17. Mitochondrial inheritance  Flashcards

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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?

A

MELAS

25
Q

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

A

Most LHON patients are homoplasmic so all offspring inherit mutation

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