17. Mitochondrial inheritance

Question 1

What is the role of the mitochondria?

Answer 1

Produce cellular energy in form of ATP via oxidative phosphorylation (OXPHOS)

Important for regulation of cellular metabolism, haemoglobin synthesis, apoptosis

Question 2

Describe the mitochondrial genome

Answer 2

• Circular dsDNA enconding 37 genes
• No introns
• Termination codons created post-transcriptionally by polyadenylation

Question 3

Why is a high mutation rate seen in mtDNA?

Answer 3

Inefficient DNA repair + localised oxidative environment

Question 4

Define homoplasmy & heteroplasmy

Answer 4

Homoplasmy - all copies of mtDNA identical

Heteroplasmy - mixture of 2 or more genotypes

Question 5

What is the ‘threshold level’

Answer 5

The level of heteroplasmy which is clinically relevant

Question 6

Why does the level of heteroplasmy differ between family members

Answer 6

Bottleneck effect

Different gametes have varying levels of heteroplasmy

Question 7

Describe the general profile of mitochondrial disorders

Answer 7

• Involve multiple organ systems, tissues with high metabolic demand (nervous, skeletal muscle, heart)
• Varying age of onset

Question 8

Why is it important to test affected tissue where possible?

Answer 8

Mutation levels change of over time and within tissue types

E.g. increase in muscle, decrease in blood

Question 9

What is MELAS and what causes it?

Answer 9

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes

Most commonly m.3243A>G (heteroplasmic) n MT-TL1 - encodes tRNA

Question 10

What is MERFF and what causes it?

Answer 10

Myoclonic epilepsy with ragged red fibers

Includes epilepsy, myopathy, ataxia

Most commonly m.8344A>G (heteroplasmic) in MT-TK

Question 11

What is NARP?

Answer 11

Sensory neuropathy, ataxia, retinitis pigmentosa

Forms a continuum with Leigh syndrome

Various heteroplasmic variants, m.8993T>G most common

Question 12

What is LHON?

Answer 12

Leber hereditary optic neuropathy

Visual failure and optic atrophy

Mostly homoplasmic

Question 13

What do mtDNA deletions cause?

Answer 13

Pearson syndrome, Kearns-Sayre syndrome, CPEO

Heteroplasmic

Question 14

How do mutations differ in CPEO and Kearns-Sayre?

Answer 14

Both caused by mtDNA deletions

CPEO - in skeletal muscle only
Kearns-Sayre - in all tissues

Question 15

Given an example of nuclear genes which directly affect mtDNA maintenance and expression

Answer 15

POLG, POLG2, TWNK

Question 16

What is the role of genes such as SLC25A4 and RRM2B?

Answer 16

Indirectly effect mtDNA
maintenance and expression through disruption of nucleoside transport, salvage, synthesis

Cause depletion of mtDNA

Question 17

What is the role of genes such as SURF1 and MEGDEL?

Answer 17

Encode components of the respiratory chain - mutations cause mitochondrial dysfunction

Question 18

What is the role of genes such as MFN2 and OPA1?

Answer 18

Involved in mitochondrial fusion and fission

Mutations affect number and distribution of mitochondria, and communication between mito.

Question 19

How are mitochondrial diseases diagnosed?

Answer 19

MTD approach: clinical assessment, FH, biochem., histopathology, histochemistry, genetics

NGS means genetics is often now done first, but still need accurate clinical info for interpretation

Question 20

What is the role of histochemistry in diagnosing mitochondrial disorders?

Answer 20

Stain muscle biopsy, e.g. for ragged red fibres

Test for specific enzymes e.g. SDH, COX

Question 21

What is the role of biochemistry in diagnosing mitochondrial disorders?

Answer 21

Measure rates of flux, substrate oxidation, ATP production

Question 22

For which mt disease is urine a particularly good alternative to muscle?

Answer 22

MELAS

Question 23

What shows that nuclear factors are important in the presentation of mt disease?

Answer 23

Most LHON patients are homoplasmic so all offspring inherit mutation

But only 50% of males and 10% of femailes are symptomatic