17. Mitochondrial inheritance Flashcards
What is the role of the mitochondria?
Produce cellular energy in form of ATP via oxidative phosphorylation (OXPHOS)
Also important for regulation of cellular metabolism, haemoglobin synthesis, apoptosis
Describe the mitochondrial genome
- Circular dsDNA enconding 37 genes
- No introns
- Multiple copies of mtDNA per mitochondria, multiple mitochondria per cell
- Termination codons created post-transcriptionally by polyadenylation
Why is a high mutation rate seen in mtDNA?
Inefficient DNA repair + localised oxidative environment
Define homoplasmy & heteroplasmy
Homoplasmy - all copies of mtDNA identical
Heteroplasmy - mixture of 2 or more genotypes
What is the ‘threshold level’
The level of heteroplasmy which is clinically relevant
Why does the level of heteroplasmy differ between family members
Bottleneck effect
During production of primary oocytes, each oocyte has a different number of mtDNA molecules
These are then rapidly replicated
Describe the general profile of mitochondrial disorders
- Involve multiple organ systems, tissues with high metabolic demand (nervous, skeletal muscle, heart)
- Varying age of onset
Why is it important to test affected tissue where possible?
Mutation levels change of over time and within tissue types
E.g. increase in muscle, decrease in blood
What is MELAS and what causes it?
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
How is MERFF characterised and what causes it?
Myoclonic epilepsy with ragged red fibers
Epilepsy, myopathy, ataxia
Most commonly heteroplasmic m.8344A>G
How is NARP characterised & what causes it?
Sensory neuropathy, ataxia, retinitis pigmentosa
Forms a continuum with Leigh syndrome
Various heteroplasmic variants, m.8993T>G most common
How is LHON characterised?
Leber hereditary optic neuropathy
Visual failure and optic atrophy
Mostly homoplasmic
What do mtDNA deletions cause?
Pearson syndrome, Kearns-Sayre syndrome, CPEO
Heteroplasmic
What is the phenotype of Kearns-Sayre syndrome?
Pigmentary retinopathy, CPEO, and cardiac conduction abnormality
What is the phenotype of Pearson syndrome?
Pancytopenia, pancreatic dysfunction, poor weight gain
How do mutations differ in CPEO and Kearns-Sayre?
Both caused by mtDNA deletions
CPEO - in skeletal muscle only
Kearns-Sayre - in all tissues
Given an example of nuclear genes which directly affect mtDNA maintenance and expression
POLG, POLG2, TWNK
What do mutations in genes such as SLC25A4 and RRM2B cause?
Depletion of mtDNA
Effect mtDNA maintenance and expression
What is the role of genes such as SURF1 and MEGDEL?
Encode components of the respiratory chain - mutations cause mitochondrial dysfunction
What is the role of genes such as MFN2 and OPA1?
Involved in mitochondrial fusion and fission
Mutations affect number and distribution of mitochondria, and communication between mito.
How are mitochondrial diseases diagnosed?
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
What is the role of histochemistry in diagnosing mitochondrial disorders?
Stain muscle biopsy, e.g. for ragged red fibres
Test for specific enzymes e.g. SDH, COX
What is the role of biochemistry in diagnosing mitochondrial disorders?
Measure rates of substrate oxidation, ATP production
For which mt disease is urine a particularly good alternative to muscle?
MELAS
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
