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(OMS1) MOD Exam 1 > Lecture 5: Genetic Disorders > Flashcards

Lecture 5: Genetic Disorders Flashcards

1
Q

What are the three categories of human genetic disorders?

A
  1. Single gene mutation
  2. Chromosomal disorder
  3. Complex multigenic disorder
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2
Q

What is an example of a single gene mutation disorder?

A

Sickle cell anemia

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3
Q

What is the most common type of human gentic disorder?

A

Complex multigenic disorders

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4
Q

What are some examples of complex multigenic disorders?

A

Atherosclerosis, diabetes, hypertension, autoimmune diseases, height, weight

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5
Q

What is the definition of a mutation?

A

Permanent change in DNA

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6
Q

Germ cell mutations give rise to ___________

A

Inherited diseases

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7
Q

Somatic cell mutations give rise to __________ and ____________

A

Cancer

Congenital malformations

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8
Q

Define:

Missense

A

Alter the meaning of a sequence of the encoded protein

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9
Q

Define:

Nonsense

A

Pre mature STOP CODON

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10
Q

***

What are the major 3 transcription factors associated with noncoding sequences?

A

MYC, JUN, p53

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11
Q

What happens if 3 base pairs, or multiple of 3 occurs in a DNA strand?

A

Reading frame remains intact, however get an abnormal protein

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12
Q

What happens if a deletion or insertion does NOT occur in a multiple of 3?

A

Alteration in reading frame = frameshift mutation

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13
Q

What is a trinucleotide-repeat?

What do they contain?

A

Amplification of a sequence of 3 nucleotides

*nearly all contain guanine (G) and cytosine (C)

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14
Q

What are a couple of diseases that are examples of trinucleotide-repeat?

A

Huntingtons Disease

Myotonic dystrophy

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15
Q

What is anticipation in relation to genetic disorders?

A

“A genetic disorder is passed on to the next generation, the symptoms become apparent at an earlier age with each generation. In most cases, an increase in severity of symptoms is also noted.”

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16
Q

State what type of deletion or insertion is occuring with the following disorders:

Cystic Fibrosis

ABO (blood type)

Tay-Sachs

A

Cystic Fibrosis = 3 base deletion

ABO (blood type) = Single base deletion

Tay-Sachs = 4 base insertion

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17
Q

Define:

Codominance

A

Both alleles contribute to phenotype

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18
Q

Define:

Pleiotropism

A

Single mutant gene

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19
Q

Define:

Genetic heterogeneity

A

Mutations at several loci may produce the same trait

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20
Q

Autosomal dominant disorders

New mutations seem to occur in germ cells of _________________

A

Relatively older fathers

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21
Q

What is incomplete penetrance?

A

(+) mutation

Normal phenotype

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22
Q

What is variable expressivity?

A

(+) for trait

however

EXPRESSED differently

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23
Q

What is an example of a loss-of-function mutation?

A

Familial hypercholesterolemia

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24
Q

What is an example of a gain-of-function mutation?

A

Huntingtons protein toxic to neurons

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25
Q

What are the two main patterns of disease with autosomal dominant disorders?

A
  1. Regulation of complex metabolic pathways
  2. Key structural proteins: collagen and cytoskeletal elements of RBC membrane
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26
Q

What is an example of an autosomal dominant disorder that demonstrates the “regulation of complex metabolic pathways” pattern of disorder?

A

LDL receptor in familial hypercholesterolemia

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27
Q

What is an example of an autosomal dominant disorder that demonstrates the “key structural protein compromise” pattern of disorder?

A

Osteogenesis imperfecta

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28
Q

How do autosomal dominant disorders keep getting passed on if they are so detrimental?

A

Age of onset is delayed in many of these conditions

This allows the genes to continue to get passed onto offspring

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29
Q

What are the major autosomal recessive disorders we discussed in lecture?

A

Cystic Fibrosis

Phenylketonuria

Niemann-Pick

MPS (Hurler)

Gaucher

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30
Q

Describe the characteristics of autosomal recessive disorders

A

Largest category of disorder

Both alleles are mutated

Trait usually does NOT affect parent

If mutation is low frequency in population, strong likelihood proband product of consanguineous marriage

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31
Q

How can you differentiate autosomal dominant vs autosomal recessive disorders?

A

Autosomal recessive disorders demonstrate:

  • Uniform expression of defect
  • Complete penetrance
  • Onset is early in life
  • Many mutatations involve enzymes
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32
Q

What is the primary defect in cystic fibrosis?

What gene?

What chromosome?

A

Abnormal function of an epithelial chloride channel protein

CFTR gene

Chromosome 7q31.2

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33
Q

What is the most common lethal genetic disease that affects Caucasian populations?

A

Cystic fibrosis

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34
Q

What is the major bacteria associated with cystic fibrosis?

A

Pseudomonas aeruginosa

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35
Q

What are the major GI indications for Cystic Fibrosis?

A

Meconium ileus

Pancreatic insufficiency

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36
Q

What is a major manifestation of cystic fibrosis specifically in males?

A

Male urogenital abnormalities

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37
Q

What are the cirteria for diagnosis of cystic fibrosis?

A

One or more characteristic phenotypic features;

  • OR a history of CF in a sibling
  • OR a positive newborn screening test result

AND

An increased sweat chloride concentration on two or more occasians

  • OR identification of two CF mutations
  • OR demonstration of abnormal epithelial nasal ion transport
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38
Q

What type of inheritance does Phenylketonuria (PKU) follow?

What is the mechanism of Phenylketonuria?

A

Autosomal recessive disorder

Deficiency in phenylalanine hydroxylase (PAH) which leads to HYPERPHENYLALANINEMIA

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39
Q

What is the typical profile of a patient with phenylketonuria (PKU)?

A

Scandinavian descent

Light skinned

6mo severe mental retardation, hypopigmentation

Strong musty or mousy odor in urine and sweat

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40
Q

What are the two major X-linked recessive disorders covered in lecture?

A

Glucose-6-phosphate dehydrogenase dificiency

Fragile X syndrome

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41
Q

What does an X-linked disorder pedigree look like?

A

Only males are affected

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42
Q

What does mitochondrial inheritance look like on a pedigree?

A

*Remember, mitochondrial inheritance ALWAYS comes from the mother.

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43
Q

What is a mendelian disorder?

A

Alterations in a single gene which produces

an abnormal product or decrease in normal product

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44
Q

What are the three potential outcomes of having an enzyme defect?

A
  1. Accumulation of substrate
  2. Decreased amount of end product
  3. Failure to inactivate a tissue-damaging substrate
45
Q

Name the main example associated with the 3 potential outcomes of enzyme defects

  1. Accumulation of substrate
  2. Decreased amount of end product
  3. Failure to inactivate a tissue-damaging substrate
A
  1. Accumulation of substrate : Galactosemia
  2. Decreased amount of end product : Lesch-Nyhan
  3. Failure to inactivate a tissue-damaging substrate : Alpha1-antitrypsin
46
Q

What is the mechanism behind familial hypercholesterolemia?

A

Decreased synthesis or decreased function of LDL receptor

leads to defective transport of LDL into cells

Which causes increase of cholesterol synthesis

47
Q

What is the

inheritance pattern

gene

product defect

in MARFANS?

A

Autosomal dominant

FBN1 (more common), FBN2 (less common)

Fibrillin-1

48
Q

What is the phenotype of someone with Marfans?

A

Unusually tall

Exceptionally long extremities

“Double jointed”

Long headed

Prominent supraorbital ridges

Ectopia lentis

Aortic dissection

49
Q

Describe Ehlers-Danlos Syndromes (EDS)

A

Defect in the synthesis or structure of fibrillar collagen

Skin is hyperextensible and joints are hypermobile

Skin is extremely stretchable–> vunlerable to trauma

50
Q

How do patients with Ehlers-Danlos Syndromes typically die?

A

Rupture of the colon and large arteres

51
Q

What are the complications related to these types of EDS?

EDS CLassic (I/II)

Vascular (IV)

Kyphoscoliosis (VI)

*When I say “unique” I mean additional features in these subtypes that are not found in other types

A

EDS CLassic (I/II) : diaphragmatic hernia

Vascular (IV): uterine and arterial rupture

Kyphoscoliosis (VI): corneal rupture, retinal detachment, scoliosis

52
Q

What is a primary accumulation lysosomal storage disease?

A

Catabolism of the substrate of the missing enzyme remains incomplete, leading to the accumulation within the lysosomes

53
Q

What causes a secondary accumulation lysosomal storage disorder?

A

Impaired autophagy

54
Q

Tay-Sachs disease

What chromosome?

Severe deficiency of and leads to accumulation of what?

Common in what population?

A

What chromosome –> Chr 15

Severe deficiency of–> Hexosaminidase A, accumulation of GM2 gangliosides which triggers the unfolded protein response

Common in what population –> Ashkenazic jews

*Way to remember the chromosome number: Tay, shes a basic teenage girl and she had SEX (Tay-Sachs) at age 15.

55
Q

What is a hallmark clinical finding for Tay-Sachs disease?

What are the pathological features (slides) of Tay Sachs disease?

A

Clinical: Cherry-red spot in the macula due to ganglion cells around macula filled with pale gangliosides

1-2 yo vegetative state, death by 2-3 yo

Pathology: Gm2 ganglioside accumulation in neurons, retina. stains red O and sudan black B are positive for biopsied cells

56
Q

Describe the mechanism of Niemann-Pick disease

A

Lysosomal accumulation of sphingomyelin

due to inherited deficiency of sphingomyelinase

57
Q

What is population is Niemann-Pick disease commonly found with?

A

Ashkenazi Jews

58
Q

What is the inheritance pattern of Neimann-Pick disease?

What chromosome is it found on?

A

Autosomal recessive

Chromosome 11p15.4

59
Q

What are the three types of Neimann-Pick disease?

What are the characteristics of each?

A

Type A: Severe infantile, death before 3

Type B: No CNS development

Type C: MOST COMMON due to NPC1

60
Q

What are the clinical features of Nieman-pick disease?

What is the morphology of Niemann-Pick disease cells?

A

Massive splenomegaly, also cherry red spot

Morphology: Foamy cytoplasm , Zebra bodies (lysosomes with lamellations)

61
Q

Gaucher disease

Genetic inheritance?

Type of mutation?

Where does material collect and what is the consequence?

A

Autosomal recessive

Glucocerebrosidase mutation leading to Glucocerebroside accumulation in phagocytes > release of IL-1,6 and TNF

62
Q

What are the major clinical features of Gaucher disease?

What is the morphology of Gaucher disease cells?

What is the treatment for Gaucher’s disease?

A

splenomegaly, bone erosioin leading to fractures and pancytopenia (slowed down hematopoiesis)

Crympled tissue paper cytoplasm, distended phagocytc cells (Gaucher cells)

stem cell transplant or enzyme replacement

63
Q

What is the inheritance pattern for Mucopolysacchariodoses (MPS)?

A

All are autosomal recessive

EXCEPT Hunter syndrome which is X-linked recessive

64
Q

What are the general clinical manifestations of Mucopolysaccharidoses (MPS)?

A

coarse facial features, joint stiffness mental retardation

major complications include cardiovascular deposits of the glycosaminoglycan sulfates + brain lesions

65
Q

What is the pathological features of MPS?

A

balloon cells (clear cytoplasm with swollen lysozomes (seen with periodic acid Schiff stain)

66
Q

What is the difference between Hurler and Hunter type of MPS?

A

Hurler: nl at birth, hepatosplenomegaly at 6-24 months, death at 6-10 yo + corneal clouding

Hurler: milder course, no corneal clouding

67
Q

Hunter vs. Hurler?

A

Children with Hunter’s syndrome do not have corneal clouding because you need to “see” in order to hunt

To remember that it is X-linked, picture a hunter with a bow and arrow. The box and arrow cross each other making an X

68
Q

Glycogen storage diseases:

What are the 3 major sub groups?

A
  1. Hepatic forms
  2. Myopathic forms
  3. Miscellaneous
69
Q

Glycogen storage diseases:

What is an example of each of the three sub groups?

A

Hepatic forms: Von Gierke

Myopathic form: McArdle disease

Misc: Pompe disease

70
Q

What is the enzyme involved in:

McArdle disease

Pompe disease

Von Gierke disease

A

McArdle: Phosphorylase (V, VI)

Pompe: Lysosomal acid maltase or branching enzyme

Von Gierke: Glucose 6 phosphatase

71
Q

What are the clinical manifestations of …

von Gierke

McArdle

Pompe

A

von Gierke without treatment: FTT, hepatorenomegaly, hypoglacemia leading to convulsions, hyperlipidemia, hyperuriciemia, gout, xanthomas, bleeding

McArdle: muscle cramps, worse with exercise

Pompe: cardiomegaly leading to cardiorespiratory failure within 2 years

72
Q

What deficiency is associated with galactosemia?

What are the complications?

A

transferase enzyme that converts galactose to glucose

fatty liver and cirrhosis in infant (severe type)

73
Q

What is multifactorial inheritance?

A

Interaction of enviornmental influences with two or more genes

74
Q

What are common examples of Multifactorial inheritance?

A

Cleft lip

Cleft palate

Neural tube defects (e.g. B9 supplementation)

75
Q

If a disease has variable severity, what is this suggestive of?

A

complex multigenic disorder or mendelian disorder (variable penetrance and expressivity)

76
Q

Define:

Euploid

Aneuploid

A

Euploid: any exact multiple of haploid number (23)

Aneuploid: NOT an exact multiple of 23

77
Q

Define:

Mosaicism

A

Mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement in the same individual

78
Q

What is a ring chromosome?

Inversion mutation?

Isochromosome?

Translocation?

A
  • both chromosomes have breaks at the end and they fuse
  • part of chromosme incorporated upside down (paracentric involves one arm, pericentric involves both arms)
  • chromosome containing 2 long arms or 2 short arms only
  • one part of chromosome attached to another chromosome (balanced if they exchanged material)
79
Q

What is a Robertsonian translocation?

A

(Centric fusion)

Translocation between 2 acrocentric chromosomes (13,14,15,21,22) ; typically breaks appear closer to the centromeres of each chromosome (e.g. top part of chromosome 22 fused with chromosome 21, leaving a very long chromosome 21 and very small chromosome 22)

80
Q

How does a Robertsonian translocation result in Trisomy 21?

A

q arm of chromosome 21 attached to another chromosome. Both chromosomes gets replicated and result in 3 copies of the q arm

81
Q

What is are strong influencers of trisomy 21?

What does mosaicism relate to trisomy 21?

A

Maternal age

3-4% due to Robertsonian translocation

-Some patients are mosaics with some cells containing normal 46 with other cells containing 47 = milder symptoms

82
Q

What are the clinical manifestations of trisomy 21?

A

Flat facial profile

Oblique palpebral fissures

Epicanthic folds

40% have congenital heart disease due to septal defects

predisposition to lung infections and thyroid autoimmunity

10-20 fold increased risk of developing leukemia and alzheimer’s disease <40 yo

simian crease

83
Q

What syndrome does this baby have?

A

Trisomy 13: Patau syndrome

84
Q

What syndrome does this baby have?

A

Trisomy 18: Edwards syndrome

85
Q

What syndrome does this baby have?

A

Trisomy 21: Down Syndrome

86
Q

What is chromosome 22q11.2 deletion syndrome

A

deletion in band of chromosome 22 results in DiGeorge Syndrome/Velocardiofacial syndrome

general features: Congenital heart defects, abnormalities of the palate, facial dysmorphism

87
Q

What are the clinical manifestations of DiGeorge syndrome?

What are the clinical manifestations of Velocardiofacial syndrome?

A

thymic and parathyroid hypoplasia leading to T cell deficiency and hypocalcemia + facial and cardiac abnormalities

facial dysmorphism, cleft palate, cardiac anomalies

88
Q

What is lyonization?

What is a Barr body?

A

Inactivation (heteropyknosis) of one X chromosome, which X chromosome gets inactivated happens randomly in each cell of the blastocyst

Barr body: inactive X that appears as a small mass attached to the nuclear membrane during interphase

89
Q

What are the characteristics of sex chromosome disorders?

A

symptoms relate to sexual development and fertility and appear at puberty

the more X chromosomes the greater the likelihood of mental retardation

90
Q

What is the genetic makeup of someone with Klinefelter syndrome?

A

47, XXY

91
Q

What are Klinefelter syndrome patients at higher risk for aquiring?

A

Type 2 DM

mitral valve prolapse

Breast cancer

Male inferfility

Osteoporosis

autoimmune diseases

92
Q

What is the genetic makeup of a patient with Turner syndrome?

A

45, X

93
Q

What is oberved upon birth of a patient with Turner syndrome?

A

Cystic hygroma (neck swelling in the infant due to lymph stasis) results in bilateral neck webbing

94
Q

What is the clinical presentation of a Turner’s patient?

A

Short stature

Webbing of neck

Cardiovascular malformations

Amenorrhea

Lack of secondary sex characteristics

FIbrotic ovaries/streak ovaries

95
Q

What is the difference between a true hermaphrodite and a pseudohermaphrodite?

A

True: presence of both ovarian and testicular tissue

Pseudo: have phenotypes of both (named after what gonad they have, so a male pseudohemaphrodite has a testis but female external genitalia, and vice versa)

96
Q

Describe a trinucleotide-repeat mutation

A

Expansion of trinucleotide repeats is an important genetic cause of human disease…

Particularly Neurodegenerative disorders

97
Q

How do trinucleotide repeat mutations cause disease?

A
  1. loss of function of the affected gene (e.g. Fragile X syndrome)
  2. toxic gain of function (e.g. Huntingtons)
  3. Toxic gain of function via mRNA (e.g. Fragile X tremor ataxia syndrome)
98
Q

What is a morphologic hallmark of trinucleotide repeat mutations?

A

Accumulation of aggregated mutant proteins inside large intranuclear inclusions inside nucleus

99
Q

Fragile X Syndrome

Cause?

Most distinctive feature?

A

mutation in FMR1 which makes FMRP that regulates translation of synaptic junction genes. No regulation = increased translation and alteration of synaptic junctions leading to mental retardation

Distinctive: Macro-orchidism

100
Q

How does anticipation happen in Fragile X syndrome?

A

during oogenesis, triplet repeat is amplified a lot, thus symptoms are more severe in offspring that inherits the gamete

101
Q

What syndrome do these dudes probably have?

A

Fragile X Syndrome

  • Broad forehead
  • Elongated face
  • Large prominent ears
  • Srabismus
  • Highly arched palette
102
Q

What is Hungtington’s disease?

How does anticipation happen in Huntington’s disease?

A

chromosome 4 has the HTT gene that has amplified repeats for huntingtin protein which is toxic and aggregates in the brain

polyglutamine repeats amplified during spermatogenesis, so more severe disease usually associated with paternal transmission

103
Q

What are the clinical manifestations of Huntington’s disease?

A

Progressive movement disorders (chorea)

Dementia

104
Q

in mitochondrial inheritance patterns, what does heteroplasmy and threshold effect mean ?

A

Heteroplasmy: an individual has a certain amount of cells with mutant and a certain amount of cells with normal mtDNA

Threshold effect: an individual needs to have the mutant mtDNA in a certain number of cells to express the mt inherited disorder

105
Q

What is the key prototype of mtDNA disorder?

A

Leber hereditary optic neuropathy

–> Progressive bilateral loss of central vision

106
Q

What does the vision pattern on the right reveal?

Bonus points: What type of inheritance pattern does this have?

A

Leber Hereditary Optic Neuropathy (LHON)

*has a mitochondrial inheritance pattern

107
Q

How do you remember how prader-willi syndrome and angelman syndrome is inherited?

A

Prader-willi = active gene is usually Paternal, so kids with the disease have an inactive paternal alelle so they don’t have PW gene expression at all

Angelman= active gene is usually Maternal, so kids with the disease have an inactive maternal allele so they don’t have AM gene expression at all

108
Q

What are the symptoms of Prader Willi syndrome?

What are the symptoms of Angelman syndrome?

A

PW: mental retardation, short and small, obese

Angelman: happy puppet syndrome (inappropriate laughter), ataxic, seizures

(OMS1) MOD Exam 1 (5 decks)

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