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Mitochondrial diseases
The document discusses mitochondrial disorders, highlighting their etiology, pathogenesis, symptoms, and diagnostic approaches. It emphasizes the involvement of multiple organ systems, the complexity of mitochondrial genetics, and the impact of mitochondrial dysfunction on various bodily functions. The text also reviews treatment strategies and management for complications arising from these disorders.
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Mitochondrial diseases
- 1. APPROACH TO MITOCHONDRIALDIORDERS DHANANJAY GUPTA M.S. RAMAIAH MEDICAL COLLEGE BENGALURU
- 2. MITOCHONDRIA Energy/ powerhouse of the cell ETC in the inner membrane of cell membrane Participate in oxidative phosphorylation (OXPHOS) Production of ATP Plays a role in apoptosis Introduction Etiology Pathogenesi s Presentatio n Examples Diagnosis Treatmen t Miscellaneou s Conclusion
- 3. MITOCHONDRIA Affect theorgans having high energy demands Skeletal and cardiac muscles Endocrine organs Kidney, Intestinal tract, retina, CNS As a general rule, involvement of 3 or more organ systems without a unifying diagnosis, should raise the suspicion of mitochondrial cytopathy Introduction Etiology Pathogenesi s Presentatio n Examples Diagnosis Treatmen t Miscellaneou s Conclusion
- 4. 1. CNS 3. CVS 2.Retina 5. GIT: Non-mucosal components 6. Kidneys 4. Skeletal muscles 5. GIT: Liver 7. Endocrine
- 5. GENETICS mtDNA –small circular dsDNA Encodes 13 polypeptides Polyploidy – multiple copies in same cell Thus transmission is complex with Genotypic-phenotypic variations Introduction Etiology Pathogenesi s Presentatio n Examples Diagnosis Treatmen t Miscellaneou s Conclusion
- 6. GENETICS Introduction Etiology Pathogenesi s Presentatio n ExamplesDiagnosis Treatmen t Miscellaneou s Conclusion
- 7. GENETICS Maternal inheritance ETC is the only metabolic pathway under dual control of mt/ nDNA Complex I, III, IV, V under dual, Complex II entirely coded by nDNA Pathology maybe found in either mtDNA (mitochondrial) or nDNA (nuclear) Thus disease is transferred from mother to all offsprings >150 mtDNA point mutations, >100 mtDNA deletions have been identified Introduction Etiology Pathogenesi s Presentatio n Examples Diagnosis Treatmen t Miscellaneou s Conclusion
- 9. PRIMARY MITOCHONDRIAL DISORDERS IntroductionEtiology Pathogenesis Presentatio n Examples Diagnosis Treatmen t Miscellaneou s Conclusion
- 11. SECONDARY MITOCHONDRIAL DISORDERS IntroductionEtiology Pathogenesis Presentatio n Examples Diagnosis Treatmen t Miscellaneou s Conclusion Mitochondrial dysfunction may be seen in primary defect in another pathway Like fatty acid oxidation or amino acid metabolism defects Copper metabolism disorders (Wilsons/ Menkes) Lysosomal (NCL/ fabrys) Peroxisomal diseases Pantothenate-kinase deficiency (PKAN)
- 12. VALPROATE AND MITOCHONDRIA IntroductionEtiology Pathogenesis Presentatio n Examples Diagnosis Treatmen t Miscellaneou s Conclusion Sodium valproate impairs mitochondrial function by: Induction of carnitine deficiency Inhibition of OXPHOS hepatotoxicity/ hyperammonemia Depression of intra-mitochondrial fatty acid oxidation *Thus use another AED in patients with mitochondrial diseases/ mitochondrial pol ϒ mutations
- 14. LACTIC ACIDOSIS Introduction EtiologyPathogenesis Presentatio n Examples Diagnosis Treatmen t Miscellaneou s Conclusion Product of anaerobic metabolism. Occurs when aerobic metabolism inhibited Decrease in the ratio of Ox NAD+ Red NADH Elevated plasma lactate/ pyruvate levels may be non-specific But are an important indicator of mitochondrial dysfunction Also keep in mind spurious elevations (exercise/ tourniquet causing venous stasis)
- 17. LACTIC ACID MEASUREMENT IntroductionEtiology Pathogenesis Presentatio n Examples Diagnosis Treatmen t Miscellaneou s Conclusion Traditional venepuncture can have spurious results Placement of an indwelling butterfly needle/ catheter permits Blood collection 30 mins after the patient has settled Collect samples in fluoride vessels (used for FBS/RBS) Estimated in fresh samples Bedside measurement with a handheld lactate analyser **Richard H. Haas, Sumit Parikh et.al. Mitochondrial Disease: A Practical Approach for Primary Care Physicians. Pediatrics
- 18. PYRUVATE MEASUREMENT Introduction EtiologyPathogenesis Presentatio n Examples Diagnosis Treatmen t Miscellaneou s Conclusion Collected in 8% perchlorate Immediately placed on ice Measured in a fresh sample Spurious elevations may occur for few hours after a meal Plasma Alanine levels: useful indicator of long-standing pyruvate elevations
- 19. WHEN TO SUSPECT IntroductionEtiology Pathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion Age: any age Can present with any symptom in any organ Although there are certain red flags 3 or more organ systems without a unifying diagnosis Pigmentary retinopathy in a pre-teen child is usually a fs/o mitochondrial disorder, though another aetiology is juvenile neuronal ceroid lipofuscinosis.
- 20. 1. CNS - Strokelike lesions (non- vascular) - Encephalopathy - BG disease - Neurodegeneration - Ataxia - Myoclonus - Epilesia partialis continua - MRI findings of Leighs ds - Spectroscopy peaks 2. CVS - Unexplained heart blocks in child - HOCM - CMP with lactic acidosis - DCMP with myopathy - WPW 3. Retina - Degeneration, with night blindness, colour deficits - Pigmentary retinopathy - Ophthalmoparesis - Ptosis - Disconjugate eye movements - Optic neuropathy 4. GIT - Liver failure - Dysmotility - Pseudo-obstructive episodes 5. Others - Exercise intolerance - Hypotonic floppy infant - Hypersensitivity to anaesthetics - e/o acute rhabdomyolysis
- 21. NON-SPECIFIC SYMPTOMS Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion Failure to thrive Short stature Microcephaly IUGR Family h/o sudden infant death syndrome Multi-generational maternal inheritance of migraine headache/ depression/ anxiety **Richard H. Haas, Sumit Parikh et.al. Mitochondrial Disease: A Practical Approach for Primary Care Physicians. Pediatrics
- 22. 1. CNS - Hypotonia -Infantile spasms - Epilepsy - Movement disorders - Hearing loss - Basal ganglia lesions on MRI - Axonal neuropathy - CNS/ leukodystrophy 3. CVS - Tachycardia (postural/ paroxysmal) 2. Eye - Optic nerve hypoplasia - Pigmentary retinopathy 4. GIT - Chronic cyclic vomiting - Unexplained constipation/ diarrhoea 6. Renal - RTA/ aminoaciduria - Nephrotic syndrome 5. Endocrine - Hypo/ hyperparathyroidism - Idiopathic GH deficiency 7. Peripheral - Neuropathy - Myopathy, Exercise
- 23. LEIGHS DISEASE Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion MC childhood presentation of mitochondrial disease Infancy/ early childhood <2 years. H/o Developmental delay Acute encephalitic illness (± dystonia/ hypotonia/ nystagmus/ optic atrophy/ nystagmus) Partial recovery between episodes Basal ganglia and/or brainstem dysfunction MRI: necrotic lesions in brainstem and basal ganglia
- 24. LHON Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion MC mtDNA mitochondrial disease Degeneration of retinal ganglion cells B/L optic neuropathy with sub-acute progressive vision loss “LHON plus”: cardiac abnormalities, dystonia, basal ganglia disorders Most patients have one of these 3 point mutations: o M.11778G A o M.3460G A o M.14484T C
- 27. Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion
- 28. Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion MiMyCa: Mitochondrial Myopathy with Cardiomyopathy NARP: Neuropathy, Ataxia and Retinitis Pigmentosa MELAS: Mitochondrial Encephalo-myopathy, Lactic acidosis and Stroke like episodes MERRF: Myoclonic Epilepsy, with Ragged Red Fibers GRACILE: Growth Retardation, Aminoaciduria, Cholestasis, Iron overload, Lactic acidosis and Early death
- 29. Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion
- 35. Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion
- 36. Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion
- 37. Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion **Richard H. Haas, Sumit Parikh et.al. Mitochondrial Disease: A Practical Approach for Primary Care Physicians. Pediatrics 2007;120;1326
- 38. ELEVATED ORGANIC ACIDS IntroductionEtiology Pathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion Serum lactate, pyruvate Urine malonate, fumarate Ethyl-malonic acid and methyl-glutaconic acid may be elevated but tend to be high in infants owing to renal immaturity Elevation of 3-methylglutaconic acid in a young male with hypotonia, cardiomyopathy and neutropenia is indicative of Barth syndrome
- 39. MELAS AND NARP IntroductionEtiology Pathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion Serum lactate, pyruvate Elevated alanine levels Reduced citrulline levels Inverse correlation between alanine and citrulline
- 40. MNGIE Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion Mitochondrial NeuroGastroIntestinal Encephalomyopathy AR, mutation in the nDNA gene (ECGF-1) or TP (thymidine phosphorylase) Ptosis, ophthalmoparesis, GI dysmotility, peripheral neuropathy, leukoencephalopathy Decreased TP activity (HPLC) Increased substrates of TP (thymidine/ deoxyuridine) Seen in serum, urine and tissue samples
- 41. OTHER BIO-MARKERS Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion mtDNA copy number in WBCs (can indicate disease severity) Methods for oxidative damage Micronucleus assay f/b FISH Comet assay (single cell gel electrophoresis) Peripheral type BZD receptor assays (PBR) Urinary acids – fumarate and malate **M. Mancuso*, D. Orsucci. Diagnostic Approach to Mitochondrial Disorders: the Need for a Reliable Biomarker. Current Molecular Medicine 2009, 9, 1095-1107
- 42. NEUROIMAGING Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion CT/MRI features depend on the age of patient, severity of disease and metabolic brain ds Usually involve the cortical and sub-cortical grey matter Basal ganglia (GP), thalami Brainstem Cerebellar nuclei Some of them are characteristic
- 43.
- 44. B. LEIGHS DISEASE/SUBACUTE NECROTIZING ENCEPHALOMYELOPATHY (SNEM) Thalami, GP STN, SN, thalami PV-WM
- 45. B. LEIGHS DISEASE/SUBACUTE NECROTIZING ENCEPHALOMYELOPATHY (SNEM) STN, SN PV-WM Medial thalamic nuclei GP
- 46.
- 47. D. MERRF: **S. Ito,W. Shirai. Clinical and Brain MR Imaging Features Focusing on the Brain Stem and Cerebellum in Patients with Myoclonic Epilepsy with Ragged-Red Fibers due to Mitochondrial A8344G Mutation. AJNR 2008 Feb.
- 48. E. MENKES/ TRICHOPOLIODYSTROPHY/KINKY HAIR KINKY VESSEL SX:
- 49. E. MENKES/ TRICHOPOLIODYSTROPHY/KINKY HAIR KINKY VESSEL SX:
- 50. 1H-MR-SPECTROSCOPY Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion Mainly a research tool as of date Rarely an adjunct in diagnosis – brain or muscle CSF in ventricles may be a sensitive site for MRS Demonstrate impaired oxidative metabolism Lactate accumulation – doublet peak @ 1.3 ppm Decreased N-acetyl-aspartate and choline – index of neuronal loss/ dysfunction
- 52.
- 53. **M. Cristina Bianchi.Proton MR Spectroscopy of Mitochondrial Diseases: Analysis of Brain Metabolic Abnormalities and Their Possible Diagnostic Relevance. Am J Neurorad. November 2003
- 54. 31P-MR-SPECTROSCOPY Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion Phosphorus MRS fluctuations can be studied during exercise Measure phosphocreatine (Pcr) and inorganic phosphate (Pi) Low Pcr/ Pi at rest Low post-exercise recovery With a delay in post-exercise ADP recovery
- 55. NUCLEAR SCANS Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion FDG-PET reduced regional glucose metabolism observed in the frontotemporal region of two siblings with mtDNA multiple deletions and a MNGIE-like disorder, SPECT DATSCAN (imaging of the striatal dopamine transporter by SPECT)
- 56. EEG Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatmen t Miscellaneou s Conclusion Broad spectrum of EEG changes Slowing or epileptiform discharges Alpers–Huttenlocher syndrome: high amplitude, slow activity EEG, with super- imposed polyspikes of lower amplitude found predominantly over posterior regions. Between regions of slow activity, there may be relative flattening of baseline
- 57. NERVE CONDUCTION STUDIES IntroductionEtiology Pathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion Length dependant Axonal sensory-motor neuropathy Reduced amplitude with preserved velocities EMG: shows neurogenic pattern in distal muscles
- 58. TISSUE BIOPSY Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion Muscle, liver, brain or nerve biopsy Measuring the activity of ETC enzymes Advantages Drawbacks 1. Skin biopsy • Least invasive • Skin fibroblasts can be stored for long • Renewable source of DNA for future studies False negative May be normal in patients 2. Muscle biopsy Easily accessible Can show f/s/o mitochondrial proliferation Ragged red fibres Staining for cytochrome oxidase c and succinate dehydrogenase activity CoQ10 levels estimation Invasive Artefacts if not evaluated immediately Poorly prepared specimens – may show deficiencies of other enzymes
- 59. RAGGED RED FIBRES IntroductionEtiology Pathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion
- 60. RAGGED RED FIBRES IntroductionEtiology Pathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion
- 61. MELAS PARADOX Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatmen t Miscellaneou s Conclusion Ragged red fibres in MELAS are “COX- positive” Compared to MERFF and KSS – they are “COX” negative
- 62. ACUTE MANAGEMENT Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatment Miscellaneou s Conclusion Usually supportive and specific to the presenting complaints Encephalopathy/ seizures/ stroke-like events May require respiratory support Lactic acidosis managed with fluid therapy ± bicarbonate Infections may be a precipitating event for episodic diseases Cardiac rhythm management
- 63. L-ARGININE FOR STROKELIKE EPISODES Introduction Etiology Pathogenesi s Presentation Examples Diagnosis Treatment Miscellaneou s Conclusion Arginine levels are found to be lower in MELAS Cause of stroke in MELAS: o Mitochondrial cytopathy – impaired ETC o Mitochondrial angiopathy o Non-ischemic vascular cellular mechanism o Endothelial dysfunction o Decreased endothelial dialation/ relaxation
- 64. L-ARGININE FOR STROKELIKE EPISODES Introduction Etiology Pathogenesi s Presentation Examples Diagnosis Treatment Miscellaneou s Conclusion Arginine plays an imp role in endothelial dependant vascular relaxation Acute IV infusions shown to be beneficial in small trials Need further evaluation
- 65. NEUROLOGICAL COMPLICATION Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatment Miscellaneou s Conclusion 1. Proximal weakness with waddling gait: gait therapy 2. Anti-spasticity drugs 3. Prevention of contractures/ joint arthrosis 4. Non-ambulant child: 24-hour postural support for sitting and sleeping 5. AED: CBZ/ levetiracetam preferred 6. Valproate should be avoided; esp in POLG1 mutations/ Alpers–Huttenlocher syndrome 7. SNHL: cochlear implants
- 66. CARDIAC COMPLICATION Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatment Miscellaneou s Conclusion 1. Usually symmetrical BiV hypertrophy/ HCM 2. Conduction defects 3. ACE-I and βB for prophylaxis of CMP 4. Pacemaker devices 5. Cardiac transplantation 6. Barth syndrome (X-linked recessive): taffazin mutation: aggressive disease
- 67. GIT COMPLICATION Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatment Miscellaneou s Conclusion Due to MNGIE/ pearson syndrome or neuromuscular dysfunction of peristalsis Bulbar weakness Drugs to promote gastric motility/ emptying Enteral/ parentral feeding Swallowing therapy Early supplementary PEG
- 68. RESPIRATORY COMPLICATION Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatment Miscellaneou s Conclusion Due to muscle weakness/ aspirations/ spinal deformities Monitoring of respiratory function essential Central resp. dysfunctions in Leighs – recurrent apnoeas Nocturnal hypoventilation may be there Pneumococcal and influenza vaccination Prevent aspirations/ NIV/ invasive ventilation Physiotherapy and antibiotics as indicated
- 69. ANESTHETIC MANAGEMENT Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatment Miscellaneou s Conclusion General anesthesia may be required for various indications No significant complications have been reported Use lactate free IV fluids Otherwise routine PAC/ peri-op management
- 70. VITAMIN SUPPLEMENTATION –COQ Introduction Etiology Pathogenesi s Presentation Examples Diagnosis Treatment Miscellaneou s Conclusion Ubiquinone, Q= quinone, 10= number of isoprenyl units in tail Coenzyme Q10 shown to decrease pyruvate/ lactate levels In small trials High dose, 5mg/kg/day used in cases of ubiquinone deficiency CoQ not approved by FDA for any condition So used as a food supplement
- 71. IDEBENONE Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatment Miscellaneou s Conclusion Man made product Synthetic analogue of CoQ10 Anti-oxidant activity Acts as a transporter in ETC – increases ATP production Originally developed for Alzheimers and cognitive deficits Positive effect on neuro function and cardiac hypertrophy Now being used in LHON, MELAS and DMD
- 74. MITO Q7 Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatment Miscellaneou s Conclusion Ascorbic acid 100 MG+ Benfotiamine 100 MG+ Carnitine 500 MG+ Coenzyme Q10 30 MG+ Pyridoxine 40 MG+ Riboflavine 20 MG+ Vitamin E 25 IU
- 75. Introduction Etiology Pathogenesi s PresentationExamples Diagnosis Treatment Miscellaneous Conclusion RIBOFLAVIN Useful in some disorders ETC complex I/II deficiency disorders Usually a trial given for 3-6 months and then May be discontinued if adverse effects or no clinical benefits
- 76. **Udhayabanu T, ManoleA, Rajeshwari M, Varalakshmi P, Houlden H, Ashokkumar B. Riboflavin Responsive Mitochondrial Dysfunction in Neurodegenerative Diseases. J Clin Med. 2017;6(5):52. Published 2017 May 5.
- 78. GENETIC COUNSELLING Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatment Miscellaneous Conclusion Depends on the genetic disorders Patients with nDNA disorders – recurrence risk of 1:2 or 1:4 (AD/ AR) mtDNA – inherited maternally Genotypic and phenotypic heterogeneity among progeny
- 81. POTENTIAL THERAPIES Introduction EtiologyPathogenesi s Presentation Examples Diagnosis Treatment Miscellaneous Conclusion 1. Hypoxia – protects against mitochondrial damage 2. Liver and bone marrow transplantation 3. PGC 1α : increases mitochondrial biogensis and functioning 4. Benzafibrate is a PGC 1α stimulator 5. Mitochondrial donation/ pronuclear transfer
- 82. POTENTIAL THERAPIES –HETEROPLASMY SHIFT Introduction Etiology Pathogenesi s Presentation Examples Diagnosis Treatment Miscellaneous Conclusion Eliminate/ reduce the mutated mtDNA By restriction endonucleases Zinc finger endonucleases Transcription activator-like effector endocleases (TALENs)
- 83. TAKE HOME MESSAGE! IntroductionEtiology Pathogenesi s Presentation Examples Diagnosis Treatment Miscellaneous Conclusion Introduction Definitions Etio-pathogenesis Clinical Presentation Biochemical Diagnosis Biopsy and Neuro-Imaging Treatment and management Mitochondrial diseases are being increasingly recognized Heterogenous group of disorders of impaired energy production Mainly maternal inheritance, but may also have mendelian inheritance Chronic, progressive, multi-system affection at any age Elevated lactate, pyruvate levels (lactate: pyruvate ratio >2.5) Ragged red fibres, Thalami and GP hyperintensities Mainly supportive therapy with vitamin supplementation
Editor's Notes
- #5 Lactate peak at 1.3 ppm TE (time to echo) at 35 and 135. Succinate peak at 2.4 ppm
- #9 Most of these nDNA mutations are inherited by mendelian inheritance – usualy autosomal recessive, usually present in childhood, are more severe and usually no lactic acidosis
- #11 Some mitochondria will contain higher levels of mutated mtDNA and these may through chance, segregate together in a particular cell
- #12 PKAN – hallevorden spatz – NBIA
- #13 PKAN – hallevorden spatz – NBIA
- #15 PKAN – hallevorden spatz – NBIA
- #17 Basically anything that might impair normal aerobic metabolism – like reduced blood supply- hypoT, shock, reduced oxygen, any other gas competing with oxygen – CO, impaired respiratiory mechanism – due to central or peripheral disease.
- #18 PKAN – hallevorden spatz – NBIA
- #19 PKAN – hallevorden spatz – NBIA
- #21 Lactate peak at 1.3 ppm TE (time to echo) at 35 and 135. Succinate peak at 2.4 ppm
- #23 Lactate peak at 1.3 ppm TE (time to echo) at 35 and 135. Succinate peak at 2.4 ppm
- #35 Gradual degeneration of rods/ cones - triad of RP is arteriolar attenuation, retinal pigmentary changes (could be either hypopigmentation and/or hyperpigmentation in form of bone-spicule and pigment clumpings), and waxy disc pallor.
- #45 T2 hypersignal on b/l pallidi and thalamus. Onset of ophthalmmoparesis and pigmentary retinopathy <20yr. Biopsy – ragged red fibres
- #46 heterogeneous and differ depending on the underlying genetic abnormality Generally, the distribution is symmetrical, brainstem periaqueductal grey matter medulla midbrain putamen: characteristic but not always present. involvement of cerebral or cerebellar white matter is unusual
- #47 T1: usually demonstrates reduced signal in T2 abnormal areas, although some areas of hyperintensity can be seen, as can some enhancement. Elevated choline/ lactate, decreased NAA
- #48 Infancy/ childhood multifocal strokes – crossing vascular boundries, shifting spread pattern, predilection for posterior parietal and occipital lobes. Spectroscopy elevated lactate even in normal appearing brain
- #49 Absence of strokes. atrophy of the mid pons, middle cerebellar peduncles, and cerebellar hemisphere and severe atrophy of the superior cerebellar peduncles. abnormal hyperintensities are found bilaterally around the periaqueductal gray matter
- #50 Non functioning copper dependant ETC enzymes. Prominent WM changes. T1 basal ganglia hyperintensities due to chronic hepatic encephalopathy
- #51 Tortuous vessels on angiograms. b/l epidural collections or hemorrhages
- #55 right affected putamen demonstrates resonances at 1.33 and 0.9 ppm coming respectively from lactate (Lac) and lipids or branched amino-acids. Abnormally high brain lactate (Lac) is also revealed located in paraventricular white matter
- #61 defects in nuclear or mitochondrial DNA and result in decreased energy availability for cell processes. When muscle is stained with Gomori Trichrome, characteristic ragged-red fibers are visible under the microscope.
- #62 accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber. may extend throughout the muscle fiber as the sevverity increases. mitochondrial aggregates cause the contour of the muscle fiber to become irregular, causing the "ragged" appearance
- #76 Because of its predomminent antioxidant properties
- #77 A cocktail for mito ds. 390 for 10 tabs
- #79 Riboflavin deficiency leads to deficiency of flavinoiids/ flavin nucleotides – FAD/ MN, involved in mitochondrial ETC – secondary dysfunction
- #80 Infact in a no of neuro degenerative ds – dysfunction is seen
- #83 Mother has it– all children will inherit, father has it – none will