Mitochondrial Disorders and Cerebral Folate Deficiency in Autism Spectrum Disorder
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  • Also, please see this post and the Nature article on which it was based (link within the article) - http://www.collective-evolution.com/2013/09/18/a-horrifying-cause-of-autism-dna-damage-from-synthetic-antibiotics/
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  • On slide 39 you noted that fluoroquinolones are 'probably okay.' This statement is incorrect and misleading. They cause significantly more mitochondrial damage than any other class of antibiotics. Please see this article for more information - http://www.bu.edu/abl/files/stm_kalghatgi.pdf Also, per this article, http://www.jimmunol.org/content/184/9/4827.full.pdf, “Interestingly, as an inhibitor of bacterial topoisomerase II and an inducer of DNA double-strand breaks, ciprofloxacin was also shown to deplete the mitochondrial DNA (mtDNA) content, thus leading to mitochondrial dysfunction and retarded cellular growth (15–17).” And this article notes that oxidative stress is caused by fluoroquinolones - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249743/?report=printable More information about the dangers of fluoroquinolones can be found on http://floxiehope.com/fluoroquinolones-links-resources/ Ciprofloxacin has a 43 page warning label - http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019537s082,020780s040lbl.pdf - what do you think causes so many adverse effects? Answer - mitochondrial damage and oxidative stress. Revision of slide 39 would do your readers a service.
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  • 1. Mitochondrial Disorders and Cerebral Folate Deficiency in Autism Spectrum DisorderRichard E. Frye, M.D., Ph.D. Director of Autism Research Associate Professor of Pediatrics Arkansas Children’s Hospital
  • 2. The Rise in Autism CDC estimates the prevalence of Autism Spectrum Disorder is as high as 7 per 1,000 or 1 in 150!Debate over whether this is due to a shift in diagnosisor a true rise in the number of cases. Does it matter??Either way there are a lot of children that need care.
  • 3. Autism Defined
  • 4. The Etiology of Autism: More than Genetic Disorders Estimated Prevalence of Genetic AbnormalitiesCytogenetic Abnormalities 5%Fragile X 5%Rett Syndrome (Females only) 5% (~1% overall)Chromosomal Microarray 10%Total 21%This leaves about 79%+ children with ASD without anidentified genetic diagnosis.. (Schaefer and Mendelson, Genetics in Medicine, 2008)
  • 5. New Understanding of Autism• Autism is defined as a collection of symptoms• Symptoms of Autism are associated with underlying medical disorders in may cases• In many cases, Autism is a multisystemic disorder with primary neurological manifestations.• The rise in Autism cases is probably due to complex interactions between genetics, environment and the dynamics of physiological development.
  • 6. Mitochondrial Dysfunction and Cerebral Folate Deficiency/Insufficiency is becoming recognized as highly prevalent in autism spectrum disorderThis talk will review – Evidence for Mitochondrial Dysfunction in Autism Spectrum Disorder – Biomarkers for mitochondrial dysfunction – Importance of cerebral folate deficiency/insufficiency and the folate receptor autoantibody – How cerebral folate deficiency/insufficiency is diagnosed and treated
  • 7. Evidence for MitochondrialDisease and Dysfunction inAutism Spectrum Disorder
  • 8. Biomarkers of Abnormal Energy Metabolism in Children with Neurodevelopmental Disorders A review of metabolic studies from 133 consecutive patients evaluated in a medically-based autism clinicExamined a wide range of metabolic markers in children with autism including markers of fatty-acid oxidation disorders
  • 9. 6 Biomarkers Reviewed4 Groups with high prevalence IdentifiedLactate, Alanine-to-Lysine & Acyl-Carnitine 34.3% with AST 53.0%
  • 10. Acyl-Carnitine Elevation Group3-hydroxy-3-methylglutaryl is a metabolite of Acetyl-CoA, thestarting point of the citric acid cycle. Suggests that the citric acidcycle is working inefficiently. It can also be seen in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency but at much higher levels.
  • 11. Muscle Biopsy of child with acyl-carnitine elevations
  • 12. Altered brain phospholipid and acylcarnitine profiles in propionic acidinfused rodents: further development of a potential model of autismspectrum disorders. J Neurochem. 2010 Apr;113(2):515-29.Derrick MacFabe et al.
  • 13. Defining Mitochondrial DiseaseSeveral systematic criteria are used to diagnose mitochondrialdisease.Here we consider the Morava et al. (2006) criteria which usesthe following findings:I. ClinicalII. Metabolic and neuroimagingIII. Mitochondrial morphologicalPatients are classified into 4 categories:• Not likely (<=1)• Possible (2-4 points)• Probable (5-7 points)• Definite (>=8 points).•Score of 3+ suggests a muscle or skin biopsy should be done
  • 14. I. Clinical signs and symptoms, 1 point/ symptom (max. 4 points) Probably associated Might be associated Probably not with ASD (% in ASD) with ASD associated with ASDA. Muscular Muscle weakness Abnormal EMG Ophthalmoplegia†(max. 2 points) (myopathies) Exercise intolerance Facies myopathica RhabdomyolysisB. CNS Develop delay (100%) Extrapyramidal signs Stroke-like episode(max. 2 points) Loss of skills (33%) Myoclonus Migraine Seizures (25%) Pyramidal signs Cortical Blindness Brainstem abnormalC. Multisystem GI tract (7-91.4%) Heart Vision(max. 3 points) Endocrine/growth Kidney Hearing Familial (10.9%) Hematological Neuropathy† Scores 2 points. ‡ Scores 4 points.EMG = electromyography (Frye and Rossignol, Ped Research, 2011)
  • 15. II. Metabolic/imaging studies (max. 4 points)Probably associated with ASD Might be associated Probably not associated(% in ASD) with ASD with ASDElevated lactate† (17.1- 76.6%) Elevated CSF lactate† Ethylmalonic aciduriaElevated L/P ratio (27.6%) Elevated CSF protein Leigh syndrome/MRI†Elevated alanine† (36.0%) Elevated CSF alanine (0%)Elevated lactate/MRS (11.1%) Urinary TA excretion† Stroke-like picture/MRI† Scores 2 points. ‡ Scores 4 points.L/P = lactate/pyruvate;TA = tricarbon acid.;CSF = Cerebrospinal fluid (Frye and Rossignol, Ped Research, 2011)
  • 16. III. Mitochondria Morphology (max. 4 points)Probably associated with Might be associated with Probably not associatedASD (% in ASD) ASD with ASDAbnormal mitochondria/EM† COX-negative fibers‡Reduced COX staining‡ Reduced SDH stainingRagged red/blue fibers‡ SDH positive blood vessels†† Scores 2 points. ‡ Scores 4 points.COX = cytochrome c oxidase; SDH = succinate dehydrogenase; EM = electronmicroscopy (Frye and Rossignol, Ped Research, 2011)
  • 17. Weissman et al 2008 Review of 25 children diagnosed with autism eventually diagnosed with a mitochondrial disorder High rate of non-neurologic symptoms High rate of fatigability – 68% Unusual regression -- 60%
  • 18. Morning Fasting Suspect Pyruvic Acid CO2 Mitochondrial CMA CMP LFTs Disorder MitoMet mtDNA point mutations Glucose Start Supplements Lactic Acid L-Carnitine (Carnitor) Amino Acids Ubiquinol (Douglas Labs) Ammonia B-Complex (Supra-Nu Thera) Acyl-Carnitine No Diagnosis Creatine Kinase If Lab Urine Organic Acids Muscle Biopsy Abnormal Histology Suspect Repeat to Electron MicroscopyFatty Acid Confirm Electron Transport Chain Studies Disorder mtDNA Content Studies RBC Zinc & Copper, Biotin More Specific Diagnosis Triglyceride & Cholesterol Panel Urine Acyl-Glycine & Ketones Testing of Specific Genes No Diagnosis mtDNA sequencing Skin Biopsy with Fatty-acid oxidation and electron transport Specific Therapy chain studies, MitoMet
  • 19. A New Type of Mitochondrial Disorder: Complex IV Hyperfunction.
  • 20. Electron Transport Chain Studies From 14 Children with ASD and Mitochondrial Diseasedefined by Morava et al. criteria
  • 21. Corrected ETC Function
  • 22. Maximum Corrected ETC Function by Subject
  • 23. Why Is Mitochondrial DiseaseAssociated with Autism?
  • 24. Brain growth peaks just after the first year of life. Braingrowth requires energy. A deficit in energy during thisessential time may result in a failure in brain development
  • 25. Mitochondrial DysfunctionEnvironmental Toxins Genetic Defects Increased Free Radicals Cell Damage and Death
  • 26. Treatment ofMitochondrial Disorders
  • 27. Treatment ofMitochondrial Disease
  • 28. Treatment of Mitochondrial Disease• Prevention of Regression – Avoid Dehydration – Avoid Fever – Avoid Viral Illness – Avoid Specific Drugs
  • 29. Treatment of Mitochondrial Disease • Prevention of Regression28 patients with ASD and mitochondrial disease.17 individuals had a history of regression71% (12 of 17) regressed with fever24% (4 of 17) fever followed vaccination
  • 30. Drug Interactions• Antibiotics to avoid: • Antibiotics that are probably – Linezolid and other oxazolidinone okay: antibiotics – Fluoroquinolones – Rifampin (Ciprofloxacin, floxin, levaquin), – Tetracycline – Macrolides – Chloramphenicol (azithromycin, clarithromycin, ert hromycin) – Imipenem – Cephaloglycin, – Cephalogycin – Bactrim – Beta-lactam (penicillin and cephalosporin)• Other substances to avoid : – Alcohol – Cigarette smoke – monosodium glutamate – Acetaminophen – Antipsychotics – Fasting – Dehydration – Sleep Deprivation
  • 31. Preventive Strategies: Drug Interactions
  • 32. Treatment of Mitochondrial Disease• Diets – Ketogenic Diet – Modified Atkins Diet – Complex Carbohydrate Supplementation
  • 33. Treatment of Mitochondrial Disease• Secondary Effects of Mitochondrial Disorders – Gastrointestinal Dysfunction- Dysmotility – Thyroid Dysfunction – Adrenal Dysfunction – Immune System Dysfunction – Cardiovascular Dysfunction – Brain Dysfunction • Cerebral Folate Deficiency • Seizures • Neurotransmitter Deficiencies – Acetylcholine – Excitatory-Inhibitory Balance
  • 34. Cerebral Folate Deficiency
  • 35. Antibodies to the FR1 (Folate Receptor 1) block folate fromcrossing the blood-brain barrier. Since this is an energy dependentprocess disorder of energy metabolism will also reduce folatetransport into the central nervous system (Ramaekers and Quadros, in press)
  • 36. Symptoms of Classic Cerebral Folate Deficiency (Ramaekers et al., NEJM, 2005)
  • 37. Conditions Associated with Autism and Cerebral Folate DeficiencyAntibody Mediated Cerebral folate deficiency• Infantile-onset cerebral folate deficiency• Low-IQ autism with neurological deficitsEnergy Mediated Cerebral Folate Deficiency syndromes•Mitochondrial encephalopathies (deficits in mitochondrialfunction)Unknown Mechanisms (both mitochondrial and antibody?)•Rett Syndrome
  • 38. Ramaekers et al., 2007 Neuropediatrics 38(6):276-81
  • 39. The Expanding Association between Autism and Cerebral Folate DeficiencyWide Range of Children with Autism Spectrum DisorderEnergy Mediated Cerebral Folate Deficiency syndromes• Mitochondrial Complex IV Hyperfunction (Frye and Naveux, Journal of Pediatric Neurology, 2012)
  • 40. More than half of children with Autism Spectrum Disorder referred to two autism specialty clinics test positive for antibodies to the folate transporter (n=93) Frye et al, Molecular Psychiatry, 2012
  • 41. 75% of children with Autism Spectrum Disorder referred totwo autism specialty clinics test positive for one of the two antibodies to the folate transporter Frye et al, Molecular Psychiatry, 2012
  • 42. 44 children with Autism and Positive autoantibodies weretreated with 2mg/kg of folinic acid in an open-label fashion fora mean of 4 months and compared to a wait list control groupof children with autism and positive autoantibodies.
  • 43. Reduced central nervous system folate results indecreased de novo purine synthesis which leads todecrease tetrahydrobiopterin (BH4) production (Ramaekers et al., Neurology, 2003)
  • 44. Cerebral folate deficiencyTreatment: Folinic Acid 1-2mg/kg/day
  • 45. Ramaekers et al., 2008 Dev Med Child Neurol 50(5):346-52
  • 46. Ramaekers et al., 2008 Dev Med Child Neurol 50(5):346-52
  • 47. Questions?