Chapter 5 Flashcards Preview

MOD I Exam II > Chapter 5 > Flashcards

Flashcards in Chapter 5 Deck (129)
Loading 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
  1. 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)
  2. 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
Q

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?

A

Galactosemia (deficiency in GIP uridyltransferase)

Lysosomal storage diseases (deficiency in degradative enzymes)

26
Q

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?

A

Albinism = lack of tyrosinase —> melanin deficiency

Lesch-Nyhan syndrome = deficiency of end product —> overproduction of intermediates that are injurious at high concentrations

27
Q

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?

A

Alpha-1-antitrypsin deficiency = destruction of elastin in walls of lung alveoli d/t inability to inactivate neutrophil elastase —> emphysema

28
Q

How do single-gene defects affect membrane receptors in terms of familial hypercholesterolemia?

A

Reduced synthesis of functional LDL receptors —> defective transport of LDL into cells —> excessive cholesterol synthesis

29
Q

How do single-gene defects affect transport systems in cystic fibrosis?

A

Defective Cl- transport —> injury to lungs and pancreas

30
Q

What happens when those with G6PD deficiency are given antimalarial drugs?

A

Severe hemolytic anemia

D/t single-gene defect leading to enzyme defiency that is unmasked after exposure to certain drugs

31
Q

Etiology of Marfan syndrome

A

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
Q

2 fundamental mechanisms by which loss of fibrillin leads to clinical manifestations of Marfan syndrome

A

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
Q

Skeletal abnormalities in Marfan syndrome

A

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
Q

Ocular changes with Marfan syndrome

A

Ectopia lentis - bilateral subluxation or dislocation of lens

35
Q

Cardiovascular lesions are the most life threatening complications associated with Marfans. What are some examples?

A

Mitral valve prolapse

Dilation of asending aorta d/t cystic medionecrosis potentially leading to aortic dissection

36
Q

Describe effect of valve lesions in Marfan syndrome

A

Valve lesions + lengthening of chordae tendinae lead to mitral regurg

37
Q

Etiology of Ehlers-Danlos syndrome

A

Defect in synthesis or structure of fibrillar collagen

Mode of inheritance encompasses all 3 mendelian patterns

38
Q

Describe classic type (I/II) of Ehlers-Danlos syndrome

A

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
Q

Describe kyphoscoliosis type (VI) Ehlers-Danlos syndrome

A

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
Q

Describe vascular type (IV) Ehlers-Danlos syndrome

A

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
Q

Etiology of familial hypercholesterolemia

A

Mutation in gene encoding receptor for LDL which is involved in transport and metabolism of cholesterol

42
Q

Why do people with familial hypercholesterolemia have increased synthesis of LDL?

A

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
Q

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?

A

Xanthomas

Premature atherosclerosis

44
Q

Different classes of mutations leading to familial hypercholesterolemia

A
Class I = no synthesis
Class II = no transport
Class III = no binding
Class IV = no clustering
Class V = no recycling
45
Q

Describe class I mutations leading to familial hypercholesterolemia

A

No synthesis

Relatively uncommon

Complete failure of synthesis of the receptor protein (null allele)

46
Q

Describe class II mutations leading to familial hypercholesterolemia

A

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
Q

Describe class III mutations leading to familial hypercholesterolemia

A

No binding!

Affect LDL binding domain of receptor

Encoded proteins reach the cell surface but fail to bind LDL (or do so poorly)

48
Q

Describe class IV mutations leading to familial hypercholesterolemia

A

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
Q

Describe class V mutations leading to familial hypercholesterolemia

A

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
Q

Types of lysosomal storage diseases

A
Glycogenoses
Sphingolipidoses
Sulfatidoses
Mucopolysaccharidoses
Mucolipidoses
Fucosidoses
Mannosidoses
Aspartylglycosaminuria
Wolman disease
Acid phosphate deficiency
51
Q

Enzyme defect in Tay Sachs disease

A

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
Q

Clinical presentation of Tay Sachs

A

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
Q

Morphologic findings of Tay Sachs

A

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
Q

Enzyme defect in types A and B of Niemann Pick disease and its genetic basis

A

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
Q

Defect in Type C Niemann Pick disease (most common)

A

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
Q

Clinical presentation of Type A Niemann Pick

A

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
Q

Clinical presentation of Type B Niemann Pick

A

Patients have organomegaly but generally no CNS involvement

Usually survive into adulthood

Most common in Ashkenazi jews

58
Q

Clinical presentation of Type C Niemann Pick

A

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
Q

Morphologic findings in Niemann Pick disease

A

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
Q

Enzyme defect in Gaucher disease (most common lysosomal storage disorder)

A

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
Q

Clinical presentation of Type I Gaucher disease (most common form)

A

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
Q

Clinical presentation of Type II Gaucher disease

A

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
Q

Clinical presentation of type III gaucher disease

A

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
Q

Morphologic findings in Gaucher disease

A

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
Q

Enzyme defect in mucopolysaccharidoses

A

Deficiencies of enzymes involved in degradation of mucopolysaccharides (glycosaminoglycans such as dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate)

66
Q

All mucopolysaccharidoses are autosomal recessive except which one?

A

Hunter syndrome is X-linked recessive

67
Q

General clinical presentation of mucopolysaccharidoses

A

Progressive, characterized by coarse facial features, clouding of the cornea, joint stiffness, and mental retardation

Urinary excretion of accumulated MPSs is often increased

68
Q

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

A

Hurler syndrome (MPS I-H)

69
Q

Mucopolysaccharidosis characterized by a milder clinical course than Hurler syndrome without corneal clouding

A

Hunter syndrome

70
Q

Morphologic findings of mucopolysaccharidoses

A

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
Q

Enzyme defect in Von Gierke disease vs. McArdle disease

A

Von Gierke disease (hepatic type) = G6P deficiency —> low BG

McArdle disease (myopathic type) = Muscle phosphorylase deficiency —> low energy

72
Q

Enzyme defect and clinical presentation of Pompe disease type II

A

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
Q

Clinical presentation of Von Gierke disease

A

FTT, stunted growth, hepatomegaly, renomegaly

Hypoglycemia

Hyperlipidemia, hyperuricemia —> gout and skin xanthomas

Bleeding tendency d/t platelet dysfunction

74
Q

Clinical presentation of McArdle disease

A

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
Q

Morphologic findings in Von Gierke vs. McArdle disease

A

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
Q

Morphologic findings in pompe disease

A

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
Q

2 usual causes of aneuploidy

A

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
Q

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

A

Mosaicism

[most commonly occurs in sex chromosomes —> Turner’s syndrome, can be viable in autosomal mosaics with Down syndrome]

79
Q

Difference between chromosomal deletion, ring chromosome, and isochromosome

A

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
Q

Difference between interstitial and terminal chromosomal deletions

A

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
Q

Reciprocal translocation vs. Robertsonian translocation

A

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
Q

Incidence of trisomy 21

A

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
Q

Trisomy 21 associated karyotypes

A

Trisomy 21 type = 47,XX + 21

Translocation type = 46,XX, der(14;21)(q10)(q10), +21

Mosaic type = 46,XX/47,XX+21

84
Q

Diagnostic clinical features for trisomy 21

A

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
Q

Compare trisomy 13 and 18 clinically

A

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
Q

Chromosomal anomaly in DiGeorge syndrome/velocardial facial syndrome

A

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
Q

Clinical presentation/features in DiGeorge syndrome and velocardiofacial syndrome

A

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
Q

Lyon hypothesis

A
  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
Q

Incidence of Klinefelter syndrome

A

1/660 live male births

90
Q

Karyotype of klinefelter syndrome

A

Classic pattern = 47,XXY d/t nondisjunction at first meiotic division

91
Q

Clinical features of Klinefelter syndrome

A

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
Q

Karyotypic abnormalities associated with Turner’s syndrome

A

Approximately 57% are missing an entire X chromosome = 45,X

Most are mosaics because 45,X is thought to be inviable

93
Q

Clinical features of Turner syndrome

A

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
Q

Single most important cause of primary amenorrhea

A

Turner syndrome

95
Q

Hermaphrodite vs. pseudohermaphrodite

A

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
Q

Nucleotides involved in trinucleotide repeats

A

Causative mutations are associated with expansion of stretch of nucleotides that usually share nucleotides G and C

Usually CAG repeats —> polyglutamine diseases

97
Q

Diseases associated with trinucleotide-repeat expansions in noncoding regions

A

Fragile X syndrome (CGG triplet —> transcriptional silencing —> LoF)

Friedrich Ataxia (GAA triplet —> transcriptional silencing —> LoF)

Myotonic dystrophy

98
Q

Disorders associated with trinucleotide repeats in coding regions

A

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
Q

Morphologic hallmark of trinucleotide repeats

A

Accumulation of aggregated mutant proteins in large intranuclear inclusions — may be protective d/t sequestration of misfolded proteins

100
Q

Clinical features of fragile X syndrome

A

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
Q

Affected gene and protein in fragile X syndrome

A

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
Q

For fragile X syndrome, discuss concept of anticipation

A

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
Q

Differentiate fragile X tremor/ataxia from fragile X syndrome

A

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
Q

Best molecular diagnosis technique for fragile X syndrome

A

Southern blotting — determines if gene has a full mutation, its approximate size, whether the gene has been methylated, and if there is mosaicism

105
Q

For mutations in mitochondrial genes, discuss “threshold effect” as it applies to heteroplasmy

A

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
Q

Discuss concept of genomic imprinting

A

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
Q

Compare/contrast genomic defect in Prader-Willi vs. Angelman syndromes

A

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
Q

Clinical manifestations of Prader-Willi vs. Angelman syndrome

A

PW = mental retardation, short stature, hypotonia, profound hyperphagia, obesity, small hands and feet, hypogonadism

Angelman = mental retardation, ataxic gait, seizures, inappropriate laughter

109
Q

Define uniparental disomy and its net effect

A

Inheritance of both chromosomes of a pair from one parent

Net effect = person does not have functional set of genes from [nonimprinted] chromosome

110
Q

Indications for prenatal cytogenetic analysis

A

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
Q

Indications for newborn/childhood cytogenetic testing

A

Multiple congenital anomalies

Suspicion of metabolic syndrome

Unexplained mental retardation and/or developmental delay

Suspected aneuploidy or other syndromic chromosomal abnormality

112
Q

Indications for cytogenetic analysis in older patients

A

Inherited cancer syndromes

Atypically mild monogenic disease (e.g. attenuated CF)

Neurodegenerative disorders

113
Q

Contribution of genetic analysis toward diagnosis and management of cancer

A

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
Q

Contribution of genetic analysis toward diagnosis and management of infectious disease

A

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
Q

Clinical utility of PCR

A

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
Q

Clinical utility of FISH

A

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
Q

Clinical utility of MLPA

A

Detect CFTR changes in CF

118
Q

Clinical utility of SNP genotyping arrays

A

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
Q

Clinical utility of polymorphic markers using PCR

A

PDK1 gene in adult polycystic kidney disease

Also used for paternity, forensics, transplant chimerism in allogeneic hematopoeitic stem cell transplant patients

120
Q

Clinical utility of RNA analysis

A

RNA viruses such as HIV and hep C

Molecular stratification of tumors

121
Q

Clinical utility of next generation sequencing

A

CFTR

Kids with cardiomyopathy or congenital deafness, cancer

Oncology, mendelian disorders of orphans

122
Q

Example of non-conservative missense mutation

A

Sickle cell mutation: CTC —> GUG

Glutamic acid —> valine

123
Q

Example of nonsense mutation

A

Beta-thalassemia: CAG —> UAG

Glutamine to STOP

124
Q

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

A

Huntington; huntingtin

125
Q

What clinical sign is so uncommon in persons without Marfan syndrome that it’s presence is nearly diagnostic?

A

Ectopia lentis — bilateral subluxation or dislocation (outward and upward)

126
Q

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

A

Tenascin-X

127
Q

Periodic-Schiff (PAS) staining is intensely positive in what disease morphology?

A

Gaucher disease

128
Q

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

A

Turner syndrome

129
Q

Neurodegenerative disease that manifests as a progressive bilateral loss of central vision, eventually leading to blindness

A

LHON (maternally derived)