monogenic diseases

Question 1

modes of inheritance

Answer 1

1) how a disease is transmitted in families
2) predict the recurrence risk for relatives

Question 2

monogenic

Answer 2

1) traits that develop primarily due to the influence of a single gene locus
2) autosomal recessive or dominant, or x-linked recessive or dominant

Question 3

mendelian traits

Answer 3

1) monogenic traits

Question 4

discrete or qualitative (dichotomous yes/no)

Answer 4

1) if they are present, may still be variable and quantifiable in some cases
2) monogenic

Question 5

autosomal dominant traits

Answer 5

1) only one copy of a disease allele is necessary for an individual to be susceptible to expressing the phenotype
2) the trait occurs in successive generations
3) on average, 50% offspring of each parent with the trait will have it
4) male to male transmission observed
5) males and female equally likely
6) parents who do not have the trait have offspring who do not have the trait
- exception when the trait shows nonpenetrance in a particular offspring

Question 6

vertical inheritance

Answer 6

1) transmission from parent to offspring
2) ex. myotonic muscular dystrophy and Huntington disease

Question 7

penetrance

Answer 7

1) when a person inherits a gene allele or genotype that is associated with a specific trait
2) if not evident in that person, it is nonpenetrance
3) in a group of individuals that have the genotype: incomplete penetrance
—
1) ex. hypodontia, class III malocclusion, treacher collins syndrome

Question 8

variable expressivity

Answer 8

1) if the trait is present it can vary in degree of expression
2) thus, not all individuals may have it to the same extent

Question 9

autosomal recessive

Answer 9

1) two copies of the disease allele is required for the phenotype
2) 25% chance the offspring will have it with carrier parents
3) 50% chance the offspring will be carrier
4) 25% chance the offspring will inherit no copies
5) ex. cystic fibrosis

Question 10

consanguineous relationships

Answer 10

1) usually more common to observe these in couples who are related by blood

Question 11

x-linked dominant

Answer 11

1) only one copy of disease allele on X chromosome is required
2) both male and female are affected
- but male shows more severe version
- some are lethal in males
3) when a female is affected, there is a 50% chance of offspring having it
4) if male is affected, all daughters but no sons are affected
5) ex. hypophosphatemic ricketsm, oral facial digital syndrome type I, fragile X

Question 12

x-linked recessive traits

Answer 12

1) two copies of a disease is required on X chromosome for females
2) males are hemizygous so only need one copy
3) for a carrier female, with each pregnancy there is a 50% chance her sons will get it, and 50% chance for female to be carrier
4) affected women will have affected sons and carrier daughters
5) ex. duchenne muscular dystrophy, hemophilia A, hypohydrotic or anhidrotic ectodermal dysplasia

Question 13

monogenic diseases prevalence

Answer 13

1) more than 10,000 are known
2) most are individually rare, affect 1-2% of population at any one time

Question 14

huntington disease prevalence

Answer 14

1) 1:10,000
2) mostly between 30-50
3) start at any age, rare juvinile form with different clinical features

Question 15

huntington disease feature

Answer 15

1) chorea and insidious impairment of intellectual function with psychiatric disturbance and eventual dementia
- mean duration is 15-25 years
2) up to 5% are present before 20 yrs, juvenile HD with rigidity (slowing movement and clumsiness)
- decline in performance and onset of dementia, often in association with epileptic seizures
- 10-15 year duration

Question 16

HD genetics

Answer 16

1) AD inheritance, variable age of onset, almost full penetrance, and demonstrates anticipation (sometimes markedly so through paternal transmission)
2) new mutation rate is low
3) risk to offspring is 50% regardless of male or female parent affected

Question 17

HD genetics in sperm and eggs

Answer 17

1) meiotic instability is greater in spermatogenesis than oogenesis
2) reflected in anticipation, occurring mainly when the mutant allele is transmitted by a male
3) juveniles with a rigid form of HD usually inherit the mutant from their more mildly affected father
4) prenatal diagnosis is possible

Question 18

neurofibromatosis type 1 prevalence

Answer 18

1) 1:3000
2) one of most common genetic disorders

Question 19

NF1 features

Answer 19

1) small pigmented skill lesions (CAL spots) and small soft growth called neurofibromata
2) CAL eppear in early childhood and continue to increase in both size and number until puberty
3) neurofibromata are benign and appear in adolescence or adult life
4) plexifrom neurofibromata may occur and be deep seated and or cutaneous => can interfere with function
5) lisch nodules => small raised pigmented harmatomata of iris
5) mild developmental delay in 1/3 childhood cases

Question 20

NF1 genetics

Answer 20

1) AD inheritance
2) 100% penetrance
3) mutation rate is high and 50% of new cases are due to new mutations
- estimated mutation rate being 1/10,000 gametes

Question 21

myotonic dystrophy type 1 pervalence

Answer 21

1) most common form of muscular dystrophy in adults
2) 1/8000

Question 22

MD1 features

Answer 22

1) slowly progressive weakness and myotonia
- tonic muscle spasm with can be a delay in releasing grip on shaking hands
2)eye, heart, and other body diseases
3) delayed recovery from local anesthesia
4) age of onset is very variable

Question 23

MD1 genetics

Answer 23

1) AD inheritance with anticipation
2) most cases comes from the mother and presents at birth

Question 24

marfan syndrome features

Answer 24

1) first described as long limbs and fingers
2) fibrous CT disorder (fibrillin type 1 which is encoded by FBN1 gene)
2) tall and have joint laxity
3) may have ectopia lentis, and dilation of ascending aorta (can lead to dissection)
4) diagnosis: body measurements, ectocardiography, lumbar MRI

Question 25

MS genetics

Answer 25

1) AD inheritance and are linked to large FBN1 gene on 15q21

Question 26

cystic fibrosis prevalence

Answer 26

1) most common severe AR disorder in western europe
2) 1:2000 or 1:3000
3) much less in other populations

Question 27

CF features

Answer 27

1) mutation in gene changes protein for movement of salt
- thick sticky mucous in respiratory and digestive system
- increased salt and sweat
- chronic lung diseases
- most commonly affects lungs and pancreas
2) 85%, pancreatic function is impaired with reduced enzyme secretion from blockage
3) almost all males are infertile
- bilateral absence of vas deferens
4) other rare presentations are infection in pancreas and blood diseases

Question 28

CF genetics

Answer 28

1) AR inheritance and mutation rate is high

Question 29

duchenne and becker muscular dystrophies prevalence

Answer 29

1) DMD is most common severe form
- 1:3500 males
2) BMD is milder
- 1:20,000 males

Question 30

DMB and BMD features

Answer 30

1) DMD usually present between ages 2-4
- progressive muscle weakness and need wheelchair at age 11
- difficulty rising from the floor, need to push on legs and thighs (gower’s sign)
2) lumbar lordosis, joint contracture, and cardiorespiratory failure
- usually death at 20 years
3) apparent increase in size of calf (pseudohypertrophy with fat and CT)
4) mild to moderate intellectual impairment = IQ about 83

Question 31

DMD and BMD genetics

Answer 31

1) XL recessive diseases and males with DMD rarely reproduce
- genetic fitness is 0

Question 32

hemophilia A

Answer 32

1) most common with incidence 1:5000 males
2) factor VIII deficiency

Question 33

hemophilia B

Answer 33

1) 1:40,000 males
2) factor IX deficiency
2) christmas disease

Question 34

hemophilia features

Answer 34

1) similar in both forms
- mild bleeding to spontaneous bleeding into muscles and joints
2) clinical severity correlates to how much factor VIII or IX is reduced
3) 1% are usually associated with severe hemorrhagic tendency from birth

Question 35

hemophilia treatment

Answer 35

1) replacement therapy with clotting factors
2) some endogenous Abs are inhibitors which destroy them