17. Mitochondrial inheritance  Flashcards

1
Q

What is the role of the mitochondria?

A

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

Also important for regulation of cellular metabolism, haemoglobin synthesis, apoptosis

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2
Q

Describe the mitochondrial genome

A
  • Circular dsDNA enconding 37 genes
  • No introns
  • Multiple copies of mtDNA per mitochondria, multiple mitochondria per cell
  • Termination codons created post-transcriptionally by polyadenylation
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3
Q

Why is a high mutation rate seen in mtDNA?

A

Inefficient DNA repair + localised oxidative environment

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4
Q

Define homoplasmy & heteroplasmy

A

Homoplasmy - all copies of mtDNA identical

Heteroplasmy - mixture of 2 or more genotypes

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5
Q

What is the ‘threshold level’

A

The level of heteroplasmy which is clinically relevant

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6
Q

Why does the level of heteroplasmy differ between family members

A

Bottleneck effect

During production of primary oocytes, each oocyte has a different number of mtDNA molecules

These are then rapidly replicated

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7
Q

Describe the general profile of mitochondrial disorders

A
  • Involve multiple organ systems, tissues with high metabolic demand (nervous, skeletal muscle, heart)
  • Varying age of onset
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8
Q

Why is it important to test affected tissue where possible?

A

Mutation levels change of over time and within tissue types

E.g. increase in muscle, decrease in blood

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9
Q

What is MELAS and what causes it?

A

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes

Seizures, muscle weakness, exercise intolerance

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

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10
Q

How is MERFF characterised and what causes it?

A

Myoclonic epilepsy with ragged red fibers

Epilepsy, myopathy, ataxia

Most commonly heteroplasmic m.8344A>G

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11
Q

How is NARP characterised & what causes it?

A

Sensory neuropathy, ataxia, retinitis pigmentosa

Forms a continuum with Leigh syndrome

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

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12
Q

How is LHON characterised?

A

Leber hereditary optic neuropathy

Visual failure and optic atrophy

Mostly homoplasmic

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13
Q

What do mtDNA deletions cause?

A

Pearson syndrome, Kearns-Sayre syndrome, CPEO

Heteroplasmic

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14
Q

What is the phenotype of Kearns-Sayre syndrome?

A

Pigmentary retinopathy, CPEO, and cardiac conduction abnormality

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15
Q

What is the phenotype of Pearson syndrome?

A

Pancytopenia, pancreatic dysfunction, poor weight gain

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16
Q

How do mutations differ in CPEO and Kearns-Sayre?

A

Both caused by mtDNA deletions

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

17
Q

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

A

POLG, POLG2, TWNK

18
Q

What do mutations in genes such as SLC25A4 and RRM2B cause?

A

Depletion of mtDNA

Effect mtDNA maintenance and expression

19
Q

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

A

Encode components of the respiratory chain - mutations cause mitochondrial dysfunction

20
Q

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

A

Involved in mitochondrial fusion and fission

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

21
Q

How are mitochondrial diseases diagnosed?

A

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

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

22
Q

What is the role of histochemistry in diagnosing mitochondrial disorders?

A

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

Test for specific enzymes e.g. SDH, COX

23
Q

What is the role of biochemistry in diagnosing mitochondrial disorders?

A

Measure rates of substrate oxidation, ATP production

24
Q

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

25
What shows that nuclear factors are important in the presentation of mt disease?
Most LHON patients are homoplasmic so all offspring inherit mutation But only 50% of males and 10% of females are symptomatic