mitochondrial genetics Flashcards
heteroplasmy
- results in variable penetrance and variable expressivity in mitochondrial disorders
- only some mitochondria that are passed on carry disease-causing mutation (WT and mutant)
complex V deficiency
not clinically testable in US
failure in mitochondrial formation
only caused by nuclear DNA mutation
complex II
only comprised of nuclear subunits
mitDNA
-comprised of 37 genes
+13 proteins
+22 tRNAs
+2 RNAs-6S and 12S
-no introns, no recombination
-continuous replication with high mutation rate relative to nuclear DNA and no histone regulation
-disease causing mutations occur in a tissue-specific fashion
LHON c.11778G>A
protective vision mutation in certain ethnic groups
homoplasmy
can be 100% WT or mutant mitochondrial line presence
threshold effect
specific heteroplasmy load that can be tolerated in a tissue for a specific mtDNA mutation before showing signs of pathology
mit dz recurrence risk
- 1-4% if mother shows no signs or symptoms
- up to 50% if mom is symptomatic
- testing recommended in parents and siblings of a proband to reveal level of heteroplasmy and manage them
high lactic acid
- common reason for mitochondrial referral
- not sensitive or specific though
- complications: using a tournicate or having a child fight the blood stick can spike the levels, handling also tricky
plasma and CSF AAs
- high alanine
- high glycine, tyrosine, proline or sarcosine
urine OAs
- TCA intermediates
- ethyl malonate
- 3-methyl-glutaconate
- dicarboxylic acids
plasma acylcarnitines
- low free levels
- elevated bound:free ratio
- elevations suggestive of FAODs
Leigh syndrome genetics
-can be caused by mitochondrial and nuclear gene mutations; HIGH mtDNA mutation load
-involvement of brainstem, basal ganglia and cerebellum
+subacute necrotization
Brain MRI
- symmetric sign abnormality in deep gray matter
- transient v progressive
- cerebellar atrophy