Lecture 33

Question 1

Describe heteroplasmy as it relates to mitochondrial genetic disease

Answer 1

heteroplasmy describes the mixture of normal and mutated mitochondria that can occur in a person with mitochondrial genetic disease or someone who is prone to it

normal and mutated mitochondria are randomly separated during cell division, and the level ratio (of heteroplasmy) determines if that person has/doesn’t have a mito. genetic disease

heteroplasmy above the threshold = disease and below = no disease

Question 2

Describe the rules of maternal inheritance as it relates to mitochondrial disease

Answer 2

a person’s mito are ALL inherited from the mother, bc sperm do not contribute their mito to the zygote (only their DNA)

this means that a father with mito. genetic disease cannot pass it to his children, only mothers can

Question 3

Describe the threshold concept and its relationship to mitochondrial genetic disease

Answer 3

if a pt’s percentage of mutant mito to normal mito reaches or surpasses the the threshold, then they will develop a mito. genetic disease

Question 4

How many genes does the mitochondrial genome include? how many of those code for proteins?

Answer 4

the mitochondrial genome has 37 genes total

13 of them code for proteins

The other 24 code for rRNA and tRNA

Question 5

State the 2 main characteristics of mitochondrial disorders. These characteristics are due to what?

Answer 5

Clinical variability

age related progression of the disease

Both of these are due to heteroplasmy that decides the time of onset and severity of the disease
ex. 95% mutant mtDNA will develop earlier and more rapidly than 85% mutant mtDNA

Question 6

What is a mitochondrial myopathy?

Answer 6

a muscle disease caused by mitochondrial dysfunction

Question 7

List the 4 mitochondrial myopathies (include the honorable mention one as well)

Answer 7

MERRF: myoclonus epilepsy with ragged red fibers

MELAS: mitochondrial encephalopathy lactic acidosis and stroke-like episodes

KSS: Kearns-Sayre Syndrome

CPEO: Chronic progressive external opthalmoplegia

(honorable mention)
LHON: Leber hereditary optic neuropathy
(it is honorable mention because muscle is not affected by it, it causes blindness in late adolescence)

Question 8

List the clinical characteristics of mitochondrial myopathies

Answer 8

Lactic acidosis

Exercise intolerance

Muscle weakness

Other

Neurological signs (encephalopathies)

“LEMON”

Question 9

define ragged red fibers

Answer 9

aggregates of abnormal mitochondria that form red sarcolemmal blotches

(commonly found in mitochondrial myopathies)

Question 10

Describe the mutation rate of mitochondrial DNA (mtDNA) and the types of tissues that are most commonly affected by mitochondrial genetic diseases

Answer 10

mtDNA has a very high mutation rate

neurological and muscle tissue are the most affected (bc they require lots of mito to provide energy)
ex. Brain/CNS, Heart, skeletal muscle

Question 11

what proportion of a mature egg cell’s genome is composed of mtDNA?

Answer 11

1/3rd

Question 12

how many proteins construct the mitochondrial respiratory chain? how many total complexes are involved in mitochondrial respiration?

Answer 12

87 proteins

5 total complexes

Question 13

Describe what complexes I through V are involved in and what type of DNA encodes for each of them. (include why complex V is important)

Answer 13

Complexes I through IV are enzyme complexes involved in the E.T.C. that serve to oxidize NADH and FADH2

Complex V is an ATP synthase that uses the H+ gradient (created by the E.T.C.) to create ATP from ADP

Complexes I through V are encoded by both nuclear DNA and mtDNA

Question 14

List 4 distinctive characteristics of mtDNA, compared to nuclear DNA

Answer 14

It has no DNA repair mechanisms

there is no recombination of the mtDNA

mtDNA has a 10 times higher mutation rate

mtDNA is maternally inherited

Question 15

state the 2 major divisions of causes of mitochondrial mutations and the respective diseases that are caused by each (2 diseases per cause)

Answer 15

point mutations in mtDNA tRNA genes: cause MELAS and MERRF

mtDNA genome deletions and rearrangements: cause KSS and CPEO

Question 16

The following are clinical features of what mitochondrial myopathy?

involuntary jerking
epilepsy
ataxia
RRF's in skeletal muscle
seizures

Answer 16

MERRF (myoclonus epilepsy with RRF’s disease)

Question 17

The following are clinical features of what mitochondrial myopathy?

Seizures (stroke-like episodes of hemiparesis (weakness of one side of the body))
Blindness
Headaches
Anorexia
Recurrent vomiting
Lactic acidosis
RRF's in skeletal muscle

Answer 17

MELAS (mitochondrial encephalopathy lactic acidosis and stroke-like episodes)

Question 18

The following are clinical features of what mitochondrial myopathy?

Retinitis pigmentosa (degenerative eye disease leading to blindness)
At least one of the following (Cardiac conduction abnormality, Cerebellar ataxia, and Cerebral spinal protein level above 100 mg/dL)
optic atrophy
hearing loss
dementia
seizures
cardiomyopathy
lactic acidosis
RRF's in skeletal muscle

Answer 18

KSS (Kearns-Sayre Syndrome)

Question 19

The following are clinical features of what mitochondrial myopathy?

mild to moderate RRF’s in skeletal muscle
Ptosis

Answer 19

CPEO (Chronic progressive external opthalmoplegia)

Question 20

The following are clinical features of what mitochondrial myopathy?

acute, subacute, bilateral, central vision loss
degeneration of the retinal ganglion cell layer and optic nerve
no muscle issues/myopathies
one eye is initially affected, but it eventually affects both
RRF’s in skeletal muscle

Answer 20

LHON (Leber Hereditary Optic Neuropathy)

Question 21

LHON is caused by what specific type of mutation of mtDNA and what is it he average age of onset for this disease?

Answer 21

single base pair substitutions in the mtDNA that codes for complex I proteins (normal complex I should have 7 subunits)

the average age of onset is in the 20s to 30s

Question 22

90% of MERRF cases are caused by __ mutations of _____

Answer 22

2

tRNA lys

Question 23

85% of MERRF cases are due to __ to __ mutation in the mtDNA tRNA-lys gene at nucleotide position ____

Answer 23

A

G

8344

Question 24

5% of MERRF cases are due to __ to __ mutation in the mtDNA tRNA-lys gene at nucleotide position ____

Answer 24

G

C

8356

Question 25

what is the specific mutation that causes MELAS and what is the usual age of onset for it?

Answer 25

a change from A to G at the 3243 position in tRNA leu

60% of cases have an onset between 2-10 years of age

Question 26

what is the specific mutation that causes KSS and what is the usual age of onset for it?

Answer 26

85% of KSS is due to mtDNA rearrangments (this includes duplicated mtDNA, deleted mtDNA, and insertions)

there are 200 differrent deletions that are known to be associated with KSS development

the average age of onset is before age 20

Question 27

List the 3 characteristic symptoms that almost always occur in KSS patients.

Answer 27

Cardiac conduction abnormality

Cerebellar ataxia

Cerebral spinal protein level greater than 100 mg/dL