Ch 5: Genetic Disorders Flashcards
What are the three categories of human genetic disorders?
Mutations in single gene w/ large effects - highly penetrant, ie sickle cell anemia
Chromosomal Disorders - structural or numerical alteration (ie trisomy 21)
Complex multigenic disorders - disease in which a polymorphism changes the extent to which the likelihood changes with that gene (ie T2DM).
Mutations to what type of cells are transmitted to the progeny and can give rise to inherited diseases?
germ cells
Define mutation
a permanent change in the DNA
A mutation that introduces a stop codon prematurely is best described as what type of mutation?
A. conserved missense mutation
B. Non-conserved missense mutation
C. Nonsense mutation
D. polysense mutation
C. Nonsense mutation - B-thalassemia
A. conserved missense mutation - change in AA that is biochemically similar, function preserves
B. Non-conserved missense mutation - change in AA that is biochemically not similar, function reduced or altered
D. polysense mutation - DFE (dont fuckin exist m8)
How could a mutation in a noncoding sequence influence protein synthesis in a cell?
The mutation could cause problematic splicing, disturbed promoter or enhancer regions which would alter mRNA production
A 27 year old male comes into his providers office for a very expensive, non-existent DNA test to figure out why his shit so busted. Which of the following situations, if found, would count as a frameshift mutation?
A. 3 bp deletion
B. 3 bp insertion
C. 1 bp deletion
D. 6 bp insertion
C. 1 bp deletion
if a multiple of 3 occurs it is not a frameshift becasue the reading frame is maintained p. 139. as far as severity… it seems that yo shit gets busted no matter what’s deleted or inserted
Describe the mechanism of trinucleotide-repeat mutations.
An increase in three nucleotides, usually G’s and C’s. Some examples are Huntington’s or Fragile X
A 24 year old woman presents markedly unhinged. She says her mother and her mother’s siblings were all unhinged and her grandmother was unhinged. What are the odds that her grandchild by her son will be unhinged.
0%
I was trying to hint mitochondrial inheritance and now i realize questions are hard. Allison’s son will be unhinged but his kids won’t be. If this is a dumb question, hit 5 and move on
True or false: all congenital disorders are genetic
False: congenital syphilis
congenital just means born with
Define pleiotropism and give an example.
a single mutation that leads to many end effects - sickle cell anemia
Describe the autosomal dominant pattern of inheritance
disease is manifested in the heterozygous state, can occur in both males and females, and can be passed on by both males and females.
- 1 parent is affected
- 1/2 chance
- effects non-enzymatic proteins and receptors
How does incomplete penetrance affect autosomal dominant disorders?
incomplete penetrance would mean that only portion of the people who carry the mutation will express the mutation. This leads to variable expressivity
Differentiate between loss of function and gain of function mutations in autosomal dominant mutations?
Loss of function occurs when the mutation makes a defective protein or depletes a protein entirely rengering the process non-functional
Gain of function - less common, is characterized by excessive proteinfunction such as the over production of huntingtin in huntington’s disease
Describe the pattern of autosomal recessive inheritance
largest category of mendelian disorders, must have both alleles mutated in order to present with the disorder.
- parents dont show it
- children have 1/4 chance
- if there is low occurrence in gen pop then consanguineous marriage.
Name the most common features of autosomal recessive interitance
- expression is more uniform
- complete penetrance is common
- early onset
- new mutations can occur but are often undiagnosed
- many mutated products are equally matched by functional products
Why does y-linked inheritance not happen?
most mutations on Y chromosome result in infertility
Describe the X-linked pattern of inheritance
predominantly boys due to hemizygosity and inability to compensate with second X chromosome.
Characterize X-linked recessive features
- Passed down by heterozygous mother to son.
- Daughters of affected man are all carriers
What are the four mechanisms categories involved in single-gene disorders?
- Enzyme defects and their consequences
- Defects in membrane receptors and transport systems
- Alterations in the structure, function, or quantity or quantity of nonenzyme proteins
- mutations resulting in unusual reaction to drugs
Explain how an enzyme deficiency or dysfunction would result in accumulation of substrate.
depending on where the block is, the lack of the reaction will cause substrate to accumulate or will shuttle the substrate into parallel pathways with a potential accumulation of a different product.
Describe Marfan syndrome
a disorder of connective tissue, manifested by changes in skeleton, eyes, and cardiovascular system
What causes marfan syndrome and what are the two mechanisms in which the deficiency causes symptoms
results from inherent defect in an extracellular glycoprotein called fibrillin-1. Causes loss of structural support in microfibril rich connective tissues and excessive TGF-B activation
mechanisms
- fibrillin is major component of microfibrils. These are found in aorta, ligaments, and ciliary zone around lens. FBN-1 underlies marfans, FBN-2 underlies contractural arachnodactyly
- loss of fibrillin activates TGF-B which activates metalloproteases and destroys ECM.
Describe the morphology of marfan syndrome
patient is tall, long extremities, lax joints in extremities and fingers, variety of spinal deformities.
Ocular subluxation out and superiorly
Cardiovascular lesions including aneurysm and dissection - most common are mitral valve prolapse and dilation of the ascending aorta.
Treated with B-blockers
Describe ehler-danlos syndromes
comprise a clinically genetically heterogeneous group of disorders that result in some defect in the synthesis or structure of fibrillar collagen.
Which of the EDS follow an autosomal recessive pattern of genetic inheritance.
Kyphoscoliosis (VI) - hypotonia, joint laxity, congenital scoliosis, ocular fragility
Dermatosparaxis (VIIc) - severe skin fragility, cutis laxa bruising
What are the clinical findings of classic (I/II) EDS?
Skin and joint hypermobility, atrophic scars, easy bruising
What is the cause of the kyphoscoliosis (VI ) type of EDS
mutations in genes encoding lysyl hydroxylase - most common form of the autosomal recessive type
what does the vascular form (IV) of EDS result from
deficiencies in type III collagen
What do the arthrochalasia (VIIa,b) and dermatosparaxis type (VIIc) of EDS result from?
defect in the conversion of type I procollagen into collagen.
What is the cause of classic (I) EDS
mutations in type V collagen
Describe familial hypercholesterolemia
an autosomal dominant receptor disease that is a consequence of a mutation in the LDL receptor needed for the absorption of cholesterol
What is the major and immediate source of plasma LDL
IDL
What are locations the five mutation classes correspond to in familial hypercholesterolemia
1-5 is
synthesis transport Binding clustering recycling
What are the two pathologic consequences of an inherited deficiency of a functional lysosomal enzyme
- Catabolism of the substrate of the missing enzyme results in accumulation (primary) making the lysosome large and numerous
- impaired autophagy gives rise to secondary accumulation of autophagic substrates such as effete mitochondria which can lead to buildup of free radicals.
What are the three treatment approaches for lysosomal diseases?
- enzyme replacement therapy
- substrate reduction therapy
- improving enzyme function (molecular chaperone therapy)
What are GM2 gangliosidoses and which is the most common?
a group of three lysosomal storage diseases caused by an inability to catabolize GM2 gangliosides.
Tay-Sachs disease
What is the cause of Tay-sachs disease?
mutations in the alpha subunit locus on chromosome 15 that cause a severe deficiency in of hexosaminidase A
main population east european ashkenazi jewish
Describe the morphology of tay-sachs disease
deficiency in hexosaminidase A leads to a buildup of GM2 gangliosidoses in all tissues but the clinically relevant tissue is neural and retinal tissue. Cytoplasmic inclusions of fat globules with proliferation of microglia.
What are the clinical features of Tay-Sachs disease?
- Cherry red spot on macula
- Manifest symptoms at 6 mo
- motor and metal deterioration over 1-2 completely vegetative state is reached
- death age 2-3
What are you measuring established by a biochemical assay for Niemann-Pick Disease type A/B disease to make a diagnosis
sphingomyelinase
Describe Niemann-Pick diseases A and B.
They are two related disorders that are characterized by lysosomal accumulation of sphingomyelin due to an inherited deficiency in sphingomyelinase
Type A
- severe infantile form with extensive neurological involvement
- progressive wasting and death within 3 years
Type B
- organomegaly but no CNS involvement
- Survive into adulthood
Describe the morphology in Type A Niemann-Pick disease.
- missense mutation causes complete loss of sphingomyelinase
- Affected cells become large due to accumulation in lysosomes
- vacuolation and ballooning of neurons, retinal cherry-red spot present in 1/3 of people
Describe Niemann-Pick disease type C
more common than types A and B combined, mutations in NPC1 and NPC2 with NPC 1 causing 95% of cases.
responsible for transporting free cholesterol. results in hydrops fetalis or stillbirth. If survive to childhood, ataxic, vertical supranuclear gaze, dystonia, dysarthria, and psychomotor regression.
Describe gaucher disease
cluster of autosomal recessive disorders resulting from mutations in the gene encoding glucocerebrosidase
(cleaves glucose from ceramide). activation of macrophages to clear these out also activate IL-1, IL-6, TNF
Explain the clinical subtype I of gaucher disease
- Most common
- chronic nonneuronopathic form
- glucocerebrosides is limited to mononuclear phagocytes
- less but present levels of glucocerebrosidase and shorter longevity
Explain the clinical subtype II of gaucher disease
- acute neuronopathic gaucher
- infantile acute cerebral pattern
- no detectable enzyme activity
- hepatosplenomegaly
- CNS involvement leading to early death
Explain the clinical subtype III of gaucher disease
Intermediate between type one and 2
CNS involvement begins in adolescence or early adulthood
Describe the morphology of Gaucher disease
- accumulation of glucocerebrosides
- distended phagocytic cells known as gaucher cells are found in spleen, liver, bone marrow, lymph nodes, tonsils, thymus, and peyer patches
- In type I spleen is enlarged up to to 10 Kg, bone erosion, neuronal atrophy
What are the clinical features of gaucher disease
type I
- symptoms appear in adult life and are related to splenomegaly and bone problems
- compatible with long life though progressive
Type II/III
- CNS dysfunction and complete lack of enzyme
- Replacement therapy with recombinant enzymes shows promise
Describe MPS (mucopolysaccharidoses)
group of closely related syndromes that result from genetically determined deficiencies of enzymes involved in the degradation of mucopolysaccharides (glycosaminoglycans)
In general
- coarse facial features
- clouding of cornea
- Joint stiffness
- Mental Retardation
What are the glycosaminoglycans that accumulate in MPSs
dermatan sulfate, heparan sulfate, keratin sulfate, and chondroitin sulfate.
Which of the MPSs is not inherited by an autosomal recessive pattern
Hunter Syndrome (MPS II) - no corneal clouding and milder in clinical course
Describe the morphology of MPSs
- mucopolysaccharides are found in mononuclear phagocytic cells, endothelial cells, intimal smooth muscle cells and fibroblasts
- Hepatosplenomegaly, skeletal deformities, valvular lesions and subendothelial arterial deposits (particularly coronary arteries),and lesions in the brain are common threads
what deficiency occurs in Hurler’s syndrome
1-a-iduronidase
most severe form of MPS
death at 6-10
Describe the glycogen storage diseases
result in a hereditary deficiency of one of the enzymes involved in the synthesis or sequential degradation of glycogen
What type of GSD is predominant in the liver and what enzyme is deficient
Von Gierke’s type I
Glucose-6-phosphatase
Hepatomegally and hypoglycemia
What type of GSD is predominant in the myopathic forms
McArdles disease (GSD V)
Muscle Phosphorylase
Painful cramps, exercise intolerance
What type of GSD is associated with death early in life by a deficiency of a-glucosidase and lack of branching enzyme?
Pompe Disease (GSD II)
cardiomegaly most prominent feature
What are the usual causes of aneuploidy?
Non-disjunction
anaphase lag
aneuploidy is any deviation from normal 46, XX/XY
Is monosomy or trisomies of autosomal chromosomes more likely to lead to death?
monosomies
Describe the phenomenon of genetic mosaicism
mitotic errors early in development give rise to two or more populations of cells with different chromosomal complement in the same individual.
Describe the incidence and associated karyotypes of trisomy 21
most common cause of chromosomal disorders and it is a major cause of MR.
- 1 in 700
- Maternal age important
- 1:1550 <20
- 1:25 >45
What are the diagnostic criteria of Down Syndrome
- Flat facial profile
- oblique palpebral fissure
- epicanthic folds
- 40% have congenital heart disease
- 10-20X increase in developing acute leukemia
- abnormal immune responses
Describe clinical findings in trisomy 18 (edwards syndrome)
- prominent occiput
- low set ears
- micrognathia
- MR
- rocker bottom feet
Describe the clinical findings in trisomy 13 ( patau syndrome)
- microphthalmia
- cleft lip and palate
- Microcephaly and MR
- Rocker bottom feet
What is the group of chromosomal disorders to which both DiGeorge Syndrome and velocardiofacial syndrome belong
Chromosome 22q11.2 deletion syndrome.
Describe Digeorge syndrome
Thymic hypoplasia with diminished T-cell immunity and parathyroid hypoplasia (hypocalcemia)
characterized by low set ears
Describe velocardiofacial syndrome
congenital heart disease involving outflow tracts, facial dysmorphism, and developmental delay.
What is the lyon hypothesis
AKA X-inactivation
- only 1 X is genetically active
- the other of maternal or paternal origin is silenced randomly
- happens in all cells of the blastocyst
- each cell therefore derived has the same pattern of inactivation.
What is the incidence and karyotype of Kleinfelter syndrome?
- 1:660 live male births
Presence of 2+ X chromosomes with 2+ Y chromosomes
Describe the clinical findings of Kleinfelter syndrome
- hard to diagnose before puberty
- underdeveloped secondary sex characteristics
- gynecomastia
- Infertility
What is the incidence and karyotype of turner syndrome
- 1:2500
- X0
Describe the clinical findings of Turner syndrome
low posterior hairline
- webbed neck
- broad chest and wide nipples
- cubitus valgus
- streak ovaries
- coarctation of the aorta
Define hermaphrodite compared to pseudohermaphrodite
Hermaphrodite - contains both testicular and ovarian tissues
Pseudohermaphrodite - disagreement between the phenotypic and gonadal sex (androgen insensitivity)
What nucleotides are involved in trinucleotide repeats.
CAG
Fragile X is CGG
Describe the clinical features for fragile X syndrome
2nd most commom cause of MR due to mutation in FMR1 gene.
What does anticipation refer to with respect to fragile X
observation that clinicala features of fragile X syndrome worsen with each successive generation, as if the mutation becomes increasingly deleterious.
describe the threshold effect in mitochondrial diseases
A certain number of diseased mitochondria must be present in a cell to make that cell diseased.
What is genomic imprinting
Selective inactivation of either the maternal or paternal allele. It is then transmitted throughout the somatic cells.
Describe prader-willi syndrome
- MR
- short stature
- hypotonia
- profound hyperphagia
- small hands and feet
- hypogonadism
Paternal deletion/silence chromosome 15 q12
Describe Angleman syndrome
- MR
- ataxic gait
- seizures
- inappropriate laughter
Deletion of maternal chromosome 15 q12
What is uniparental disomy
When a cell has two copies of a chromosome from one parent and no copies of that chromosome from the other parent.
