Mitochondrial Disorders ✅ Flashcards

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1
Q

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

A

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

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2
Q

What does the genome of the mitochondrion contain?

A

Genes encoding proteins essential to mitochondrial function

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3
Q

What are mitochondrial disorders?

A

Disorders caused by mutations in the mitochondrial genome

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4
Q

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

A

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

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5
Q

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

A

Heteroplasmy

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6
Q

What is the clinical relevance of heteroplasmy?

A

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

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7
Q

Which parent are mitochondria inherited from?

A

Exclusively from the mother

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8
Q

Why are mitochondria inherited exclusively from the mother?

A

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

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9
Q

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

A

Mitochondrial mutations cannot be passed on by a male

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10
Q

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

A

It is hard to predict

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11
Q

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

A

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

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12
Q

In what respects do mitochondrial disorders overlap clinically?

A
  • 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
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13
Q

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

A

Tissues that use a large amount of energy

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14
Q

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

A
  • Muscle
  • Retina
  • Kidney
  • Nerves
  • Brain
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15
Q

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

A

Myopathy

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16
Q

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

A

Retinitis pigments

17
Q

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

A
  • Proximal tubulopathy

- Renal failure

18
Q

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

A

Neuropathy

19
Q

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

A
  • Pontocerebellar atrophy or hypoplasia

- Ataxia

20
Q

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

A
  • Epilepsy
  • Encephalopathy
  • Stroke-like episodes
21
Q

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

A
  • Basal ganglia
  • Pons
  • Cerebellum
22
Q

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

A

Dystonia

23
Q

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

A

During episodes of decompensation

24
Q

What are the classical mitochondrial phenotypes?

A
  • 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)
25
Q

Do mitochondrial disorders always fit into the classical phenotypes?

A

No

26
Q

What is Leigh’s syndrome?

A

Subacute necrotising encephalomyelopathy

27
Q

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

A

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

28
Q

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

A

Leigh’s syndrome

29
Q

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

A

Due to their variability and wide variety of clinical manifestations

30
Q

What are the mainstays of clinical diagnosis of mitochondrial disorders?

A
  • Neuroimaging
  • Biochemical testing, including blood and CSF lactate
  • Muscle biopsy for histology and electron microscopy
  • Skin or muscle respiratory chain enzyme analysis
31
Q

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

A
  • Nerve conduction studies
  • Urine biochemistry
  • Electroretinography
32
Q

How can DNA testing for mitochondrial disorders be carried out?

A
  • Targeted for specific mitochondrial mutations

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

33
Q

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

A

The presenting phenotype

34
Q

Is it possible to sequence the entire mitochondrial genome?

A

Yes (in some labs)

35
Q

What has allowed the entire mitochondrial genome to be sequenced?

A

The use of higher throughput techniques

36
Q

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

A
  • Using methods able to detect mutations at relatively low levels of heteroplasmy
  • Analysis of DNA extracted from muscle
37
Q

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

A

Mutation load is often higher in muscle

38
Q

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

A

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