Priority 9 from the Mitochondrial Disease PSP

UNCERTAINTY: Why are people with the same genetic mutation affected so differently in mitochondrial disease? (JLA PSP Priority 9)
Overall ranking	9
JLA question ID	0095/9
Explanatory note	Not available
Evidence	https://pubmed.ncbi.nlm.nih.gov/29880721%20 https://pubmed.ncbi.nlm.nih.gov/29560378/ https://pubmed.ncbi.nlm.nih.gov/31253706/ https://pubmed.ncbi.nlm.nih.gov/30393588/
Health Research Classification System category	Metabolic and Endocrine

Extra information provided by this PSP
Original uncertainty examples	How can family members with the same condition present at different ages with different symptoms? ~ Why do some members of a family get MELAS and others don’t. I carry 20%, my son passed away at [age] from it but my sister and my daughter don’t appear to have any down to 1% that can be tested. ~ Why do similar mutations in mtDNA give rise to such a diversity of phenotypes? ~ What is the importance of heteroplasmy in the brain with respect to CNS phenotypes? Is there regional heteroplasmy within CNS tissue? ~ I would like more research into the effects on carriers of the disease. ~ How does heteroplasmy vary between tissues and cells and what are the mechanisms involved in these changes over time? ~ Why does the heteroplasmy in some gene mutations end up being split between either high or low levels whilst middle levels are a lot more rare? ~ Why one mutation can result in different symptoms in different individuals. ~ Genetic and epigenetic profiling. ~ Role of nuclear modifying genes on mitochondrial DNA
Submitted by	6 x Healthcare professionals, 3 x Carers, 1 x Patients

Extra information provided by this PSP

Original uncertainty examples

How can family members with the same condition present at different ages with different symptoms? ~ Why do some members of a family get MELAS and others don’t. I carry 20%, my son passed away at [age] from it but my sister and my daughter don’t appear to have any down to 1% that can be tested. ~ Why do similar mutations in mtDNA give rise to such a diversity of phenotypes? ~ What is the importance of heteroplasmy in the brain with respect to CNS phenotypes? Is there regional heteroplasmy within CNS tissue? ~ I would like more research into the effects on carriers of the disease. ~ How does heteroplasmy vary between tissues and cells and what are the mechanisms involved in these changes over time? ~ Why does the heteroplasmy in some gene mutations end up being split between either high or low levels whilst middle levels are a lot more rare? ~ Why one mutation can result in different symptoms in different individuals. ~ Genetic and epigenetic profiling. ~ Role of nuclear modifying genes on mitochondrial DNA

Submitted by

6 x Healthcare professionals, 3 x Carers, 1 x Patients

PSP information
PSP unique ID	0095
PSP name	Mitochondrial Disease
Total number of uncertainties identified by this PSP.	42 (To see a full list of all uncertainties identified, please see the detailed spreadsheet held on the JLA website)
Date of priority setting workshop	19 January 2020