Mitochondrial Disorders ✅

Question 1

Why is there multiple copies of the mitochondrial genome in each cell?

Answer 1

Because each mitochondrion carries a copy of its own genome, and each cell of the body contains multiple mitochondria

Question 2

What does the genome of the mitochondrion contain?

Answer 2

Genes encoding proteins essential to mitochondrial function

Question 3

What are mitochondrial disorders?

Answer 3

Disorders caused by mutations in the mitochondrial genome

Question 4

Are the mutations present in all the mitochondria in mitochondrial disorders?

Answer 4

No, they are usually only present in a proportion of the mitochondria in any given cell, with the remainder having a normal sequence

Question 5

What is the term used to describe not all mitochondria within any given cell having mutations in the mitochondrial genome in mitochondrial disorders?

Answer 5

Heteroplasmy

Question 6

What is the clinical relevance of heteroplasmy?

Answer 6

In part, the severity of a disorder depends on the level of heteroplasmy in different tissues

Question 7

Which parent are mitochondria inherited from?

Answer 7

Exclusively from the mother

Question 8

Why are mitochondria inherited exclusively from the mother?

Answer 8

Because there are mitochondria in the egg but not in the part of the sperm that forms the zygote

Question 9

What is the result of all mitochondria being inherited from the mother?

Answer 9

Mitochondrial mutations cannot be passed on by a male

Question 10

Can you predict the level of heteroplasmy in the eggs of a women?

Answer 10

It is hard to predict

Question 11

What is the implication of it being hard to predict the level of heteroplasmy of the eggs of a woman?

Answer 11

It is difficult to predict the level or risk of mitochondrial disease in her offspring

Question 12

In what respects do mitochondrial disorders overlap clinically?

Answer 12

• Tend to affect same organs
• Often show progressive, degenerative course with episodes of decompensation during acute illness
• Lactic acidosis and/or elevated CSF lactate often present

Question 13

What kind of tissues does mitochondrial dysfunction have a tendency to affect?

Answer 13

Tissues that use a large amount of energy

Question 14

What tissues use a large amount of energy and therefore tend to be affected by mitochondrial dysfunction?

Answer 14

• Muscle
• Retina
• Kidney
• Nerves
• Brain

Question 15

What does the effect of mitochondrial dysfunction on the muscle produce?

Answer 15

Myopathy

Question 16

What does the effect of mitochondrial dysfunction on the retina produce?

Answer 16

Retinitis pigments

Question 17

What does the effect of mitochondrial dysfunction on the kidney produce?

Answer 17

• Proximal tubulopathy

- Renal failure

Question 18

What does the effect of mitochondrial dysfunction on the nerves produce?

Answer 18

Neuropathy

Question 19

What does the effect of mitochondrial dysfunction on the pons and cerebellum produce?

Answer 19

• Pontocerebellar atrophy or hypoplasia

- Ataxia

Question 20

What does the effect of mitochondrial dysfunction on the brain produce?

Answer 20

• Epilepsy
• Encephalopathy
• Stroke-like episodes

Question 21

Which parts of the brain in particular do mitochondrial disorders affect?

Answer 21

• Basal ganglia
• Pons
• Cerebellum

Question 22

What does the effect of mitochondrial dysfunction on the basal ganglia produce?

Answer 22

Dystonia

Question 23

When in particular might lactic acidosis and/or elevated CSF lactate be present?

Answer 23

During episodes of decompensation

Question 24

What are the classical mitochondrial phenotypes?

Answer 24

• Myoclonic epilepsy with ragged red fibres (MERRF)
• Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)
• Leigh’s syndrome and the overlapping disorder, neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP)

Question 25

Do mitochondrial disorders always fit into the classical phenotypes?

Answer 25

No

Question 26

What is Leigh’s syndrome?

Answer 26

Subacute necrotising encephalomyelopathy

Question 27

Are the classical phenotypes of mitochondrial disorders limited to only mitochondrial genetic abnormalities?

Answer 27

No, can also be caused by autosomal recessive mutations in conventional nuclear genes

Question 28

Give an example of a classical mitochondrial phenotype that can also be caused by autosomal recessive mutations in conventional nuclear genes?

Answer 28

Leigh’s syndrome

Question 29

Why is a high index of clinical suspicion required to diagnose mitochondrial disorders?

Answer 29

Due to their variability and wide variety of clinical manifestations

Question 30

What are the mainstays of clinical diagnosis of mitochondrial disorders?

Answer 30

• Neuroimaging
• Biochemical testing, including blood and CSF lactate
• Muscle biopsy for histology and electron microscopy
• Skin or muscle respiratory chain enzyme analysis

Question 31

What other investigations may be useful in the diagnosis of mitochondrial disorders?

Answer 31

• Nerve conduction studies
• Urine biochemistry
• Electroretinography

Question 32

How can DNA testing for mitochondrial disorders be carried out?

Answer 32

• Targeted for specific mitochondrial mutations

- Sequence for panel of common mitochondrial mutations, deletions, and duplications

Question 33

What is used to target DNA testing for specific mitochondrial mutations?

Answer 33

The presenting phenotype

Question 34

Is it possible to sequence the entire mitochondrial genome?

Answer 34

Yes (in some labs)

Question 35

What has allowed the entire mitochondrial genome to be sequenced?

Answer 35

The use of higher throughput techniques

Question 36

How is sensitivity maximised when DNA sequencing to look for mitochondrial disorders?

Answer 36

• Using methods able to detect mutations at relatively low levels of heteroplasmy
• Analysis of DNA extracted from muscle

Question 37

Why does analysis of DNA extracted from muscle increase the sensitivity when sequencing to look for mitochondrial disorders?

Answer 37

Mutation load is often higher in muscle

Question 38

What is also performed when the phenotype is also consistent with mutation in a conventional nuclear gene?

Answer 38

Targeted sequencing and/or copy number analysis of these genes is performed