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CH5 Flashcards

1
Q

Three categories of human genetic disorders are?

A

1) Disorders related to mutations in single genes with large effects: rare, Mendelian disorders, high penetrance
2) Chromosomal disorders: rare, high penetrance
3) Complex multigenic disorders: very common, polymorphisms (several must be present to create dx), multifactorial d/t environment component

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2
Q

What is a mutation?

A

Permanent change in the DNA

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3
Q

What is a point mutation? What is a nonsense mutation?

A

Change of a single base, a substitution, that changes the meaning of a DNA sequence (missense mutation)

Conservative (little change in function) vs non-conservative (normal AA replaced with biochemically different one)

A point mutation in which a stop codon is created

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4
Q

Are mutations in noncoding sequences in exons or introns?

A

Introns

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5
Q

What DNA alterations is a frameshift mutation associated with? When is this mutation UNLIKELY to be harmful?

A

Deletions or insertions

When the insertion or deletion involves 3 or multiples of three keeping the reading frame intact

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6
Q

What mutation deals with amplified sequences of three nucleotides? What nucleotides are highlighted?

A

Trinucleotide-repeat mutation

Guanine (G) and cytosine (C)

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7
Q

In sickle cell anemia, what are the names or normal and abnormal hemoglobin?

A

Normal = HbA

Abnormal (sickle) = HbS

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8
Q

What is codominance? What’s an example?

A

When both alleles of a gene pair contribute to the phenotype

A person’s blood type

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9
Q

A single mutant gene may lead to many end effects. What’s this called? Many mutant genes may converge on one trait. What’s this called? Give examples.

A

Pleiotropism (sickle cell anemia)

Genetic heterogeneity (deafness, diabetes)

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10
Q

Mutations of single genes follow what 3 patterns of inheritance?

A

Autosomal dominant, autosomal recessive, X-linked

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11
Q

Define incomplete penetrance. Define variable expressivity. What are these mechanisms likely affected by?

A

Represented mathematically as a mutant gene that has a % chance of expressing as a normal vs mutant phenotype

A different expression among individuals of the same mutant gene

Environmental actors

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12
Q

What does dominant negative, in reference to a mutant allele, mean? What’s an example?

A

A mutant allele that impairs the function of a normal allele

Collagen (trimer, if one monomer has a mutation the whole complex doesn’t form)

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13
Q

What are the results of gain-of-function mutations?

A

Upregulation of protein activity

Acquired is a wholly new activity unrelated to protein’s normal function

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14
Q

What is a consanguineous marriage? What is this pertinent to?

A

Marriage between two people who are related as second cousins or closer.

Autosomal Recessive Disorders regarding low-frequency mutant genes

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15
Q

What features apply to autosomal recessive disorders, distinguishing them from autosomal dominant disorders?

A

Defect expression is more uniform
Complete penetrance common
Onset usually early in life
New mutations associated with recessive disorders occur but rarely present clinically
Many of the mutations pertain to enzymes (heterozygotes produce equal amounts of normal and defective enzymes
Include most of inborn metabolism errors

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16
Q

All sex-linked disorders are what?

A

X-linked and almost all recessive

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17
Q

Are the Y and X chromosomes homologous/have corresponding alleles?

A

No

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18
Q

What’s responsible for lysosomal storage dx’s?

A

Excessive accumulation of substrates within lysosomes as a result of deficiency in pertinent degradative enzymes

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19
Q

What enzyme may be defective an albanism?

A

Tyrosinase

Converts tyrosine to melanin in melanocytes

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20
Q

What are two dx that result in defects of transport systems?

A

Familial hypercholesterolemia (LDL R)

Cystic fibrosis (CL- R)

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21
Q

What’s the difference between hemoglobinopathies and thalassemias?

A

Hemoglobinopathies result from defective proteins and defective globin

Thalassemias result from defect in amount of globin proteins available

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22
Q

What is pharmicogenetics?

A

The study of genetic polymorphisms that lead to adverse affects from drugs

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23
Q

What is Marfan syndrome? What is its most striking feature What glycoprotein is involved/lost? What are the two mechanisms of this dx?

A

Disorder of connective tissues that manifests as changes in the skeleton, eyes, and cardiovascular system

Skeletal abnormalities (pectus excavatum, long extremeties, spinal deformities)

Fibrillin-1

1) Loss of structural support in microfibril (ECM component) rich connective tissue
2) Excessive activation of TGF-B

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24
Q

What are the homologous forms of fibrillin and what are their associated genes? Which is associated with Marfan syndrome?

A

Fibrillin-1, FBN1, associated with Marfan syndrome

Fibrillin-2, FBN2, congenital contractural arachnodactylyl

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25
Q

What do microfibrils sequester? If this ability is lost, what occurs?

A

TGF-B

Marfan syndrome d/t excessive TGF-B and thus metalloprotease activity, affects primarily the aorta and mitral valves

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26
Q

What is a mitral prolapse? What dx state can it be associated with?

A

Improper closure of the mitral valve (between LA and LV)

Marfan syndrome

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27
Q

Why does Marfan syndrome present in so many different ranges?

A

Depends on the mutation that affected the fibrillin locus, more than 600 possible

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28
Q

What is the most common form of the autosomal recessive kinds of Ehlers-Danlos Sydromes? What is the gene defect in?

A

Kyphoscholiosis

Lysyl hydroxylase

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29
Q

What abnormalities do vascular type of EDSs result from? What gene are these mutations on?

A

Abnormalities in type 3 collagen

COL3A1

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30
Q

What is the defect in the EDS’s arthrochalasia type and dermatosparaxis type? What are the specifics to each?

A

Conversion of Type 1 procollagen to collagen

Arthrochalasia type: mutation on one of the two type 1 collagen genes (COL1A1, COL1A2), abnormal pro-collagen resists peptidase cleavage at N-terminals, autosomal dominant negative effect

Dermatosparaxis type: proacollagen-N-peptidase gene mutation, autosomal recessive form of inheritance

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31
Q

What is the immediate and major source of plasma LDL?

A

IDL via metabolic processing that removes most TGs leaving only cholesterol

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32
Q

How does cholesterol feed back?

A

Cholesterol that enters the cytoplasm:
1) suppresses cholesterol synthesis within the cell by inh 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase which is the rate-liming enzyme in the synthetic pathway

2) activates acyl-coenzyme A (favors excess cholesterol storage)
3) suppresses synthesis of LDL R’s (protecting cells from excessive cholesterol accumulation)

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33
Q

What does familial hypercholesteremia derive from?

A

LDL R mutation (over 900 variations) that prevents cholesterol from being taken up normally by cells, raising plasma cholesterol levels

34
Q

What are the 5 classes for LDL mutations?

A

Class 1: uncommon, complete synthesis failure of LDL R
Class 2: common, defective proteins encoded accumulate in ER
Class 3: R’s reach cell surface but can’t bind LDL (domain bad)
Class 4: R’s normal but not localized in coated pits, aren’t internalized
Class 5: R’s and internalization occur, pH-dependent dissociation doesn’t occur, R’s trapped in endosome and aren’t recycled

35
Q

What do statins do?

A

Lower cholesterol by inhibiting HMG CoA reductase (cell synthesis of cholesterol) and thus encouraging LDL R synthesis

36
Q

What’s primary and secondary accumulation about?

A

Primary: accumulation of a metabolite within a lysosome d/t deficiency in an enzyme, lysosome grows too large an interferes with other cell functions

Secondary: impaired autophagy, leaves damaged mitochondria around which can leak apoptotic factors

37
Q

What can’t be catabolized in GM2 gangliosidoses lysosomal storage diseases? Why?

A

GM2 gangliosides

Enzyme defects

38
Q

What is Tay-Sachs disease? What population is it most prevalent in? What’s the clinical picture dominated most by? What’s the morphological findings? At what age does it present? What are the symptoms?

A

A GM2 gangliosidoses disease (the most common of the three, lysosomal storage dx) where a deficiency in hexosaminidase A (alpha-subunit) due to a mutation on chromosome 15 leads to GM2 ganglioside accumulation in lysosomes.

Eastern European Jews

Neurons in the central and autonomic nervous systems, and neurons of the retina

Ballooned neurons with cytoplasmic vacuoles (distended lysosomes) filled with gangliosides, cherry-red spot in the macula

~6 months post-birth

Motor and mental deterioration, blindness, dementia, cherry-red spot in macula, death at age 2-3

39
Q

What are the differences between Niemann-Pick Dx Type A & B? What group is this common in? Is there genetic preference?

A

A has neurologic involvement leading to early death

B has no neurologic involvement and life expectancies go into adulthood

Ashkenazi Jews

Yes, to maternal chromosome

40
Q

What gene is mutated in Niemann-Pick Dx?

A

Acid sphingomyelinase gene, chromosome 11

41
Q

What are the morphological findings in Niemann-Pick Dx?

A

Accumulation of sphengomyelin in lysosomes (particularly phagocytes) d/t def in sphengomyelinase, innumerable small vacuoles/secondary lysosomes impart foaminess to cytoplasm and house myelin figures (zebra bodies), splenomegaly, hepatomegaly, enlarged lymph nodes, shrunken gyri and widened sulci, retinal cherry-red spot sometimes (but neurons have many vacuoles and neurons balloon)

42
Q

What genes are mutated in Niemann-Pick Dx Type C? What does this cause? When does NPC present?

A

NPC1 (most common, membrane bound), NPC2 (soluble)

Primary defect in non-enzymatic lipid transport, transport of free cholesterol from lysosomes to the cytoplasm

Most commonly during childhood as progressive neurologic damage, ataxia, dystonia, dysarthria, psychomotor regression

43
Q

What is the most common lysosomal storage disorder? What enzyme is involved? What happens?

A

Gaucher Disease

Glucocerebrosidase, cleaves glucose residue from ceramide

Glucocerebroside accumulates mostly in phagocytes, sometimes CNS

44
Q

What are the three subtypes of Gaucher Disease?

A

Type 1: most common, Jews, storage o glucocerebrosides limited to phagocytes, no CNS involvement, splenomegally, bone erosion (accumulation of Gaucher cells in bone marrow), reduced but detectable glucocerebrosidase actcivity, longevity somewhat shortened

Type 2: acute neuronopathic, infantile acute cerebral pattern, no Jew connection, no glucocerebrosidase activity, hepatosplenomegaly, death at early age, no lipid storage involvement (macros by neurons store and release inflammatory cytokines)

Type 3: combo of the two, sx begin in adolescence/early adulthood

45
Q

What is the primary tx avenue for Gaucher Disease?

A

Replacement enzyme therapy (expensive, used for those with type 1)

46
Q

Where are mucopolysaccharides abundant? When they accumulate, what sx occur? What do they accumulate in?

A

Part of proteoglycans in connective tissue

Coarse facial features, clouding of the cornea, oint stiffness, mental retardation

Phagocytic cells, endothelial cells, smooth. Muscle cells, fibroblasts

47
Q

Name the lysosomal disorder and its associated accumulation.

A

Tay-Sachs: GM2 gangliosides
Niemann-Pick (A & B): sphingolyelin
Niemann-Pick C: cholesterol and glangliosides
Gaucher: glucocerebroside
Mucopolysaccharidoses: mucopolysaccharides

48
Q

What are the different forms of glycogen storage diseases (glycogenoses)? What enzymes are associated with them?

A

Hepatic form (glucose-6-phosphate, debranching enzyme, phosphorylase)

Myopathic form (muscle phosphorylase, muscle phosphofructokinase)

Glycogenoses associated with 1) def of a-glucosidase (acid maltase), and 2) lack of branching enzymes

49
Q

What is myoglobin?

A

Myoglobin is the oxygen reserve used by muscles, myoglobinuria seen in pts with myopathic-type glycogenoses

50
Q

Are all polymorphisms weighed the same in dx?

A

No, some are very important and contribute more risk to a dx than others, some polymorphisms pertain to multiple dx while some are dx-specific

51
Q

What is the study of chromosomes called? When’s a great time to study them during mitosis?

A

Karyotyping

Metaphase (via arrest, Colcemid)

52
Q

Give the karyotype for a male pt with down syndrome.

A

47, XY, +21

53
Q

What are the arm names of chromosomes?

A

Short arm = p (for petit)

Long arm = q (next letter in alphabet)

54
Q

What does Xp21.2 mean?

A

X chromosome, short arm
Region 2
Band 1
Sup-band 2

55
Q

What is euploid vs aneuploidy? What two things cause aneuploidy?

A

Euploid is a chromosome complement that’s an exact multiple o the haploid number of chromosomes, 23.

Aneuploidy refers to a chromosome complement that isn’t an exact multiple.

Nondisjunction and anaphase lag

56
Q

Is monosomy involving a sex chromosome compatible with life? What about involving an autosome?

A

Yes

No, too much genetic info lost

57
Q

What is mosaicism? Is autosomal or sex chromosome mosaicism more common?

A

Individual with two or more populations of cells with different chromosomal complements

Sex Chromosome

58
Q

46, XY, r(14). What does this denote?

A

A ring chromosome. The key thing to note is the r before 14, ring chromosome of chromosome 14.

59
Q

An individual with a balanced reciprocal translocation has risk for what?

A

No risk of being phenotypically different themselves, but may produce abnormal gametes which aren’t generally compatible with life

60
Q

Which translocation pattern results in one small chromosome and one big one?

A

Robertsonian translocation (centric fusion)

61
Q

How does mosaicism show up in Down syndrome? Is maternal age a factor?

A

Mitotic nondisjunction of chromosome 21 occurs during early states of embryogenesis, versus before fertilization.

No

62
Q

What is a defining facial feature of Patau syndrome?

A

Cleft lip and palate, polydactylyl, rocker-bottom feet

63
Q

What is one of the genes TBX1 targets, and what is it associated with?

A

PAX9, development o the palate, parathyroids, and thymus

64
Q

What’s more common, sex chromosome genetic dx or autosomal genetic dx?

A

Sex chromosome, dx much better tolerated

65
Q

What’s a Barr body?

A

Small mass that represents the “inactive” X chromosome genetic material, seen in females

66
Q

What in the plasma has altered concentrations in Klinefelter syndrome? What does this have to do with feminization degrees?

A

Increased FSH & estradiol
Decreased Testosterone

Estradiol:Testosterone ration determines degree of feminization

67
Q

What dx is an important genetic cause o reduced spermatogenesis and male fertility?

A

Klinefelter syndrome

68
Q

Why does lyonization effect those with Klinefelter syndrome?

A

Some of the “inactive” X chromosome genes escape repression, and because of additional X chromosomes in KS, the escaped genes are “extra doses”. This leads to hypogonadism. Hypogonadism is also exacerbated by inactivation of sensitive androgen R’s; the longest CAG repeats are preserved while shorter ones are inactivated.

69
Q

What dx is most common for sex chromosome abnormalities in females?

A

Turner Syndrome

70
Q

What are the structural abnormalities of the X chromosome in Turner Syndrome?

A

In order of frequency..

1) isochromosome of the long arm, loss of short arm (46,X,i(X)(q10))
2) deletion of portions of long and short arms resulting in ring chromosome (46,X,r(X))
3) deletion of portions of the short OR long arm (46,X,del(Xq)) or (46,X,del(Xp))

71
Q

If a pt (female) with Turner Syndrome has a whole or fragments of a Y chromosome, what are they at risk for?

A

Development o a gonadal tumor (gonadoblastoma)

72
Q

What is the most important cause of amenorrhea (lack of a period/menstruation)?

A

Turner Syndrome

73
Q

What is the short stature gene (that results in short stature if lost/haploinsufficiency)? What happens if excess copies are active?

A

SHOX

Leads to tall stature

74
Q

What differentiates a hermaphrodite from a psuedohermaphrodite?

A

Hermaphrodite: has both ovarian and testicular tissue

Psuedophermaphrodite: phenotypic and gonadal sexes are opposite (female has ovaries but male external genitalia, male has testicular tissue but female genitalia)

75
Q

What diseases are characterized by progressive neurodgeneration around midlife?

A

Polyglutamine diseases

76
Q

What are the two most common genetic causes of mental retardation?

A

1) Down Syndrome

2) Fragile X Syndrome

77
Q

What does macro-orchidism mean?

A

Large testicles

78
Q

What patterns of transmission are not typically associated with X-linked recessive disorders that are associated with Fragile X Syndrome?

A

Carrier males (normal transmitting males)
Affected females (30-50% of carrier females are affected)
Risk of phenotypic effects (risk depends on position in pedigree)
Anticipation (clinical features worsen with each successful generation)

79
Q

What does FMRP do?

A

Translation regulator at synaptic junctions, suppresses protein synthesis here and maintains a balance that prevents abnormal synaptic activity that leads to mental retardation

80
Q

What is heteroplasmy?

A

Harboring of both wild-type and mutant mitochondrial DNA.

81
Q

What epigenetic process is responsible for the difference between paternal and maternal alleles? Where does it occur?

A

Imprinting

Ovum or sperm

82
Q

What locus is affected on what chromosome in Prader-Willi and Angelman syndromes?

A

Band q12 on chromosome 15, which dx depends on imprinting (maternal vs paternal)

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