General characterization of mitochondrial pathology. Clinical symptoms. Diagnostics. Treatment. As. Prof. Sakharova Inna Ye., MD,PhD

2 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). 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).mitochondriaorganelleseukaryotic cellsmitochondriaorganelleseukaryotic cells

3 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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5 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.

6 A primary cause of mitochondrial diseases is a defect in nuclear DNA (nDNA) encoding for mitochondrial protein or in mitochondrial DNA (mtDNA).

7 Secondary causes of mitochondrial diseases are brought on by factors such as ischemia, reperfusion, cardiovascular diseases, renal failure, pancreatic and hepatic damage, diabetes, infectious agents, gastrointestinal diseases, oncologic diseases, alcohol, smoking, stress, drugs and aging.

8 Every 30 minutes a child is born who will develop a mitochondrial disease by age 10. UMDF, 2009

9 At least 1 in 200 individuals in the general public have a mitochondrial DNA mutation that may lead to disease. At least 1 in 200 individuals in the general public have a mitochondrial DNA mutation that may lead to disease. UMDF, 2009

10 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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12 Mitochondrial diseases should be considered in any patient with unexplained multi-system involvement with a progressive course.

13 Hallmarks of Mitochondrial Disease 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

14 Newborn Assessment (Catastrophic Presentations of Metabolic Disease in the Newborn) Nonspecific findings may mimic shock, sepsis or SIDS Nonspecific findings may mimic shock, sepsis or SIDS Lethargy, irritability, hyperactivity Lethargy, irritability, hyperactivity Failure to feed well Failure to feed well Hypothermia or fevers (fevers due to viral illnesses and those in which no cause is discovered) Hypothermia or fevers (fevers due to viral illnesses and those in which no cause is discovered) Cyanosis Cyanosis Seizures Seizures Vomiting Vomiting Jaundice (early and/or prolonged) Jaundice (early and/or prolonged) Diarrhea or abdominal bloating Diarrhea or abdominal bloating

15 Exam of the Infant Odor Odor Neurologic: tone, level of alertness, deep tendon reflexes Neurologic: tone, level of alertness, deep tendon reflexes General: dysmorphic features, large liver or spleen General: dysmorphic features, large liver or spleen

16 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.

17 POSSIBLE SYMPTOMS of MD Brain * Developmental delays * Mental retardation * Dementia * Seizures * Neuro-psychiatric disturbances * Migraines * Atypical Cerebral Palsy * Strokes * Autistic featues

18 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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20 Many experts refer to Mitochondrial Disease as the "Notorious Masquerader" because it wears the mask of many different illnesses.

21 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).

22 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.

23 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.

24 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.

25 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.

26 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.

27 DIAGNOSTICS ?

28 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

29 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)

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

31 Purposes of Treatment alleviate symptoms slow down progression of the disease

32 Key Points for Treatment Dietary Vitamins and supplements Avoidance of stressful factors Exercise Additional therapies

33 Supplement Purpose CoQ10 provide energy beyond enzyme defect site, antioxidant levo-carnitine (Carnitor®) transports long-chain fatty acids, binds unused metabolic products Riboflavin (B2) precursor of 2 cofactors involved in electron transport chain Suggested To Most Patients

34 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) antioxidant Selinium co enzyme for pyruvate dehydrogenase & alpha ketogluatarate dehydrogenase B-carotene antioxidant

35 Research supporting the link between mitochondrial dysfunction and some of these other common illnesses includes: Mitochondrial coenzyme Q10 levels are reduced in patients with Parkinson’s disease and mitochondrial function in these patients is impaired. Mitochondrial coenzyme Q10 levels are reduced in patients with Parkinson’s disease and mitochondrial function in these patients is impaired. Results of the first placebo-controlled clinical trial of the compound coenzyme Q10 suggest that it can slow disease progression in patients with early- stage Parkinson’s disease. Results of the first placebo-controlled clinical trial of the compound coenzyme Q10 suggest that it can slow disease progression in patients with early- stage Parkinson’s disease. 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. 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.

36 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. 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. 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. 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. 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. 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.

37 Researchers have found a very consistent decline in mitochondrial function that is found in diabetes and pre-diabetes. Researchers have found a very consistent decline in mitochondrial function that is found in diabetes and pre-diabetes. 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. 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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