Mitochondrial Genetics and Disease Flashcards
what is one of the biggest things to keep in mind when dealing with mitochondrial inheritance?
IT COMES FROM THE MOTHER
What are the diseases that we talked about?
- MELAS
- MERFF
- Chronic progressive external ophthalmoplegia
- Kearns-Sayre syndrome
speak on mitochondria and its DNA
- it has is own DNA
- they have their own genome - contains 37 proteins and 24 parts of the machinery to make proteins (rRNA, tRNA)
what is mitochondrial myopathy?
a muscle disease caused by mitochondrial dysfunction; degeneration of muscle fibers caused by accumulation of abnormal mitochondria
what are the characteristics of mitochondrial disorders?
actually, they express clinical variability and age related progression of disease
how many major types do mitochondrial genetic diseases come in?
4
what are they?
MERRF: Myoclonus Epilepsy with Ragged Red Fibers
MELAS: Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes
KSS: Kearns-Sayre Syndrome
CPEO: Chronic Progressive External Opthalmoplegia
what is the honorable mention and whats it about?
LHON: Leber Hereditary Optic Neuropathy - blindness in late adolescence (muscle not affected)
what are the clinical characteristics of mitochondrial myopathies?
- muscle weakness
- exercise intolerance
- lactic acidosis (cramping)
- neurological signs: mitochondrial encephalopathies
- other associated abnormalities:
- vomiting, seizures, dementia
- stroke-like episodes
- Ptosis (drooping of the eye)
- opthalmoplegia (paralysis of extraocular muscles)
- blindness
- cardiomyopathy
what are ragged red fibers?
aggregates of abnormal mitochondria that form red sarcolemmal blotches
what happens if theres mitochondrial DNA mutation?
a mixture of normal mitochondria and mutant mitochondria in one cell - this is called heteroplasmy
the mutations segregate during cell division by chance
what is interesting about abnormalities in mitochondrial DNA?
the need of a certain level of aberrant mitochondria vs normal mitochondria for disease to occur; this leas to the concept of the threshold effect
threshold effect of mutant mitochondria are required for disease manifestation
what do you need for disease to occur?
need mutation to occur AND a certain percentage of the mitochondria to be aberrant
when reading a Pedigree, whats important to keep in mind?
MALES DO NOT PASS MITOCHONDRIA (THUS CANNOT PASS DISEASE IF THEY, THEMSELVES, ARE DISEASED)
Males do not pass on mitochondrial defects to offspring; only females pass on mitochondria to their offspring
how many proteins does the mitochondrial respiratory chain consist of?
87 proteins; encoded by nuclear and mitochondrial genome
how many of these 87 proteins does the mitochondrial genome encode?
13
how many complexes for the mitochondrial respiration?
5 total
ETC: 4 enzyme complex: I - IV - oxidize NADH and FADH2
complex V is an ATP synthase - uses the H+ ion gradient to alter ADP to ATP
how many gene products does the mtDNA encode for?
37 gene products:
- 13 proteins
- 22 tRNAs
- 2 rRNAs
where does transcription/ translation of mt mRNA occur?
in the mitochondria
what are the two major divisions of mitochondrial mutations?
point mutations in mtDNA tRNA genes: leads to MELAS and MERRF
mtDNA genome deletions and rearrangements: leads to KSS and CPEO
What’s MERRF? what are the clinical features?
myoclonus epilepsy with ragged red fibers
clinical features:
- myoclonus - often first symptom
- M.E.
- Ataxia
- Ragged Red Fibers (muscle tissue)
- Seizures, dementia
what causes MERRF?
90% caused by 2 mutations of tRNA lysine gene
85% of MERRF cases:
- A to G mutation
- position 8344 in mtDNA tRNA-lys gene
5% of MERRF cases:
- G to C
- position 8356 in mtDNA tRNA gene
what causes clinical variability and age related progression of disease?
heteroplasmy
whats MELAS?
Mitochondrial Encephalopathy, Lactic Acidosis with Stroke-like episodes
what are the clinical presentations of MELAS?
seizures strokelike episodes of hemiparesis blindness headaches anorexia recurrent vommiting **lactic acidosis **ragged red fibers
what is the cause of this? and whats the age onset??
caused by A3243G mutation in t-RNA-leu
age of onset usually between 2-10 years (60%)
Whats KSS?
Kearns-Sayre Syndrome
- retinitis pigmentosa (degenerative eye disease leading to blindness)
- at least one of the following
- cardiac conduction abnormality
- cerebellar ataxia
- cerebral spinal protein level above 100 mg/dL
- May have other presentations: optic atrophy, hearing loss, dementia, seizures, cardiomyopathy, lactic acidosis
what causes KSS?
85% of KSS due to mtDNA rearrangements including duplicated mt DNA, deleted mtDNA and insertions
200 different deletions
RRF are seen in skeletal muscle
what is CPEO?
chronic progressive external opthalmoplegia
mild to moderate mitochondrial myopathy (RRF observed in skeletal muscle)
mtDNA rearrangments
**Ptosis (eg drooping of eyelid)
whats LHON?
Leber Hereditary Optic Neuropathy
blindness in late adolescence (muscle not affected)
elaborate on this disease
- mito mutation only affects optic nerve
- no muscle involvement
- acute or subacute, bilateral, central vision loss
- degeneration of the retinal ganglion cell layer and optic nerve
- age of onset = 20s to 30s
- mtDNA mutations in coding genes of complex proteins I
interesting facts about LHON
its not tRNA or mtRNA rearrangements
its mutations that affect mtDNA genes encoding Complex I PROTEINS - (SINGLE BASE PAIR SUBSTITUTIONS)
