Lecture 5: Genetic Disorders Flashcards
1
Q
What are the three categories of human genetic disorders?
A
- Single gene mutation
- Chromosomal disorder
- Complex multigenic disorder
2
Q
What is an example of a single gene mutation disorder?
A
Sickle cell anemia
3
Q
What is the most common type of human gentic disorder?
A
Complex multigenic disorders
4
Q
What are some examples of complex multigenic disorders?
A
Atherosclerosis, diabetes, hypertension, autoimmune diseases, height, weight
5
Q
What is the definition of a mutation?
A
Permanent change in DNA
6
Q
Germ cell mutations give rise to ___________
A
Inherited diseases
7
Q
Somatic cell mutations give rise to __________ and ____________
A
Cancer
Congenital malformations
8
Q
Define:
Missense
A
Alter the meaning of a sequence of the encoded protein
9
Q
Define:
Nonsense
A
Pre mature STOP CODON
10
Q
***
What are the major 3 transcription factors associated with noncoding sequences?
A
MYC, JUN, p53
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
12
Q
What happens if a deletion or insertion does NOT occur in a multiple of 3?
A
Alteration in reading frame = frameshift mutation
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)
14
Q
What are a couple of diseases that are examples of trinucleotide-repeat?
A
Huntingtons Disease
Myotonic dystrophy
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.”
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
17
Q
Define:
Codominance
A
Both alleles contribute to phenotype
18
Q
Define:
Pleiotropism
A
Single mutant gene
19
Q
Define:
Genetic heterogeneity
A
Mutations at several loci may produce the same trait
20
Q
Autosomal dominant disorders
New mutations seem to occur in germ cells of _________________
A
Relatively older fathers
21
Q
What is incomplete penetrance?
A
(+) mutation
Normal phenotype
22
Q
What is variable expressivity?
A
(+) for trait
however
EXPRESSED differently
23
Q
What is an example of a loss-of-function mutation?
A
Familial hypercholesterolemia
24
Q
What is an example of a gain-of-function mutation?
A
Huntingtons protein toxic to neurons
25
What are the two main patterns of disease with autosomal dominant disorders?
1. Regulation of **complex metabolic pathways**
2. **Key structural proteins**: collagen and cytoskeletal elements of RBC membrane
26
What is an example of an autosomal dominant disorder that demonstrates the "regulation of complex metabolic pathways" pattern of disorder?
LDL receptor in **familial hypercholesterolemia**
27
What is an example of an autosomal dominant disorder that demonstrates the "key structural protein compromise" pattern of disorder?
Osteogenesis imperfecta
28
How do autosomal dominant disorders keep getting passed on if they are so detrimental?
Age of onset is **delayed** in many of these conditions
This allows the genes to continue to get passed onto offspring
29
What are the major **autosomal recessive** disorders we discussed in lecture?
Cystic Fibrosis
Phenylketonuria
Niemann-Pick
MPS (Hurler)
Gaucher
30
Describe the characteristics of **autosomal recessive** disorders
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_
31
How can you differentiate autosomal dominant vs autosomal recessive disorders?
Autosomal recessive disorders demonstrate:
- **Uniform** expression of defect
- Complete penetrance
- Onset is **early** in life
- Many mutatations involve **enzymes**
32
What is the **primary defect in cystic fibrosis?**
What gene?
What chromosome?
Abnormal function of an **epithelial chloride channel protein**
CFTR gene
Chromosome 7q31.2
33
What is the most common lethal genetic disease that affects Caucasian populations?
Cystic fibrosis
34
What is the major bacteria associated with cystic fibrosis?
Pseudomonas aeruginosa
35
What are the major GI indications for Cystic Fibrosis?
Meconium ileus
Pancreatic insufficiency
36
What is a major manifestation of cystic fibrosis specifically in males?
Male urogenital abnormalities
37
What are the cirteria for diagnosis of cystic fibrosis?
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
38
What type of inheritance does **Phenylketonuria (PKU)** follow?
What is the mechanism of **Phenylketonuria?**
Autosomal recessive disorder
Deficiency in **phenylalanine hydroxylase (PAH)** which leads to HYPERPHENYLALANINEMIA
39
What is the typical profile of a patient with **phenylketonuria (PKU)?**
Scandinavian descent
Light skinned
6mo severe mental retardation, hypopigmentation
**_Strong musty or mousy odor in urine and sweat_**
40
What are the two major **X-linked recessive** disorders covered in lecture?
Glucose-6-phosphate dehydrogenase dificiency
Fragile X syndrome
41
What does an X-linked disorder pedigree look like?
Only males are affected
42
What does **mitochondrial inheritance** look like on a pedigree?
\*Remember, mitochondrial inheritance ALWAYS comes from the mother.
43
What is a **mendelian disorder?**
Alterations in a **single gene** which produces
an _abnormal product_ or _decrease in normal product_
44
What are the three potential outcomes of having an **enzyme defect?**
1. Accumulation of substrate
2. Decreased amount of end product
3. Failure to inactivate a tissue-damaging substrate
45
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
1. Accumulation of substrate : **Galactosemia**
2. Decreased amount of end product : **Lesch-Nyhan**
3. Failure to inactivate a tissue-damaging substrate : **Alpha1-antitrypsin**
46
What is the mechanism behind **familial hypercholesterolemia?**
Decreased synthesis or decreased function of **LDL receptor**
leads to defective **transport of LDL into cells**
Which causes increase of **cholesterol synthesis**
47
What is the
inheritance pattern
gene
product defect
in **MARFANS?**
Autosomal dominant
FBN1 (more common), FBN2 (less common)
Fibrillin-1
48
What is the phenotype of someone with **Marfans?**
Unusually tall
Exceptionally long extremities
"Double jointed"
Long headed
Prominent supraorbital ridges
Ectopia lentis
Aortic dissection
49
Describe **Ehlers-Danlos Syndromes (EDS)**
Defect in the synthesis or structure of **fibrillar collagen**
Skin is **hyperextensible** and joints are **hypermobile**
Skin is extremely **stretchable**--\> vunlerable to trauma
50
How do patients with **Ehlers-Danlos Syndromes** typically die?
Rupture of the colon and large arteres
51
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
_EDS CLassic (I/II)_ : diaphragmatic hernia
_Vascular (IV):_ uterine and arterial rupture
_Kyphoscoliosis (VI)_: corneal rupture, retinal detachment, scoliosis
52
What is a **primary accumulation lysosomal storage disease?**
Catabolism of the substrate of the missing enzyme remains incomplete, leading to the _accumulation within the lysosomes_
53
What causes a **secondary accumulation lysosomal storage disorder?**
Impaired autophagy
54
**Tay-Sachs disease**
What chromosome?
Severe deficiency of and leads to accumulation of what?
Common in what population?
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
What is a hallmark clinical finding for **Tay-Sachs disease?**
What are the pathological features (slides) of Tay Sachs disease?
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
Describe the mechanism of **Niemann-Pick** disease
Lysosomal accumulation of **sphingomyelin**
due to inherited deficiency of **sphingomyelinase**
57
What is population is **Niemann-Pick** disease commonly found with?
Ashkenazi Jews
58
What is the inheritance pattern of **Neimann-Pick** disease?
What chromosome is it found on?
Autosomal recessive
Chromosome 11p15.4
59
What are the three types of **Neimann-Pick disease?**
What are the characteristics of each?
Type A: Severe infantile, death before 3
Type B: No CNS development
Type C: MOST COMMON due to **NPC1**
60
What are the clinical features of Nieman-pick disease?
What is the morphology of **Niemann-Pick** disease cells?
Massive splenomegaly, also cherry red spot
Morphology: Foamy cytoplasm , Zebra bodies (lysosomes with lamellations)
61
**Gaucher disease**
Genetic inheritance?
Type of mutation?
Where does material collect and what is the consequence?
Autosomal recessive
Glucocerebrosidase mutation leading to Glucocerebroside accumulation in phagocytes \> release of IL-1,6 and TNF
62
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?
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
What is the inheritance pattern for **Mucopolysacchariodoses (MPS)?**
All are autosomal recessive
EXCEPT **Hunter syndrome** which is X-linked recessive
64
What are the **general** clinical manifestations of **Mucopolysaccharidoses (MPS)?**
coarse facial features, joint stiffness mental retardation
major complications include cardiovascular deposits of the glycosaminoglycan sulfates + brain lesions
65
What is the pathological features of MPS?
balloon cells (clear cytoplasm with swollen lysozomes (seen with periodic acid Schiff stain)
66
What is the difference between Hurler and Hunter type of MPS?
Hurler: nl at birth, hepatosplenomegaly at 6-24 months, death at 6-10 yo + corneal clouding
Hurler: milder course, no corneal clouding
67
Hunter vs. Hurler?
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
Glycogen storage diseases:
What are the 3 major sub groups?
1. Hepatic forms
2. Myopathic forms
3. Miscellaneous
69
Glycogen storage diseases:
What is an example of each of the three sub groups?
Hepatic forms: Von Gierke
Myopathic form: McArdle disease
Misc: Pompe disease
70
What is the enzyme involved in:
McArdle disease
Pompe disease
Von Gierke disease
McArdle: Phosphorylase (V, VI)
Pompe: Lysosomal acid maltase or branching enzyme
Von Gierke: Glucose 6 phosphatase
71
What are the clinical manifestations of ...
von Gierke
McArdle
Pompe
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
What deficiency is associated with galactosemia?
What are the complications?
transferase enzyme that converts galactose to glucose
fatty liver and cirrhosis in infant (severe type)
73
What is **multifactorial inheritance?**
Interaction of enviornmental influences with two or more genes
74
What are common examples of **Multifactorial inheritance?**
Cleft lip
Cleft palate
Neural tube defects (e.g. B9 supplementation)
75
If a disease has variable severity, what is this suggestive of?
complex multigenic disorder or mendelian disorder (variable penetrance and expressivity)
76
# Define:
Euploid
Aneuploid
Euploid: any exact multiple of haploid number (23)
Aneuploid: NOT an exact multiple of 23
77
# Define:
Mosaicism
Mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement in the same individual
78
What is a ring chromosome?
Inversion mutation?
Isochromosome?
Translocation?
- 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
What is a **Robertsonian translocation?**
(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
How does a Robertsonian translocation result in Trisomy 21?
q arm of chromosome 21 attached to another chromosome. Both chromosomes gets replicated and result in 3 copies of the q arm
81
What is are strong influencers of trisomy 21?
What does mosaicism relate to trisomy 21?
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
What are the clinical manifestations of **trisomy 21?**
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
What syndrome does this baby have?
Trisomy 13: Patau syndrome
84
What syndrome does this baby have?
Trisomy 18: Edwards syndrome
85
What syndrome does this baby have?
Trisomy 21: Down Syndrome
86
What is **chromosome 22q11.2 deletion syndrome**
deletion in band of chromosome 22 results in DiGeorge Syndrome/Velocardiofacial syndrome
general features: Congenital heart defects, abnormalities of the palate, facial dysmorphism
87
What are the clinical manifestations of DiGeorge syndrome?
What are the clinical manifestations of Velocardiofacial syndrome?
thymic and parathyroid hypoplasia leading to T cell deficiency and hypocalcemia + facial and cardiac abnormalities
facial dysmorphism, cleft palate, cardiac anomalies
88
What is **lyonization**?
What is a Barr body?
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
What are the characteristics of sex chromosome disorders?
symptoms relate to sexual development and fertility and appear at puberty
the more X chromosomes the greater the likelihood of mental retardation
90
What is the genetic makeup of someone with **Klinefelter syndrome?**
47, XXY
91
What are **Klinefelter syndrome** patients at higher risk for aquiring?
Type 2 DM
mitral valve prolapse
Breast cancer
Male inferfility
Osteoporosis
autoimmune diseases
92
What is the genetic makeup of a patient with **Turner syndrome?**
45, X
93
What is oberved upon birth of a patient with **Turner syndrome?**
Cystic hygroma (neck swelling in the infant due to lymph stasis) results in bilateral neck webbing
94
What is the clinical presentation of a **Turner's patient?**
Short stature
Webbing of neck
Cardiovascular malformations
Amenorrhea
Lack of secondary sex characteristics
FIbrotic ovaries/streak ovaries
95
What is the difference between a **true hermaphrodite** and a **pseudohermaphrodite?**
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
Describe a **trinucleotide-repeat mutation**
Expansion of trinucleotide repeats is an important genetic cause of human disease...
Particularly **Neurodegenerative disorders**
97
How do trinucleotide repeat mutations cause disease?
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
What is a morphologic hallmark of **trinucleotide repeat mutations?**
Accumulation of aggregated mutant proteins inside **large intranuclear inclusions inside nucleus**
99
Fragile X Syndrome
Cause?
Most distinctive feature?
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
How does anticipation happen in Fragile X syndrome?
during oogenesis, triplet repeat is amplified a lot, thus symptoms are more severe in offspring that inherits the gamete
101
What syndrome do these dudes probably have?
Fragile X Syndrome
- Broad forehead
- Elongated face
- Large prominent ears
- Srabismus
- Highly arched palette
102
What is Hungtington's disease?
How does anticipation happen in Huntington's disease?
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
What are the clinical manifestations of **Huntington's disease?**
Progressive movement disorders (chorea)
Dementia
104
in mitochondrial inheritance patterns, what does heteroplasmy and threshold effect mean ?
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
What is the **key prototype** of mtDNA disorder?
Leber hereditary optic neuropathy
--\> Progressive bilateral loss of central vision
106
What does the vision pattern on the right reveal?
Bonus points: What type of inheritance pattern does this have?
Leber Hereditary Optic Neuropathy (LHON)
\*has a mitochondrial inheritance pattern
107
How do you remember how **prader-willi syndrome** and **angelman syndrome** is inherited?
**_P_**rader-willi = active gene is usually **_P_**aternal, so kids with the disease have an inactive paternal alelle so they don't have PW gene expression at all
Angel**_man_**= active gene is usually **_M_**aternal, so kids with the disease have an inactive maternal allele so they don't have AM gene expression at all
108
What are the symptoms of Prader Willi syndrome?
What are the symptoms of Angelman syndrome?
PW: mental retardation, short and small, obese
Angelman: happy puppet syndrome (inappropriate laughter), ataxic, seizures
