulbar musclar atrophy (Kennedy disease)
Huntington disease (CAG triplet —> polyglutamine expansions with misfolding —> GoF)
Dentatorubral-pallidoluysian atrophy (Haw River syndrome)
Spinocerebellar ataxia types 1, 2, 3, 6, and 7
99
Morphologic hallmark of trinucleotide repeats
Accumulation of aggregated mutant proteins in large intranuclear inclusions — may be protective d/t sequestration of misfolded proteins
100
Clinical features of fragile X syndrome
Mental retardation with IQ 20-60
Characteristic phenotype w/ long face, large mandible, large everted ears, large testicles (macroorchidism is most distinctive feature!)
Also hyperextensible joints, high arched palate, mitral valve prolapse
101
Affected gene and protein in fragile X syndrome
Trinucleotide mutation in familial mental retardation-1 gene (FMR1) on Xq27.3
Multiple tandem repeats of CGG, amplification occurs in females (oogenesis)
Loss of function of familial mental retardation protein (FMRP) — widely expressed cytoplasmic protein most abundant in brain and testis — FMRP is a translation regulator at the synaptic junction
102
For fragile X syndrome, discuss concept of anticipation
Refers to observation that clinical features of fragile X worsen with each successive generation, as if mutation becomes increasingly deleterious as it is transmitted from generation to generation
Occurs d/t amplification to full mutation in females during oogenesis
103
Differentiate fragile X tremor/ataxia from fragile X syndrome
Fragile X tremor/ataxia is a GAIN of function (not LoF like fragile X syndrome) in CGG repeats so that they continue to be transcribed
In males leads to progressive neurodegenerative syndrome starting in 6th decade
Characterized by intention tremors and cerebellar ataxia; may progress to Parkinsonism
104
Best molecular diagnosis technique for fragile X syndrome
Southern blotting — determines if gene has a full mutation, its approximate size, whether the gene has been methylated, and if there is mosaicism
105
For mutations in mitochondrial genes, discuss “threshold effect” as it applies to heteroplasmy
Heteroplasmy = cells have both wild-type and mutant mtDNA because mutation only affects some
A minimum number of mutant mtDNA must be present before oxidative dysfunction leads to disease
106
Discuss concept of genomic imprinting
Epigenetic process that results in functional differences between paternal and maternal alleles
In most cases, selectively inactivates either maternal or paternal allele
Occurs in ovum or sperm before fertilization, then is stably transmitted to all somatic cells via mitosis
Loss of functional (nonimprinted) allele leads to diseases like PW and Angelman
107
Compare/contrast genomic defect in Prader-Willi vs. Angelman syndromes
Prader-willi = deletion affects paternally derived chromosome 15; no single gene has been implicated (possibly SNORP)
Angelman = deletion affects maternally derived chromosome 15; affected gene is ubiquitin ligase = UBE35A
108
Clinical manifestations of Prader-Willi vs. Angelman syndrome
PW = mental retardation, short stature, hypotonia, profound hyperphagia, obesity, small hands and feet, hypogonadism
Angelman = mental retardation, ataxic gait, seizures, inappropriate laughter
109
Define uniparental disomy and its net effect
Inheritance of both chromosomes of a pair from one parent
Net effect = person does not have functional set of genes from [nonimprinted] chromosome
110
Indications for prenatal cytogenetic analysis
Advanced maternal age
Parent known to carry balanced chromosomal rearrangement
Fetal anomalies observed on US
Maternal blood screening indicating increased risk of Down syndrome or other trisomy
111
Indications for newborn/childhood cytogenetic testing
Multiple congenital anomalies
Suspicion of metabolic syndrome
Unexplained mental retardation and/or developmental delay
Suspected aneuploidy or other syndromic chromosomal abnormality
112
Indications for cytogenetic analysis in older patients
Inherited cancer syndromes
Atypically mild monogenic disease (e.g. attenuated CF)
Neurodegenerative disorders
113
Contribution of genetic analysis toward diagnosis and management of cancer
Detection of tumor specific acquired mutations and cytogenetic alteration that are hallmarks of specific tumors
Determination of clonality as an indicator of neoplastic condition
Identification of specific genetic alterations that can direct therapeutic choices
Determination of treatment efficacy
Detection of drug-resistant secondary mutations in malignancies treated with genetically tailored therapies
114
Contribution of genetic analysis toward diagnosis and management of infectious disease
Detection of microorganism specific genetic material for definitive diagnosis
Identification of specific genetic alterations in genomes of microbes that are associated with drug resistance
Determinations of treatment efficacy
115
Clinical utility of PCR
Detection of oncogenic mutation at codon 600 of BRAF gene
Fragile X syndrome (may be better diagnosed by southern blot)
BCR-ABL changes in chronic myelogenous leukemia
116
Clinical utility of FISH
Tx of patients with acute myeloid leukemia with retinoic acid
Detection of aneuploidy, subtle microdeletions, or complex translocations such as HER2 in breast cancer or NMYC in neuroblastoma
117
Clinical utility of MLPA
Detect CFTR changes in CF
118
Clinical utility of SNP genotyping arrays
Copy number abnormality detection in pediatric patients when karyotype is normal but structural abnormality is still suspected
Common indications = congenital abnormalities, dysmorphic features, developmental delay, autism
Also useful in cases of mosaicism
Example: high hyperdiploid childhood acute lymphoblastic leukemia
119
Clinical utility of polymorphic markers using PCR
PDK1 gene in adult polycystic kidney disease
Also used for paternity, forensics, transplant chimerism in allogeneic hematopoeitic stem cell transplant patients
120
Clinical utility of RNA analysis
RNA viruses such as HIV and hep C
Molecular stratification of tumors
121
Clinical utility of next generation sequencing
CFTR
Kids with cardiomyopathy or congenital deafness, cancer
Oncology, mendelian disorders of orphans
122
Example of non-conservative missense mutation
Sickle cell mutation: CTC —> GUG
Glutamic acid —> valine
123
Example of nonsense mutation
Beta-thalassemia: CAG —> UAG
Glutamine to STOP
124
Gain of function mutations are almost always autosomal dominant. _______ disease occurs when trinucleotide repeat gives rise to abnormal protein called ____that is neurotoxic; even heterozygotes develop a neurologic deficit
Huntington; huntingtin
125
What clinical sign is so uncommon in persons without Marfan syndrome that it’s presence is nearly diagnostic?
Ectopia lentis — bilateral subluxation or dislocation (outward and upward)
126
The classic type of ehlers danlos syndrome can come from mutations in other genes not related to collagen synthesis, but the synthesis of other proteins that impact collagen later on. This is the case with EDS-like condition caused by mutation of _______ that affects synthesis and fibril formation of types VI and I collagen
Tenascin-X
127
Periodic-Schiff (PAS) staining is intensely positive in what disease morphology?
Gaucher disease
128
Patients severely affected with this disease are born with edema of the dorsum of the hand and foot due to lymph stasis. There may also be swelling of the nape of the neck (cystic hygroma). The swellings subside but often leave bilateral neck webbing and persistent looseness of the skin on the back of the neck
Turner syndrome
129
Neurodegenerative disease that manifests as a progressive bilateral loss of central vision, eventually leading to blindness
LHON (maternally derived)
