Saba Ahmad, MD
Assistant Professor of Clinical Pediatrics
Division of Neurology
July 26, 2013
Caused by a mtDNA deletion detected by
Southern Blot performed on the muscle biopsy
Yes. But it doesn’t really matter.
Extremely heterogeneous group of disorders
characterized by failure of mitochondria to
meet the energy needs of a cell
 Organelles found in
most cells
 Known as the
cellular power
plants
 Have their own DNA
and replicate
independently
wit...
 Dominant role is the production of ATP by
oxidative phosphorylation
 Also involved in cell signaling, Calcium
homeostas...
In order to do their
jobs, mitochondria
need about 1500
proteins
BUT
mtDNA only has 37
genes.
mtDNA encodes for a total of 13 peptides of
the ETC found in complexes I, III, IV, and V
(the other 67 are nuclear)
2 mtDN...
 The vast majority of genes involved in
mitochondrial function are actually nuclear
chromosomal DNA
◦ Proteins are synthe...
Mosaicism
Analogous to
chromosomal
mosaicismwhere
nuclear DNA within an
individual can vary
amongst various
tissues
The presence of
different mtDNA
populations within
a cell: At
conception, you get
a bunch of
mitochondria from
mom, and th...
 A cell can have some mitochondria that have a
mutation in the mtDNA and some that do not.
 Homoplasmy refers to a cell ...
This explains why mothers can carry a low
mutation load (have a low level of heteroplasmy)
and be asymptomatic, and have m...
Lets go back to
embryology and
Pretend we have a
zygote undergoing
replication….
 Nuclear genes are responsible for a large portion
of mitochondrial function: replication, ATP
synthesis pathways
 Norma...
Nervous system:
ataxia, dystonia, chorea, athetosis,
myoclonus, leukodystrophy, seizur
es, infantile spasms, cerebral
atro...
 She had mtDNA testing for the mtDNA point
mutations known to cause MELAS and MERRF
in 2004. It was negative.
 She was f...
 Based on her clinical presentation she had
1-encephalopathy (manifested by seizures and
regression)
2-lactic acidosis
3-...
Mitochondrial disorders are not single gene-
single phenotype disorders.
It is useful to recognize that there is a
constel...
mtDNA Mutation Clinical disease process
A8344G MERRF, MELAS, Leigh’s syndrome, Multiple Symmetric
Lipomatosis, Parkinson w...
 Most proteins involved in mitochondrial
functioning are actually nuclear in origin
 They undergo more typical inheritan...
When you have some combination of
 Lactic acidosis
 Myopathy
 Developmental regression
 Failure to thrive
 Unexplaine...
When its really weird
When its really bad
When you can’t find another explanation
Work up the patient in a stepwise manner:
amino/organic acids (elevated alanine?),
lactate/pyruvate, acylcanitine profile,...
 Mitochondrial diseases are typically
progressive (either slowly or catastrophically)
 There is no cure for these disord...
Studies to see if mitochondrial dysfunction is
implicated in a host of other diseases:
Alzheimer’s, Parkinson’s, atheroscl...
Questions?
Mitochondrial disorders overview
Mitochondrial disorders overview
Mitochondrial disorders overview
Mitochondrial disorders overview
Mitochondrial disorders overview
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Transcript of "Mitochondrial disorders overview"

  1. 1. Saba Ahmad, MD Assistant Professor of Clinical Pediatrics Division of Neurology July 26, 2013
  2. 2. Caused by a mtDNA deletion detected by Southern Blot performed on the muscle biopsy
  3. 3. Yes. But it doesn’t really matter.
  4. 4. Extremely heterogeneous group of disorders characterized by failure of mitochondria to meet the energy needs of a cell
  5. 5.  Organelles found in most cells  Known as the cellular power plants  Have their own DNA and replicate independently within the cell  Inherited only from mothers
  6. 6.  Dominant role is the production of ATP by oxidative phosphorylation  Also involved in cell signaling, Calcium homeostasis, apoptosis, its own replication
  7. 7. In order to do their jobs, mitochondria need about 1500 proteins BUT mtDNA only has 37 genes.
  8. 8. mtDNA encodes for a total of 13 peptides of the ETC found in complexes I, III, IV, and V (the other 67 are nuclear) 2 mtDNA genes encode rRNA, and 22 encode tRNA
  9. 9.  The vast majority of genes involved in mitochondrial function are actually nuclear chromosomal DNA ◦ Proteins are synthesized in the cell nucleus and imported into the organelle  A mitochondrial organelle can contain 2-10 copies of its mtDNA  There is this thing called heteroplasmy
  10. 10. Mosaicism Analogous to chromosomal mosaicismwhere nuclear DNA within an individual can vary amongst various tissues
  11. 11. The presence of different mtDNA populations within a cell: At conception, you get a bunch of mitochondria from mom, and they randomly separate as cells divide in in the embryo
  12. 12.  A cell can have some mitochondria that have a mutation in the mtDNA and some that do not.  Homoplasmy refers to a cell that has a uniform collection of mtDNA: either completely normal mtDNA or completely mutant mtDNA.  A unique feature of mtDNA is that, at cell division, the mitochondria sort randomly among daughter cells. Therefore, in cells where heteroplasmy is present, each daughter cell may receive different proportions of mitochondria carrying normal and mutant mtDNA.
  13. 13. This explains why mothers can carry a low mutation load (have a low level of heteroplasmy) and be asymptomatic, and have much more severely affected children-because when eggs are formed, they get random distributions of mitochondrial populations ALSO, Different tissues have varying degrees of sensitivity to mutation loads, related to energy requirements: CNS, myocardium, skeletal muscle, retina, kidneys very commonly involved in mitochondrial disease
  14. 14. Lets go back to embryology and Pretend we have a zygote undergoing replication….
  15. 15.  Nuclear genes are responsible for a large portion of mitochondrial function: replication, ATP synthesis pathways  Normal mitochondria can accumulate mutations over time due to high replication rate, lack of error checking, mitochondrial toxins (mutations in mtDNA occur at a rate of 10-100x that of nuclear DNA)  Maternally inherited mitochondrial mutations which are generally heteroplasmic at birth, undergo a loss of heteroplasmy over time from cell replication
  16. 16. Nervous system: ataxia, dystonia, chorea, athetosis, myoclonus, leukodystrophy, seizur es, infantile spasms, cerebral atrophy, myopathy, neuropathy, st roke, deafness, headache/migraine , developmental delay, regression, dementia, tremo r, bradykinesia, retinopathy, optic atrophy, ophthalmoplegia Constitutional: exercise intolerance, growth failure, microcephaly, cachexia, lac tic acidosis, hyperalaninemia, SIDS GI: nausea, vomiting, dysmotility, pse udoobstruction, constipation, diarr hea, pancreatitis, liver failure, dysphagia, abdominal pain Endocrine: diabetes, hypothyroidism, hypoparathyroidism, ovarian failure, Addison’s, hypopituitarism Renal: FSGS, renal cysts, nephrotic syndrome, RTA Cardiac: cardiomyopathy, conductions defects (WPW), bundle branch block, CAD/atherosclerosis, sudden death Psychiatric: psychosis, mood disorders, autism spectrum disorders Neoplastic: lymphomas, renal cell carcinomas, leiomyomatosis, pheochromocytomas And much much more…
  17. 17.  She had mtDNA testing for the mtDNA point mutations known to cause MELAS and MERRF in 2004. It was negative.  She was found to have mtDNA deletion. The extent of the deletion, genes involved, or her percentage of heteroplasmy is unknown.
  18. 18.  Based on her clinical presentation she had 1-encephalopathy (manifested by seizures and regression) 2-lactic acidosis 3-strokes (she also had RTA, failure to thrive, pancreatic dysfunction, myopathy)
  19. 19. Mitochondrial disorders are not single gene- single phenotype disorders. It is useful to recognize that there is a constellation of features that would indicate a possible mitochondrial disorder, but the specific clinical syndrome is becoming increasingly less useful to identify the underlying genetic problem
  20. 20. mtDNA Mutation Clinical disease process A8344G MERRF, MELAS, Leigh’s syndrome, Multiple Symmetric Lipomatosis, Parkinson with Neuropathy and Myopathy T8356C MERRF, MELAS G8363A MERRF, Cardiomyopathy G8342A PEO with Myoclonus A8296G Deafness and Diabetes G8313A MELAS, MNGIE A2343G MELAS, Cardiomyopathy, PEO, Diabetes, Rhabdomyolysis C3256T MERRF with diabetes/optic atrophy/retinopathy, Diabetes, SIDS T3250C MELAS, riboflavin sensitive myopathy T5824C MNGIE, PEO, MELAS, myopathy
  21. 21.  Most proteins involved in mitochondrial functioning are actually nuclear in origin  They undergo more typical inheritance patterns: AD, AR, X-linked  The presentation tends to be earlier in life, often catastrophic, due to the fact that all cells are typically equally affected (though tissues might be unequally affected due to energy needs)
  22. 22. When you have some combination of  Lactic acidosis  Myopathy  Developmental regression  Failure to thrive  Unexplained cardiomyopathy  Retinopathy/eye movement problems  Sensorineural hearing loss
  23. 23. When its really weird When its really bad When you can’t find another explanation
  24. 24. Work up the patient in a stepwise manner: amino/organic acids (elevated alanine?), lactate/pyruvate, acylcanitine profile, ammonia. Consider storage diseases, VLCFA’s MRI/MRS for radiographic characteristics (does it look like Leigh’s? MELAS?), lactate peak LP for cells, protein, amino acids, lactate/pyruvate. neurotransmitters (movement disorders, progressive epilepsy) Consider muscle biopsy to measure ETC chain enzyme activity, look for ragged red fibers Consider whole mitochondrial genome sequencing, deletion/duplication analysis
  25. 25.  Mitochondrial diseases are typically progressive (either slowly or catastrophically)  There is no cure for these disorders. EXTREMELY limited evidence that supplements like CoEnzyme Q10 and carnitine may slow progression of the disease (but no randomized trials)
  26. 26. Studies to see if mitochondrial dysfunction is implicated in a host of other diseases: Alzheimer’s, Parkinson’s, atherosclerotic disease, autism
  27. 27. Questions?
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