Mitochondrial disease Notes

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This Osmosis High-Yield Note provides an overview of Mitochondrial disease essentials. All Osmosis Notes are clearly laid-out and contain striking images, tables, and diagrams to help visual learners understand complex topics quickly and efficiently. Find more information about Mitochondrial disease:

Mitochondrial myopathy

Pyruvate dehydrogenase deficiency

NOTES NOTES MITOCHONDRIAL DISEASE GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Impaired mitochondrial activity → disorder CAUSES ▪ Nuclear, mitochondrial DNA mutations SIGNS & SYMPTOMS ▪ Muscle weakness, visual/hearing problems, neurological signs/symptoms, heart, kidney, respiratory disorders DIAGNOSIS DIAGNOSTIC IMAGING LAB RESULTS ▪ Molecular genetic testing ▫ Southern blot (deletions/duplications) ▫ Sequencing ▫ Polymerase chain reaction (PCR) ▪ Serum tests ▪ ↑ levels metabolites made by shunt pathways TREATMENT MEDICATION ▪ Enzyme stimulation OTHER INTERVENTIONS ▪ Supplementation ▪ Diet MRI ▪ Brain lesions MITOCHONDRIAL MYOPATHY osms.it/mitochondrial-myopathy PATHOLOGY & CAUSES ▪ Mitochondrial disorders ▫ Inability to produce ATP ▪ Muscles and brain: require high levels of ATP ▫ Only muscles: myopathy ▫ Muscles, brain: encephalomyopathy ▪ Variable clinical phenotypes with myopathy as main/minor feature; phenotypes can overlap Isolated myopathy ▪ Nuclear DNA mutations ▫ Respiratory chain defects, coenzyme Q10 deficiency ▪ Rarely caused by mtDNA mutations Chronic progressive external ophthalmoplegia, Kearns–Sayre syndrome ▪ Autosomal dominant/autosomal recessive/ maternal inheritance ▪ Nuclear DNA, mtDNA mutations can cause same clinical presentation OSMOSIS.ORG 283
Encephalomyopathy ▪ Infants, children Myopathy with diseases of multiple systems ▪ Barth’s syndrome ▫ X-linked inheritance; TAZ gene mutation; associated with cardiomyopathy, muscle weakness, neutropenia ▪ Myoclonic epilepsy with ragged red fibers (MERRF) ▫ mtDNA mutation → maternally inherited ▪ Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) ▫ mtDNA mutation → maternally inherited CAUSES ▪ Nuclear/mitochondrial DNA (mtDNA) mutation RISK FACTORS ▪ Mitochondrial DNA maternally inherited; only biological females can pass mutations to children SIGNS & SYMPTOMS Isolated myopathy ▪ Fatigue, myalgia, chronic progressive extraocular ophthalmoplegia (CPEO), progressive extraocular muscles paresis, bilateral ptosis Kearns–Sayre syndrome ▪ Chronic progressive extraocular ophthalmoplegia ▪ Retinal pigment degeneration ▪ Onset < 20 years old Encephalomyopathy in infants, children ▪ Hypotonia, respiratory muscle weakness, poor feeding, seizures Barth’s syndrome ▪ Underdeveloped, weak muscles; delayed growth; MERRF ▪ Myoclonus (visible muscle spasms) ▪ Neurological defects ▪ Usually begins after normal early development 284 OSMOSIS.ORG MELAS ▪ Stroke-like episodes ▪ Lactic acidosis ▪ Hearing, weight loss DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Lesion within deep gray matter in both hemispheres, cerebrum/cerebellum atrophy, lesions similar to stroke LAB RESULTS ▪ Serum ▫ ↑ lactate and pyruvate, ↑ alanine, ↑ creatine kinase ▪ Urine analysis ▫ Tests for organic acids (↑ Krebs cycle intermediates) ▫ Myoglobinuria (in isolated myopathy) ▪ Muscle biopsy ▫ Mitochondrial buildup in subsarcolemmal area of affected muscle → ragged red fibers ▪ Histochemical studies ▫ Gomori trichrome stain: ragged red fibers ▫ Succinate dehydrogenase: ragged blue fibers ▪ Biochemical analysis ▫ ↓ respiratory chain complex function OTHER DIAGNOSTICS Electromyography (EMG) ▪ Short-lasting, polyphasic motor unit potentials
Chapter 49 Mitochondrial Disease TREATMENT OTHER INTERVENTIONS ▪ Aerobic exercises ▪ Coenzyme Q10, L-carnitine, creatine supplementation ▪ MELAS ▫ Intravenous arginine hydrochloride with saline, fluids with dextrose ▪ Avoid ▫ Valproic acid, tetracyclines, barbiturates, chloramphenicol, aminoglycosides, metmorfin PYRUVATE DEHYDROGENASE DEFICIENCY osms.it/PDH-deficiency PATHOLOGY & CAUSES ▪ X-linked disease characterized by abnormal pyruvate metabolism CAUSES ▪ E1 alpha gene mutation ▫ Pyruvate dehydrogenase E1 alpha subunit deficiency → ↓ production of acetyl-coenzyme A (CoA) → limited citrate production → citric acid cycle (Krebs cycle) impairment ▪ Impaired Krebs cycle ▫ Energy production disorder; brain needs energy from Krebs cycle → neurological symptoms ▫ Pyruvate accumulation → transformation to lactate, alanine → lactate buildup → lactic acidosis → metabolic symptoms ▪ Residual activity of enzyme determines clinical presentation ▫ Severe deficiency → congenital brain malformations ▫ Moderate deficiency → neurological symptoms onset in infancy/later childhood COMPLICATIONS ▪ Intellectual disability, microcephaly, blindness ▪ Leigh syndrome ▫ Gray matter degeneration, capillary proliferation, focal necrosis SIGNS & SYMPTOMS ▪ Metabolic disorders ▫ Lethargy, poor feeding, mental/ psychomotor delay ▪ Neurological symptoms ▫ Ataxia, hypotonia, progressive encephalopathy, abnormal eye movements, seizures, dystonia ▪ Acidosis respiratory symptoms ▫ Dyspnea, Cheyne–Stokes breathing, respiratory failure OSMOSIS.ORG 285
DIAGNOSIS DIAGNOSTIC IMAGING Magnetic resonance spectroscopy ▪ ↑ lactate levels MRI ▪ Cerebral atrophy ▪ Corpus callosum absence ▪ Medullary pyramids absence LAB RESULTS ▪ Pyruvic acid test ▫ ↑ lactate, pyruvate levels in blood, cerebrospinal fluid ▪ Serum, urine analysis ▫ ↑ alanine in serum, urine 286 OSMOSIS.ORG TREATMENT OTHER INTERVENTIONS ▪ Thiamine, carnitine, lipoic acid cofactor supplementation ▪ Ketogenic diet ▫ Controls lactic acidosis ▪ Dichloroacetate ▫ Stimulation of pyruvate dehydrogenase

Osmosis High-Yield Notes

This Osmosis High-Yield Note provides an overview of Mitochondrial disease essentials. All Osmosis Notes are clearly laid-out and contain striking images, tables, and diagrams to help visual learners understand complex topics quickly and efficiently. Find more information about Mitochondrial disease by visiting the associated Learn Page.