1. Saba Ahmad, MD
Assistant Professor of Clinical Pediatrics
Division of Neurology
July 26, 2013

3. Caused by a mtDNA deletion detected by
Southern Blot performed on the muscle biopsy

4. Yes. But it doesn’t really matter.

5. Extremely heterogeneous group of disorders
characterized by failure of mitochondria to
meet the energy needs of a cell

6.  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

7.  Dominant role is the production of ATP by
oxidative phosphorylation
 Also involved in cell signaling, Calcium
homeostasis, apoptosis, its own replication

11. In order to do their
jobs, mitochondria
need about 1500
proteins
BUT
mtDNA only has 37
genes.

12. 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

13.  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

14. Mosaicism
Analogous to
chromosomal
mosaicismwhere
nuclear DNA within an
individual can vary
amongst various
tissues

15. 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

16.  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.

17. 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

18. Lets go back to
embryology and
Pretend we have a
zygote undergoing
replication….

19.  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

20. 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…

21.  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.

22.  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)

23. 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

24. 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

26.  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)

27. When you have some combination of
 Lactic acidosis
 Myopathy
 Developmental regression
 Failure to thrive
 Unexplained cardiomyopathy
 Retinopathy/eye movement problems
 Sensorineural hearing loss

28. When its really weird
When its really bad
When you can’t find another explanation

29. 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

30.  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)

31. Studies to see if mitochondrial dysfunction is
implicated in a host of other diseases:
Alzheimer’s, Parkinson’s, atherosclerotic
disease, autism

32. Questions?