Transcript Lecture 3. Mitochodrial pathology

General characterization of
mitochondrial pathology.
Clinical symptoms.
Diagnostics. Treatment.
As. Prof. Sakharova Inna Ye., MD,PhD
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Mitochondrial diseases (MD) are a group
of disorders relating to the mitochondria,
the organelles that are the "powerhouses"
of the eukaryotic cells that compose
higher-order life-forms (including humans).
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Mitochondria are responsible for creating more
than 90% of the energy needed by the body to
sustain life and support growth.
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Food is converted into ATP (stored energy)
by means of enzymes in the electron
transport chain (or respiratory chain) inside
the mitochondria. The process itself is called
oxidative phosphorylation. Defects in either
the mitochondrial DNA or the DNA of the
nucleus can impair this process and cause
mitochondrial failure.
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A primary cause of mitochondrial
diseases is a defect in nuclear DNA
(nDNA) encoding for mitochondrial
protein or in mitochondrial DNA
(mtDNA).
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Secondary causes of mitochondrial diseases
are brought on by factors such as
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ischemia,
reperfusion,
cardiovascular diseases,
renal failure,
pancreatic and hepatic damage,
diabetes,
infectious agents,
gastrointestinal diseases,
oncologic diseases,
alcohol, smoking, stress, drugs and aging.
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Every 30 minutes a child is born who
will develop a mitochondrial
disease by age 10.
UMDF, 2009
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At least 1 in 200 individuals in the
general public have a mitochondrial
DNA mutation that may lead to
disease.
UMDF, 2009
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Patients’ symptoms can range from extremely
mild to severe, involve one or more body
systems, and can emerge at any age. Most
patients’ symptoms fluctuate over the course
of their illness - at some times experiencing no
or few symptoms while at other times
experiencing many and/or
severe symptoms.
Even family members
with the same disorder
can experience vastly
different symptoms
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Mitochondrial diseases should be
considered in any patient with
unexplained multi-system involvement
with a progressive course.
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Hallmarks of Mitochondrial
Disease
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A “common disease” has atypical features
that set it apart from the pack.
More than one organ systems are involved
Recurrent setbacks or flare-ups in a chronic
disease occur with infection
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Newborn Assessment (Catastrophic
Presentations of Metabolic Disease in the
Newborn)
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Nonspecific findings may mimic shock, sepsis or
SIDS
Lethargy, irritability, hyperactivity
Failure to feed well
Hypothermia or fevers (fevers due to viral illnesses
and those in which no cause is discovered)
Cyanosis
Seizures
Vomiting
Jaundice (early and/or prolonged)
Diarrhea or abdominal bloating
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Exam of the Infant
Odor
 Neurologic: tone, level of alertness,
deep tendon reflexes
 General: dysmorphic features, large
liver or spleen
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Mitochondrial Disease in Adults
As varied as in children, more complicated to
diagnosis because adults have acquired
other diseases through the years.
Mitochondrial diseases tend not to present
as catastrophic events.
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POSSIBLE SYMPTOMS of MD
 Brain
* Developmental delays
* Mental retardation
* Dementia
* Seizures
* Neuro-psychiatric disturbances
* Migraines
* Atypical Cerebral Palsy
* Strokes
* Autistic featues
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Eyes & Ears
* Visual loss/blindness
* Ptosis ( droopy eyelids)
* Ophthalmoplegia
* Optic Atrophy
* Hearing Loss/deafness
* Acquired strabismus (squint)
* Retinitis pigmentosa
Muscles
• Weakness
• Muscle pain
• Pseudo-obstruction
• Irritable Bowel Syndrome
• Cramping
• Diarrhea or Constipation
• Dysmotility
• Gastroesophogeal reflux
• Hypotonia
•Gastrointestinal problems
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Many experts refer to Mitochondrial Disease
as the "Notorious Masquerader"
because it wears the mask
of many different illnesses.
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In 2004 several criteria for
mitochondrial diseases were published,
as Walker criteria, Nijgemen criteria,
Nonaka criteria and Wolfson criteria.
Mitochondrial diseases were classified
by the International Classification of
Diseases with clinical modification
(ICD-10-CM).
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The following syndromes are important
for the understanding of mitochondrial
medicine:
1. KSS – (Kearns-Sayre Syndrome) with
ophthalmoplegia, retinal pigmental
degeneration, sometimes heart block,
ataxia, hyperparathyroidism and short
stature. There is a defect in coenzyme
Q metabolism in KSS and it becomes
manifest before the age of 20 years.
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2. MERRF – (myoclonic epilepsy and
ragged red fibers syndrome) with
intensemyoclonus, epilepsy,
progressive ataxia, muscle weakness
and wasting, deafness, and dementia.
Maternal inheritance and reduced
activities of Complexes I and IV are
established in MERRF.
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3. MELAS – (mitochondrial myopathy,
encephalomyopathy, lactic acidosis,
and stroke-like episodes) with episodic
vomiting, lactic acidosis, and myopathy
with ragged red fibers, sometimes
dementia, generalized seizures,
deafness, and short stature. Reduced
activities in Complexes I and IV are
established.
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4. CPEO – (chronic progressive external
ophthalmoplegia) with signs and
symptoms similar to those in KSS but
in addition there is retinitis pigmentosa
and CNS dysfunction.
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5. LHON – (Leber’s hereditary optic
neuropathy) with optic atrophy and
retinal microangiopathy, and in some
patients movement disorders, bulbar
dysfunction, EEG abnormalities and
short stature. Maternal inheritance and
reduced activity of Complex I are well
established in LHON. The manifestations
appear at the age of 12–30 years.
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DIAGNOSTICS ?
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Metabolic Screening
( in all patients)
- Basic Chemistries
- Liver enzymes &
Ammonia
- Complete Blood Count
- Creatine Kinase
-Blood Lactic and
Pyruvic acids
-Quantitative Plasma
Amino Acids
- Quantitative Urine
Organic Acids
- Plasma Acylcarnitine
Profile
Metabolic Screening
In Spinal Fluid
( for patients with
neurological symptoms)
- Blood Lactic and Pyruvic
acids
- Quantitative Amino Acids
- Neurotransmitter studies
- Routine studies including
Glucose, Protein, and Cell
Count
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Clinical
Neurogenetic
Evaluation (for those
with developmental
delays)
-Echocardiogram
- Electrocardiogram
(EKG)
- Ophthalmic Exam
- Auditory Exam
-Brain MRI
Characterize
Systemic
Involvement
- Karyotype
- Fragile X Testing
- Neurology Consult
-Genetics Consult
-Muscle biopsy
(RRF - ragged red
fibers)
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Negative results have a high false
negative rate; if mitochondrial
disease is suspected, the patient
should be refered to a
Mitochondrial Disease Center.
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Purposes of Treatment
alleviate symptoms
 slow down progression of the disease
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Key Points for Treatment
Dietary
 Vitamins and supplements
 Avoidance of stressful factors
 Exercise
 Additional therapies
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Suggested To Most Patients
Supplement
CoQ10
levo-carnitine
(Carnitor®)
Riboflavin (B2)
Purpose
provide energy beyond enzyme
defect site, antioxidant
transports long-chain fatty acids,
binds unused metabolic products
precursor of 2 cofactors involved in
electron transport chain
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Supplement
Purpose
Acety-L-Carnitine
another form of carnitine, may have
more neurological effect
Thiamine (B1)
co-factor and activator of pyruvate
dehydrogenase, reduce lactate
levels
Nicotinamide (B3)
may boost electron transport chain
activity
Vitamin E
antioxidant
Vitamin C
antioxidant
Lipoic Acid (a-lipoate)
Selinium
B-carotene
antioxidant
co enzyme for pyruvate dehydrogenase &
alpha ketogluatarate dehydrogenase
antioxidant
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Research supporting the link between mitochondrial
dysfunction and some of these other common
illnesses includes:
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• Mitochondrial coenzyme Q10 levels are reduced in
patients with Parkinson’s disease and mitochondrial
function in these patients is impaired.
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• Results of the first placebo-controlled clinical trial
of the compound coenzyme Q10 suggest that it can
slow disease progression in patients with earlystage Parkinson’s disease.
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• These findings are consistent with another recent
study involving patients with early onset
Huntington’s disease. These patients showed
slightly less functional decline in groups receiving
coQ10.
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A drug once approved as an antihistamine in
Russia improved thinking processes and the
ability to function in Alzheimer’s disease
patients. The drug works by stabilizing
mitochondria.
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• Cancers are also associated with defects in the
mitochondria. Within the cell, signaling must
occur between the mitochondria and the
nucleus. When the signaling malfunctions, the
defect can cause cancer.
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• Researchers discovered that mutations in the
mitochondrial DNA may play a role in tumor
metastasis and suggests a possible new avenue
for the development of a treatment to suppress
metastasis.
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• Researchers have found a very consistent decline
in mitochondrial function that is found in diabetes
and pre-diabetes.
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• There is increasing interest in the possibility that
mitochondrial dysfunction might play an important
role in the etiology of autism. A subset of autistic
children have already been shown to manifest
biochemical alterations that are commonly
associated with mitochondrial disorders, and a few
have been linked to specific alterations in the
mitochondrial genes.
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