W6-Lecture 7.1-Principles of Genetic Inheritance – UNUSUAL mechanisms of disease (Part 2) (3)

Question 1

A transmission of all mitochondria associated disease and disoders from parent to offspring during genetic inheritance is driven by which parent?

Answer 1

Mother

Question 2

A parent playing a role in mitochondrial inheritance of a child.

Answer 2

Mother

Question 3

A cell whose all mitochondrial DNA copies are identical

Answer 3

Homoplasmy

Question 4

A cell whose mitochondrial DNA copies are not identical, and consists of both mutant and normal mitochondria

Answer 4

Heteroplasmy

Question 5

What causes heteroplasmy?

Answer 5

• Mutations on mitochondrial DNA copies of a parent mitochondria

Daughter cells inherit a population of mitochondria that may contain a mixture of wild-type and mutant mtDNA.

Question 6

What are the clinical phenotypes associated with
mitochondrial dysfunction

Answer 6

• Muscle symptoms:
  *Ptosis, external ophthalmoplegia, muscle pain, progressive proximal
  muscle weakness, fatigue, cardiomyopathy
• Central nervous system symptoms:
  *Ataxia, seizures, stroke, early onset dementia, deafness
• Metabolic disorders:
  *Diabetes mellitus, liver dysfunction

Question 7

When to consider a mitochondrial disoder as part of the differential diagnoses?

Answer 7

1. A common condition occurs with atypical features (unusual or unexpected) – E.g. A 3 year old child has a stroke
2. More than three organ systems are involved in a progressive disorder – E.g. muscle weakness, ophthalmoplegia and arrhythmias in a 20 year old patient.
3. Specific set of clinical signs
   * MELAS – mitochondrial encephalomyopathy, lactic acidosis, stroke-like
   episodes
   * NARP – neurogenic weakness with ataxia and retinitis pigmentosa

Question 8

Things to consider or look for with genetic testing for a suspected mitochondrial disorder

Answer 8

Supportive laboratory findings include:
*High serum lactate levels (persistently >2.5)
*Raised lactate: pyruvate ratio (>20)

• Sequencing of the mitochondrial genome
  *Look for point mutations and deletion/duplication analysis
  *This should be done on the affected tissue –thus a muscle biopsy is often performed

*If muscle biopsy done:
*Histology – look for ‘ragged red fibres’
*Use Immuno-histochemical stains to look for deficiencies in specific mitochondrial proteins