Mitochondrial disease includes a group of neuromuscular diseases caused by damage to intracellular structures that produce energy, the mitochondria; disease symptoms usually involve muscle contractions that are weak or spontaneous. Leber's hereditary optic neuropathy (LHON) Leigh syndrome, Myoneurogenic gastrointestinal encephalopathy (MNGIE) KSS – (Kearns-Sayre Syndrome)

1. MITOCHONDRIAL
DISEASES
Sanman Samova
Samova.sanman@gmail.com

3. mtDNA
• Mitochondrial DNA is composed of 37 genes found in the single
circular chromosome measuring 16,569 base pairs in length.
• Among these,
• 13 genes encode proteins of the electron transport chain (abbreviated
"ETC"),
• 22 encode transfer RNA (tRNA), and two encode the large and small
subunits that form ribosomal RNA (rRNA).
• The 13 proteins involved in the ETC of the mitochondrion are
necessary for oxidative phosphorylation.

6. Oxidative phosphorylation
•Oxidative phosphorylation (or OXPHOS in short) is the
metabolic pathway in which cells use enzymes to oxidize
nutrients, thereby releasing energy which is used to reform ATP.
•In most eukaryotes, this takes place inside mitochondria.
Almost all aerobic organisms carry out oxidative
phosphorylation.

8. •Mutations in these proteins results in impaired energy
production by mitochondria.
•This cellular energy deficit manifests most readily in tissues that
rely heavily upon aerobic metabolism such as the brain, skeletal
and cardiac muscles, sensory organs, and kidneys.
•This is one factor involved in the presentation of mitochondrial
diseases.

9. •Mitochondrial disease includes a group of neuromuscular
diseases caused by damage to intracellular structures that
produce energy, the mitochondria; disease symptoms usually
involve muscle contractions that are weak or spontaneous.
•There is no specific treatment for mitochondrial diseases
(myopathies).
•The prognosis varies according to the disease type; in general,
these diseases are progressive and can cause death.

11. Inherited mtDNA diseases
 mtDNA is maternally inherited - through the egg
 Complex, unpredictable pattern of inheritance
 These diseases are fatal or severely debilitating
 No cure for mtDNA disease
11

12. Mitochondrial diseases include:
• Leber's hereditary optic neuropathy (LHON)
• visual loss beginning in young adulthood eye disorder characterized by progressive
loss of central vision due to degeneration of the optic nerves and retina
• Leigh syndrome,
• subacute sclerosing encephalopathyafter normal development the disease usually
begins late in the first year of life, although onset may occur in adulthood a rapid
decline in function occurs and is marked by seizures, altered states of consciousness,
dementia, ventilatory failure
• Myoneurogenic gastrointestinal encephalopathy (MNGIE)
• gastrointestinal pseudo-obstruction
• Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like
symptoms (MELAS)
• KSS – (Kearns-Sayre Syndrome)

15. KSS
KEARNS-SAYRE SYNDROME

16. KSS – (Kearns-Sayre Syndrome)
• characterized by progressive external ophthalmoplegia (PEO),
pigmentary retinitis and an onset before the age of 20 years.
• Common additional features include deafness, cerebellar ataxia and
heart block.
• There is a defect in coenzyme Q metabolism in KSS.

17. Genetics
• The mtDNA deletions that cause Kearns-Sayre syndrome result in the loss
of genes important for mitochondrial protein formation and oxidative
phosphorylation.
• The most common deletion removes 4,997 nucleotides, which includes
twelve mitochondrial genes.
• Deletions of mtDNA result in impairment of oxidative phosphorylation and
a decrease in cellular energy production.
• Regardless of which genes are deleted, all steps of oxidative
phosphorylation are affected.

18. Symptoms
• Onset less than 20 years of age
• Progressive external Ophthalmoplegia,
• retinal pigmental degeneration,
• sometimes heart block,
• Ataxia (Ataxia is a neurological sign consisting of lack of voluntary
coordination of muscle movements)
• hyperparathyroidism and short stature.

19. Kearns-Sayre Syndrome (KSS) is defined by three criteria that
seem invariable:
• Pigmentary retinopathy
• Children with KSS appear normal at birth
• Boys and girls equally affected

20. • The Ophthalmoplegia begins at age 5, can be recognized as early as
age 2
• Parents notice ptosis or constricted eye movements.
Characteristically affects all eye muscles equally and never the pupils

21. Many other abnormalities have been found in patients with
KSS, including
•mental retardation
•Babinski signs
•limb weakness
•hearing loss
•seizures
•short stature
•delayed puberty
•various endocrine abnormalities.

22. •The Pigmentary Retinopathy (PR) a salt-and-pepper retinopathy,
called atypical to distinguish it from typical bone spicules retinitis
pigmentosa
•Pigmentary retinopathy indicates the retinal pigment epithelium
is affected
•Histologically shows abnormalities of the retinal pigment
epithelium as well as rods and cones
•PR accompanied by a mild decrease in vision in half the cases.

23. Fundus OD atypical retinitis pigmentosa. Fundus peripheral retina atypical retinitis
pigmentosa.

24. Endocrinologically, KSS patient may have:
•Delayed sexual maturation
•Short stature,
• detailed studies of growth hormone and
somatostatin have not been performed
•Diabetes mellitus appears in approximately 20%
of patients with KSS
•Hypoparathyroidism has been described

25. •Onset may be anywhere from childhood to adulthood
•Mental Retardation can again vary from mild to frank dementia
•Seizures are not a prominent feature of KSS
•Skeletal Muscle Biopsy shows in almost all patients with KSS
typical ragged-red fibers
•Heart muscle has no ragged-red fibers
•There is no histopathological difference between KSS and
PEO(progressive external ophthalmoplegia) in muscle biopsy
specimens

26. Leigh syndrome

27. Leigh Syndrome
• Leigh syndrome is a rare genetic neurometabolic disorder.
• It is characterized by the degeneration of the central nervous system (i.e.,
brain, spinal cord, and optic nerve).
• Leigh syndrome affects at least 1 in 40,000 newborns.The condition is more
common in certain populations.

28. Genetics
• Leigh syndrome can be caused by mutations in one of more than 75
different genes.
• In humans, most genes are found in DNA in the cell's nucleus, called
nuclear DNA. However, some genes are mitochondria. This type of DNA is
known as mitochondrial DNA (mtDNA).
• While most people with Leigh syndrome have a mutation in nuclear DNA,
about 20 percent have a mutation in mtDNA.

29. •Most genes associated with Leigh syndrome are involved in the
process of energy production in mitochondria.
•Mitochondria use oxygen to convert the energy from food into
a form cells can use through a process called oxidative
phosphorylation.

30. symptoms
• The symptoms of Leigh syndrome usually begin between the ages of
three months and two years, but some patients do not exhibit signs and
symptoms until several years later.
• Symptoms are associated with progressive neurological deterioration
and may include loss of previously acquired motor skills, loss of appetite,
vomiting, irritability, and/or seizure activity.
• As Leigh syndrome progresses, symptoms may also include generalized
weakness, lack of muscle tone (hypotonia), and episodes of lactic
acidosis, which may lead to impairment of respiratory and kidney
function.

31. • The earliest signs may be poor sucking ability,and the loss of head
control and motor skills.
• These symptoms may be accompanied by loss of appetite, vomiting,
irritability, continuous crying, and seizures

32. Treatment
• The most common treatment for Leigh's disease is thiamine orVitamin
B1.
• Oral sodium bicarbonate or sodium citrate may also be prescribed to
manage lactic acidosis.
• Researchers are currently testing dichloroacetate to establish its
effectiveness in treating lactic acidosis.
• In individuals who have the X-linked form of Leigh’s disease, a high-fat,
low-carbohydrate diet may be recommended.

33. 33
DIAGNOSTICS ?

34. 34
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

35. 35
Clinical Neurogenetic
Evaluation (for those with
developmental delays)
-Echocardiogram
- Electrocardiogram (EKG)
- Ophthalmic Exam
- Auditory Exam
-Brain MRI
Characterize Systemic
Involvement
- Karyotype
- Fragile XTesting
- Neurology Consult
-Genetics Consult
-Muscle biopsy (RRF - ragged red fibers)

36. 36
Negative results have a high false
negative rate;
if mitochondrial
disease is suspected, the patient
should be refered to a Mitochondrial
Disease Center.

37. There is no cure for mitochondrial disease
• Some helpful treatments include
– vitamins such as thiamine (B1), riboflavin (B12), vitamin C, and
vitamin E. Lipoic acid and coenzyme Q-10 are also useful
supplements.
• Some researchers are examining using drugs to block lactic
acid buildup in the body that is common in mitochondrial
disease.
• Others are trying very low carbohydrate diets to reduce the
workload for mitochondria.

38. Thank you