Mitochondrial Diseases

1
Mitochondrial Diseases

• Michelle Hung
• Vivian Lee
• Jenny Nhan
• Justin Sze

2
Introduction

• Mitochondrial diseases are those disorders that
  affect the function of the mitochondria and/or
  are due to mitochondrial DNA
• Nerve cells in the brain and muscles require a
  great deal of energy, and thus appear to be
  particularly damaged when mitochondrial
  dysfunction occurs
• The subclass of these diseases that have
  neuromuscular disease symptoms are known as
  mitochondrial myopathies

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Kearns-Sayre Syndrome

• Kearns Sayre Syndrome (KSS) is part of the
  subclass of mitochondrial diseases known as
  mitochondrial myopathy
• It is named for Thomas Kearns and George Sayre
• Rare neuromuscular disorder
• Onset usually before the age of 20
• It is a progressive disorder, and the prognosis
  for patients with the condition is poor. Death is
  common in the third or fourth decade of life
• Unlike most mitochondrial diseases, it is not
  maternally inherited. Rather, it occurs
  sporadically
• It is the result of abnormalities in the DNA of
  mitochondria
• Specifically, it occurs secondary to deletions in
  mitochondrial DNA (mtDNA)

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Pathophysiology

• In KSS, mtDNA deletions occur, most of which are
  sporadic and are believed to occur during
  oogenesis or very early in new embryo development
• Deletions vary in size (1.3-8 kb) and position
  within the mitochondrial genome however, the
  most common is a 4.9-kb mutation/deletion that
  accounts for one third of KSS cases
• Deletions are found in all tissues
• Neither size nor location of the deletion alone
  determines clinical presentation. Instead, the
  presentation appears to be dependent on what is
  known as heteroplasmy

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Heteroplasmy

• In certain diseases, including KSS, mtDNA
  displays heteroplasmy, a mixture of wild-type and
  mutant mtDNA within a single cell. The ratio of
  mutant DNA to wild-type DNA is an important
  factor in the pathogenesis and clinical
  presentation of mitochondrial disorders
• eg. Very high levels of mutated mtDNA in all
  tissues are likely to cause a disease known as
  Pearson syndrome, whereas lower levels of mutated
  mtDNA cause KSS

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Effects Of Deletions

• The mitochondrial genome contains 13 genes that
  encode peptides (all of which are components of
  the respiratory chain (aka Electron Transport
  Chain) complexes), and transfer RNA
• Thus, mtDNA deletions result in significantly
  lower activities of the enzymes of the
  respiratory chain, and thus, affect the
  production of energy (ATP) needed by cells
• Thus, mitochondrial diseases such as KSS may be
  expected to have the greatest effect on cells or
  organ systems with the highest energy
  requirements (eg, brain, skeletal and cardiac
  muscle, sensory organs)
• In addition, mtDNA continues to replicate, even
  in a nondividing cell thus, mutant mtDNA appears
  to accumulate primarily in nondividing tissues

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http//en.wikipedia.org/wiki/ImageEtc2.png
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Signs Symptoms

• Because mitochondria are found in cells
  throughout the body, Kearns Sayre syndrome may
  affect many different organs and body systems
• In patients with Kearns-Sayre syndrome, symptoms
  are
• Muscle weakness
• chronic and progressive decreased eye movements
  (ophthalmoplegia) and eyelid droop (ptosis)
• difficulty swallowing (dysphagia)
• skeletal muscle weakness
• CNS dysfunction
• Inability to coordinate voluntary muscles
  (Ataxia)
• Dementia
• Deafness
• Degeneration of the retina (Retinitis pigmentosa)
• Cardiac
• Heart block (a cardiac conduction defect)
• Endocrine dysfunction
• Short stature
• Hypogonadism

http//www.snof.org/maladies/kearnsSayre.html
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Treatment

• Treatment for KSS is generally symptomatic and
  supportive
• All patients with KSS require the care of an
  ophthalmologist
• Cardiac abnormalities may be treated with various
  cardiac drugs or a pacemaker
• Exercise can help patients with myopathy
  (exercise results in regeneration of muscle in
  which the proportion of wild-type DNA to mutant
  mtDNA can beneficially increase) However,
  exercising to this extent is difficult for
  affected patients
• Ubidecarenone (Coenzyme Q10, Ubiquinone)
  administration and vitamin supplements have
  proven beneficial in individual cases
• CoQ10 supplementation may support normal function

10
Relevance To Pharmacy

• Pharmacists Role
• Maintain surveillance of patient
• Be especially alert for signs or symptoms of
  diabetes mellitus and for heart block
• Encourage participation in an exercise-training
  program (can lead to an improvement in
  muscle-related symptoms, enhanced aerobic
  exercise capacity, and increased muscle strength)
  
• Coenzyme Q10 (CoQ10) administration and vitamin
  supplements have proven beneficial in individual
  cases, although effects are transient

11
What Is MELAS Syndrome?

• Mitochondrial disease, and a rare form of
  dementia
• Affects less than 20,000 individuals within U.S.
• MELAS stands for mitochondrial encephalomyopathy,
  lactic acidosis and stroke-like episodes
• Underlying disease is progressive and fatal
• Affect people at very different times in life,
  ranging from age 4 to age 40 or more
• Onset of MELAS childhood to early adulthood
  (most patients with MELAS syndrome show symptoms
  before 20 years old)

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Pathophysiology Of MELAS Syndrome (Mitochondrial
Disease)

• Mutations in the mitochondrial chromosome
  (mtDNA), each mitochondria contains approximately
  5 mtDNAs
• mtDNA is a circular molecule which encodes
  polypeptides, transfer RNA (tRNA) and ribosomal
  RNA (rRNA)
• Polypeptides from mtDNA and the nuclear genome
  are needed for ATP production via oxidative
  phosphorylation
• Mutations in mtDNA impairs mitochondrial
  respiratory chain (MRC), leads to impaired ATP
  production
• Definite pathogenic mechanisms remain unknown
• mtDNA is maternally-inherited

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Signs Symptoms

• Common symptoms Progressive External
  Ophthalmoplegia (PEO), general muscle weakness,
  exercise intolerance, hearing impairment,
  diabetes, ataxia, cataracts, heart defects and
  short stature
• As the name implies, major signs include
  encephalomyopathy, lactic acidosis, and
  stroke-like episodes and dementia
• Recurrent strokes in the brain, manifest as
  migraine-like headaches, vomiting and (less
  often) seizures, and can lead to permanent brain
  damage
• Combination of three or more of these symptoms in
  one person strongly points to mitochondrial
  disease, especially when the symptoms involve
  more than one organ system

15
Diagnostic Tests

• Main methods of diagnosis family history,
  muscle/brain biopsy, blood enzyme test, genetic
  test
• Muscle/ brain biopsy is the major diagnostic test
  used
• Shows characteristic ragged red fibers
• 1. Detects abnormal proliferation of mitochondria
  and deficiencies in cytochrome C oxidase (COX,
  which is complex IV in the electron transport
  chain).
• 2. Detects presence or absence of specific
  proteins. Can rule out other diseases or confirm
  loss of electron transport chain proteins.
• 3. Measures activities of specific enzymes. A
  special test called polagraphy measures oxygen
  consumption in mitochondria.

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Diagnostics (contd)

• Brain biopsy through the cortex and pallidal
  region patient had a 3242AgtG mutation
• A B both show neuronal loss with
  proliferation of BVs
• A shows gliosis, which is an increase
  proliferation of glial cells
• B- shows that it is even more evident in the
  outer layers
• C shows mineral deposits in the vessel walls

17
Treatment/Application To Pharmacy

• No cure for MELAS
• Disease remains progressive and fatal
• Medications used are mostly for alleviating
  symptoms associated with MELAS
• Ex. hearing aid for hearing impairment
  dichloroacetate for reducing lactic acidosis
  anti-epileptics for preventing seizures
• Pharmacists can assist in management of symptoms
  through recommending suitable medications (OTC/
  prescription products)

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Treatment/Application To Pharmacy (contd)

• Several substances though to be effective, but
  there is a lack of scientific evidence regarding
  their efficacy
• 3 dietary supplements based on three natural
  substances involved in ATP production in our
  cells
• Creatine, carnitine, coenzyme Q10 (coQ10)
• Creatine releases phosphate rapidly to enhance
  the ATP supply
• Carnitine improves the efficiency of ATP
  production (available OTC as L-carnitine)
• CoQ10 is a component of the electron transport
  chain which uses oxygen to manufacture ATP

19
Summary

• Kearns Sayre Syndrome (KSS) rare neuromuscular
  disorder with onset before the age 20
• KSS result of abnormalities in DNA of
  mitochondria, occurs secondary to deletions in
  mtDNA
• KSS not maternally inherited occurs
  sporadically during oogenesis
• mtDNA deletions result in significantly lower
  activities of the enzymes of the respiratory
  chain, and thus, affect the production of ATP
  needed by cells
• Symptoms muscle weakness, CNS and endocrine
  dysfunction, heart block
• Treatment for KSS is generally symptomatic and
  supportive
• patients with KSS require the care of an
  ophthalmologist
• Cardiac abnormalities may be treated with various
  cardiac drugs or a pacemake
• Ubidecarenone
• MELAS syndrome stands for mitochondrial
  encephalomyopathy, lactic acidosis, and
  stroke-like episodes syndrome, and is a rare form
  of dementia
• This disease is progressive and fatal, and there
  is still no cure for this disease
• MELAS is maternally-inherited and generally
  affects individuals between 4 40 years old, but
  most onset of the disease is between childhood to
  early adulthood
• Underlying cause of MELAS is mutations in
  mitochondrial DNA, leading to faulty
  mitochondrial respiratory chain thus resulting in
  impairment of ATP production
• More than one organ system is affected,
  especially those with high energy oxidation
  metabolism like muscles, brain, eye and CNS
• Some common, non-specific symptoms of MELAS
  include Progressive External Ophthalmoplegia,
  general muscle weakness and hearing impairment,
  but a combination of three or more symptoms
  generally point to mitochondrial disease
• Major diagnostic test is muscle and brain biopsy
• Current treatment focuses of alleviation of
  symptoms
• Effectiveness of dietary supplements (Creatine,
  carnitine, coQ10) unproven but no harmful SE

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References

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  ospora/more.htmlgt.
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  Vattemi G, Rizzuto N, Padovani A, Simonati A.
  Bioscience Reports Neuropathology of
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• "Kearns-Sayre Syndrome." National Institute of
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  earns_sayre/kearns_sayre.htmgt.
• Muscular Dystrophy Association
  http//www.mda.org. 2006 MDA
• Posner, Ewa. "Kearns-Sayre Syndrome." EMedicine.
  6 Nov. 2006. 23 Feb. 2008 lthttp//www.emedicine.co
  m/ped/topic2763.htmgt.
• "The Krebs Cycle and Electron Transport Chain."
  Thinkquest. 23 Feb. 2008 lthttp//library.thinkques
  t.org/27819/ch4_6.shtmlgt.
• William C. Shiel, Jr. MELAS Syndrome
  http//www.medicinenet.com/melas_syndrome/article.
  htm. 1996-2008 MedicineNet
• Pictures Found At
• http//www.snof.org/maladies/kearnsSayre.html
• http//en.wikipedia.org/wiki/ImageEtc2.png
• http//www.vitaminking.com.au/shop_image/product/5
  390caeeb91b85ddf619cec480751bb5.jpg