*Mitochondrial Inheritance and Disease
Origins of mitochondrial disease
Features of mitochondrial disease
Maternal inheritance patterns of mitochondrial diseases
Heterogeneity of mitochondrial disease
Mitochondria have their own genome
Nucleus encoded genes contribute to mitochondrial functions
Mitochondria have their own alternate genetic code
There is a much higher mutation rate in mitochondria than the nuclear genome
Complications of mitochondrial diseases
Most patients show multisystem involvement
Difficult to diagnose (genetic testing is now most common dx tool)
Can manifest at any age in any tissue system ("heterogeneous in clinical presentation")
Confusing inheritance patterns (Generally maternal w/ mtDNA mutation, but can also be AD, AR, or X linked)
Poor correlation of clinical phenotype with genotype (genetic heterogeneity - same phenotype from diff genes)
Poor correlation between mutation and clinical outcome
Sources of heterogeneity in clinical presentation of mt disorders
Overall amount of DNA (mtDNA copy # is controlled by nuclear genes)
Heteroplasmy
result of high mtDNA mutation rate
Accumulation of mtDNA mutations w/ age
Mutation in one genome may be complimented by non-mutant mtDNAs
Somatic mosaicism
Threshold effects
Tissue specific effects
Homoplasmy
Uniformity of mtDNA
presence of more than one species of mtDNA in a cell
Often involve tissues w/ high energy requirements
Heart (cardiomyopathy, conduction defects)
Brain (developmental delay, ataxia, hearing/vision loss
Skeletal muscle myopathy
Renal, liver, endocrine, diabetes
Can happen at any age in any tissue
Nearly all offspring of affected mother will be affected, no affect from the father
Maternal inheritance is only source
How an mt mutation becomes a disease
Multigenerational process from mutated mtDNA to an affected individual
The process of partitioning of egg cytoplasm and mitochondria during early embryonic cleavage may lead to a high percentage of mutated mitochondria in some blastomeres.
That blastomere eventually becomes an egg and develops into a person who may be affected by that mutation
Environmental and lifestyle factors
Do we have to know these pathologies on the slides? Nope