Mitochondrial Cytopathies

Transcription

1 Mitochondrial Cytopathies Bruce H. Cohen, M.D. Neuroscience Institute Brain Tumor and Neuro-Oncology Center Pediatric Neurology Center Cleveland Clinic 2008

2 What Are Mitochondria? Engines within the cell up to 1,000 mitochondria per cell 1 micron (1/30,000 th of an inch) long made up of 1500 proteins and enzymes cigar shaped when taken out of the cell responsible for: energy production free radical generation pivotal role in apoptosis: programmed cell death 350 types of cells, each mitochondria adapted to the needs of that cell

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4 Energy is stored within the molecule in the covalent bonds between the atoms

5 Propane Butane Octane Oleic acid (cooking oil) sugar ATP

6 H 3 CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH

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9 Chemical Reactions H 2 + O 2 H 2 O + heat 2 C 8 H O 2 16 CO H 2 O + heat C 6 H 12 O O 2 6 CO H 2 O + energy (36 ATP)

10 Phases of Energy Generation Glycolosis: sugar pyruvate PDHC: pyruvate acetyl-coa + carbon dioxide Citric Acid Cycle: C4+C2 C6 C4 + 2 carbon dioxides + 3 NADH + FADH 2 + GTP Electron Transport Chain: NADH 3 ATPs

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12 Carbs and Proteins Fats

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16 Wallace DC Annu. Rev. Genet :

17 What happens when the mitochondria do not function properly? not enough energy is produced the cells do not function the organs do not function

18 What Organs are Affected? high energy demand Brain Muscle including the muscle in the walls of the digestive system and heart Nerve including nerves that trigger the heart to beat Retina (eye) Cochlea (ear) Kidney Liver

19 Case 1 71 year old man Recurrent ER visits and admissions for coma Cirrhosis, cardiomyopathy, red nose Repeated blood alcohol levels 0 Treated with IV fluids and recovered in 2-3 days Discharge Dx: coma, seizures

20 Case 1 Exam: mildly obese Social History Ethnic Italian Wine with meals, social drinker Worked as a steamfitter until retirement No events before wife died 3 years before Diet Before wife s death: 3 meals, 3 snacks a day After wife s death:

21 Case 1 Defect in long-chain acyl CoA dehydrogenase Fasting resulted in hypoglycemia Unable to generate ketones because unable to rely on fatty acid oxidation Treatment Frequent meals Low fat diet Carnitine

22 Case 2 Fatty Acid Oxidation 4 month old girl Failure to thrive Episodes of coma Liver failure Retinitis Definitive dx 5 hours before death Family referred for genetic counseling Future embryo screened for mutation and found to be normal, implanted Child born healthy, Ohio State expanded newborn screen detected elevated 3-OH long chain fats Child treated on a no fat diet with 1 ml of cod liver oil a day and doing well

23 Brain the most common organ affected in children Embryopathy Global developmental delays Atypical cerebral palsy Autism and pervasive developmental disorders Seizures Acquired Seizures Atypical migraine Stroke and stroke-like episodes Neuropsychiatric symptoms Dementia

24 Mutation-Proven Mitochondrial Disease 1:4000 ASD 1:150 Classic Autism Possible Mito Disease Probable Mito Disease

25 Embryopathy

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27 Muscle Skeletal, Cardiac and Smooth Hypotonia (infantile presentation) - floppy baby Weakness Cramping Pain Ptosis - droopy eyelids Opthalmoplegia - eyes do not move up/down, side to side Cardiomyopathy and cardiac conduction defects Intestinal motility (smooth muscle)

28 Light Microscopy: Normal Muscle

29 Ragged Red Fibers

30 Cytochrome Oxidase Stain COX Negative Fibers

31 Electron Micrograph : Normal Muscle

32 Abnormal excess fat, disturbed muscle architecture and bizarre mitochondria Case 3: Jerry

33 Nerve Caries Electric Signal from the spinal cord to the muscle and pain from the skin back to the brain Neuropathic Pain and weakness Gastrointestinal dysmotility Reflux, pseudo-obstruction Fainting Abnormal sweating & temperature regulation Mainly acquired

34 The Gastrointestinal Tract Esophogus, Stomach, Intestines gastro-esophageal reflux - vomiting slow stomach emptying slow motility (passage for food thru intestines) pseudo-obstruction - blockage overflow incontinence failure to thrive and weight loss

35 Systemic Failure to gain weight & anorexia nervosa Short stature Fatigue Intermittent air hunger

36 Others Kidney: RTA (leaky kidneys) Eyes: retinitis pigmentosa, optic atrophy Ears: sensorineural hearing loss, aminoglycoside sensitivity Pancreas: diabetes and exocrine pancreatic failure (unable to absorb nutrients) Liver: hypoglycemia and inability to maintain glucose homeostasis, non-alcoholic cirrhosis

37 Clinical Presentation in Children Failure to thrive Mental retardation with or without seizures Failure to gain motor and language milestones Unexplained vomiting Unusual anemia, acidosis, RTA Frequent infections due to aspiration poor immune function Unexplained Fevers

38 Clinical Presentation in Children Atypical Cerebral Palsy Seizures Cardiomyopathy Severe Constipation Alterations in tone Atypical acquired neurologic symptoms

39 ATP: What does it do? all energy requiring processes require ATP brain function muscle function liver function vision hearing growth and so on.. Mitochondrial cytopathies result from a lack of normal ATP production

40 Clinical History Physical Examination Family History Analytes (Blood, Urine, CSF studies) Diagnosis End Organ (MRI/MRS, Echocardiogram) Tissue Histology (Microscopy, Immunohistochemsitry, EM, Western Blot, Blue Native Gel Electrophoresis) Biochemistry (OXPHOS, ETC in Mitochondria) Molecular Genetics

41 Evaluation - Muscle Biopsy Light Microscope and Standard Immunohistochemistry Electron Microscope Southern Blot (large scale mtdna deletions and duplications) Biochemistry electron transport chain enzymology polarography for OXPHOS function Western Blotting Genetic testing

42 Evaluation - Muscle Biopsy Is muscle biopsy the gold standard test? Fresh versus Frozen Quality Control Issues with Frozen Mitochondrial isolation complex I complex V OXPHOS: shrinking size of muscle necessary ability to look at the supercomplexes

43 Diet Changes Child or Adult with Failure to Thrive Frequent smaller meals Addition of MCT oil in small amounts Consideration of g-tube feeding, including continuous overnight feeding Change calorie make-up low fat -- high carbohydrate high fat -- low carbohydrate low protein thinner-less calorie dense formulas given at higher volumes may result in overall improved calorie supply

44 Diet Changes Adults with Obesity Calorie neutral Increase physical activity

45 17 patients - definitive diagnosis Double-blind, randomized, placebo-controlled, crossover design 2 months on each treatment, 5 week washout 3 grams creatine monohydrate bid 300 mg alpha lipoic acid bid 120 mg CoQ10 bid Results: - lower resting lactate - prevention of loss of strength at the ankle - reduction in urine 8-OH dg excretion - improved fat-free mass - no change in PFTs, peak handgrip

46 Vitamins and Supplements 55,700,000 citations in a Google Search for Vitamins 1,610,000 citation in Google Search for Vitamins and Mitochondrial Coenzyme Q10 Idebinone Levocarnitine Vitamin B1 Vitamin B2 Vitamin B3 Vitamin B5 Vitamin B6 Vitamin B12 Folic Acid Biotin Vitamin C Vitamin E Vitamin K3 Betacarotine Alpha Lipoic Acid Succinate Uridine Lysine Arginine NADH Ribose Magnisium Zinc Dichloroacetate Orotate Allopurinol

47 My Typical Treatment Maximal exercise Sleep Hygiene - Polysomnograms for Everyone Hydration and over hydration Early IV hydration during viral illnesses Basic Supplements Miralax Avoid Stress CoEnzyme Q10 - we may be using too low a dose Carnitor B2 Creatine ± Antioxidants: Selinium, E, C, lipoic acid Illness, fever, starvation, sleep

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49 Treatment Treat the symptoms of the disease! Avoid Stress Illness fever starvation sleep Do Not be Afraid to Hospitalize IV fluids ibuprofen IV carnitine forced bedrest

50 Thank you