Mitochondrial Genetics and Disease

Question 1

what is one of the biggest things to keep in mind when dealing with mitochondrial inheritance?

Answer 1

IT COMES FROM THE MOTHER

Question 2

What are the diseases that we talked about?

Answer 2

• MELAS
• MERFF
• Chronic progressive external ophthalmoplegia
• Kearns-Sayre syndrome

Question 3

speak on mitochondria and its DNA

Answer 3

• it has is own DNA

- they have their own genome - contains 37 proteins and 24 parts of the machinery to make proteins (rRNA, tRNA)

Question 4

what is mitochondrial myopathy?

Answer 4

a muscle disease caused by mitochondrial dysfunction; degeneration of muscle fibers caused by accumulation of abnormal mitochondria

Question 5

what are the characteristics of mitochondrial disorders?

Answer 5

actually, they express clinical variability and age related progression of disease

Question 6

how many major types do mitochondrial genetic diseases come in?

Answer 6

4

Question 7

what are they?

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

Question 8

what is the honorable mention and whats it about?

Answer 8

LHON: Leber Hereditary Optic Neuropathy - blindness in late adolescence (muscle not affected)

Question 9

what are the clinical characteristics of mitochondrial myopathies?

Answer 9

• muscle weakness
• exercise intolerance
• lactic acidosis (cramping)
• neurological signs: mitochondrial encephalopathies
• other associated abnormalities:
• vomiting, seizures, dementia
• stroke-like episodes
• Ptosis (drooping of the eye)
• opthalmoplegia (paralysis of extraocular muscles)
• blindness
• cardiomyopathy

Question 10

what are ragged red fibers?

Answer 10

aggregates of abnormal mitochondria that form red sarcolemmal blotches

Question 11

what happens if theres mitochondrial DNA mutation?

Answer 11

a mixture of normal mitochondria and mutant mitochondria in one cell - this is called heteroplasmy

the mutations segregate during cell division by chance

Question 12

what is interesting about abnormalities in mitochondrial DNA?

Answer 12

the need of a certain level of aberrant mitochondria vs normal mitochondria for disease to occur; this leas to the concept of the threshold effect

threshold effect of mutant mitochondria are required for disease manifestation

Question 13

what do you need for disease to occur?

Answer 13

need mutation to occur AND a certain percentage of the mitochondria to be aberrant

Question 14

when reading a Pedigree, whats important to keep in mind?

Answer 14

MALES DO NOT PASS MITOCHONDRIA (THUS CANNOT PASS DISEASE IF THEY, THEMSELVES, ARE DISEASED)

Males do not pass on mitochondrial defects to offspring; only females pass on mitochondria to their offspring

Question 15

how many proteins does the mitochondrial respiratory chain consist of?

Answer 15

87 proteins; encoded by nuclear and mitochondrial genome

Question 16

how many of these 87 proteins does the mitochondrial genome encode?

Answer 16

13

Question 17

how many complexes for the mitochondrial respiration?

Answer 17

5 total
ETC: 4 enzyme complex: I - IV - oxidize NADH and FADH2

complex V is an ATP synthase - uses the H+ ion gradient to alter ADP to ATP

Question 18

how many gene products does the mtDNA encode for?

Answer 18

37 gene products:

• 13 proteins
• 22 tRNAs
• 2 rRNAs

Question 19

where does transcription/ translation of mt mRNA occur?

Answer 19

in the mitochondria

Question 20

what are the two major divisions of mitochondrial mutations?

Answer 20

point mutations in mtDNA tRNA genes: leads to MELAS and MERRF

mtDNA genome deletions and rearrangements: leads to KSS and CPEO

Question 21

What’s MERRF? what are the clinical features?

Answer 21

myoclonus epilepsy with ragged red fibers

clinical features:

• myoclonus - often first symptom
• M.E.
• Ataxia
• Ragged Red Fibers (muscle tissue)
• Seizures, dementia

Question 22

what causes MERRF?

Answer 22

90% caused by 2 mutations of tRNA lysine gene

85% of MERRF cases:

• A to G mutation
• position 8344 in mtDNA tRNA-lys gene

5% of MERRF cases:

• G to C
• position 8356 in mtDNA tRNA gene

Question 23

what causes clinical variability and age related progression of disease?

Answer 23

heteroplasmy

Question 24

whats MELAS?

Answer 24

Mitochondrial Encephalopathy, Lactic Acidosis with Stroke-like episodes

Question 25

what are the clinical presentations of MELAS?

Answer 25

seizures
strokelike episodes of hemiparesis
blindness
headaches
anorexia
recurrent vommiting 
**lactic acidosis
**ragged red fibers

Question 26

what is the cause of this? and whats the age onset??

Answer 26

caused by A3243G mutation in t-RNA-leu

age of onset usually between 2-10 years (60%)

Question 27

Whats KSS?

Answer 27

Kearns-Sayre Syndrome

• retinitis pigmentosa (degenerative eye disease leading to blindness)
• at least one of the following
• cardiac conduction abnormality
• cerebellar ataxia
• cerebral spinal protein level above 100 mg/dL
• May have other presentations: optic atrophy, hearing loss, dementia, seizures, cardiomyopathy, lactic acidosis

Question 28

what causes KSS?

Answer 28

85% of KSS due to mtDNA rearrangements including duplicated mt DNA, deleted mtDNA and insertions

200 different deletions

RRF are seen in skeletal muscle

Question 29

what is CPEO?

Answer 29

chronic progressive external opthalmoplegia

mild to moderate mitochondrial myopathy (RRF observed in skeletal muscle)

mtDNA rearrangments

**Ptosis (eg drooping of eyelid)

Question 30

whats LHON?

Answer 30

Leber Hereditary Optic Neuropathy

blindness in late adolescence (muscle not affected)

Question 31

elaborate on this disease

Answer 31

• mito mutation only affects optic nerve
• no muscle involvement
• acute or subacute, bilateral, central vision loss
• degeneration of the retinal ganglion cell layer and optic nerve
• age of onset = 20s to 30s
• mtDNA mutations in coding genes of complex proteins I

Question 32

interesting facts about LHON

Answer 32

its not tRNA or mtRNA rearrangements

its mutations that affect mtDNA genes encoding Complex I PROTEINS - (SINGLE BASE PAIR SUBSTITUTIONS)