Trinucleotide Repeat Disorders

Question 1

Huntington Disease is a trinucleotide repeat disorder on chromosome _____ at locus _____ with trinucleotide sequence _ _ _ with _____ inheritance. The affected gene is _____ which encodes the ____ protein. The resulting deficit is a result of _______ of the protein.

Answer 1

Chromosome 4; p16.3; CAG; autosomal dominant; HTT; Huntingtin; altered structure/function

Question 2

What five categories of CAG repeats are classified? What is the penetrance/disease severity of each?

Answer 2

39 = full penetrance (affected)
>60 = juvenile onset

Question 3

X-linked Recessive Inheritance

Answer 3

Phenotype expressed in all males who carry the affected genotype
Phenotype expressed in homozygous females only
Heterozygote females are carriers

Question 4

X-linked Dominant Inheritance

Answer 4

Expressed in male hemizygotes and female heterozygotes

Question 5

Fragile X Syndrome

Answer 5

X-linked dominant
Trinucleotide repeat disorder- CGG
1 in 2500-4000 males
1 in 7000-8000 females
Most common cause of inherited developmental delay
Anticipation
Maternal transmission bias

Question 6

Clinical Manifestations of Fragile X

Answer 6

Intellectual disabilities
Dysmorphic features: large ears, long face, macroorchidism
Autistic behavior
Social anxiety
Hand flapping/biting
Aggression

Question 7

Fragile X Gene/protein/locus/mechanism

Answer 7

FMR1
FMRP
Xq27.3
Protein is essential form normal cognitive development and female reproductive function
Increase in the trinucleotide repeat number methylate the gene and the protein is not made

Question 8

Fragile X repeat ranges (4)

Answer 8

CGG Repeats
6-45 Normal range

46-55 Grey Zone

56-200 Premutation

> 200 Full Mutation

Question 9

Duchenne Muscular Dystrophy

Answer 9

Progressive muscular weakness proximal > distal
Calf hypertrophy (due to fat deposits/muscle atrophy)
Dilated cardiomyopathy
CK levels 10x
Onset before the age of 5
Wheelchair bound before 13
Death in their 30’s
Absence of Dystrophin

Question 10

DMD-associated DCM

Answer 10

Dilated cardiomyopathy presenting between 20-40 years of age
Early death
No skeletal muscle involvement
No Dystrophin in the myocardium

Question 11

Hemophilia A occurs in _____ live births (ratio), and affects ____% of carrier females.

Answer 11

X-linked recessive
I in 4000 male births
10% carrier females affected (mildly affected, no spontaneous bleeds)

Question 12

Clinical Manifestations of Hemophilia A

Answer 12

Spontaneous bleeds into joints, muscles or intracranial
Excessive bruising
Prolonged bleeding after injury or incision
Delayed wound healing

Question 13

Mutation/gene/protein causing Hemophilia A?

Answer 13

F8
Factor VIII
Chromosome Xq28
Deficiency of Factor VIII
22A inversion causes 50%

Question 14

Mitochondrial DNA (mtDNA) encodes _____ genes?

Answer 14

37

Question 15

____% of offspring of affected female will be affected?

Answer 15

100%

Question 16

____% of offspring of affected male will be affected?

Answer 16

0%

Question 17

Homoplasmy/Heteroplasmy refer to what, regarding mtDNA? How is this related to replicative segregation? To the threshhold effect?

Answer 17

At cell division the multiple copies of mtDNA replicate and sort randomly among newly synthesized mitochondria. This DNA could be mutated or normal. Heteroplasmy means having both (or many) different variants of mtDNA within a given cell. If a certain threshhold is passed (too much mutated mtDNA), the cell takes on the phenotype of that mutation and the disorder can be seen.

Question 18

4 examples of mitochondrially inherited diseases given in class.

Answer 18

Kearns-Sayre
MELAS (Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)
MERRF (Myoclonic epilepsy with ragged-red fibers)
Leber Hereditary Optic Neuropathy