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A Novel Mitochondrial Metabolic Myopathy (mtMM) Caused by Variant Mitochondrial DNA
Michael M. Rothkopf, MD, FACN, Lisa Haverstick, RD, Eleni Pellazgu, MSN, APN Metabolic Medicine Center and Darius Adams, MD, Personalized Genomic Medicine Genetics and Metabolism, Goryeb Children's Hospital Atlantic Health System, Morristown, NJ National Board of Physician Nutrition Specialists
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Case Report: AR – 26 year old male
Referred from PCP for episodic rhabdomyolysis with persistent creatine kinase (CK) elevation Has experienced collapse with severe exertion On no meds or supplements Does not drink or use recreation drugs Otherwise fit and asymptomatic Physical exam completely normal
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Laboratory and Imaging Studies
Mild hepatic dysfunction (AST = 72/ALT = 71) Mild renal dysfunction (Creat = 1.3; eGFR = 76) CK = 1712 U/L (nl ), 100% CK-MM Serum myoglobin = 277 ng/ml (nl 28-72) HbA1C = 5.8% (nl <5.7) Carnitine and micronutrient levels normal MRI of both thighs – no myositis or atrophy.
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Metabolic Myopathies (MM)
A group of hereditary muscle disorders caused by specific enzymatic defects. Most considered primary inborn errors of metabolism (IEOM) and are associated with disturbances of intracellular energy metabolism. MM diseases are grouped into abnormalities of glycogen, lipid, purine, or mitochondrial biochemistry. Also grouped by symptomatology: dynamic vs static Metabolic myopathies are rare but potentially treatable disorders. They are sometimes misdiagnosed as muscular dystrophies or inflammatory myopathies.
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Rhabdomyolysis-associated MM
Disorders of Carbohydrate Metabolism Myophosphorylase deficiency (GSD V;McArdle’s) Phorphorylase kinase deficiency (GSD IX) Phosphofructokinase deficiency (GSD VII: Tauri) acid alpha-glucosidase (GSD II; Pompe) Phosphoglycerate kinase deficiency Phosphoglycerate mutase deficiency Lactate dehydrogenase deficiency Aldolase A (GSD XII) β-enolase (GSD XIII) Disorders of Lipid Metabolism Carnitine Palmitoyltransferase Deficiency (CPT I/II) Carnitine deficiency Defects of beta-oxidation enzymes Neutral Lipid Storage Disease Lipin-1 deficiency Disorders of Purine Metabolism Myoadenylate deaminase (MADA) deficiency; erythrocyte, liver, muscle subtypes Other Defects Malignant hyperthermia Alpha-methylacyl-CoQ recemase (AMACR) deficiency Calcium adenosine triphosphates deficiency (Brody) Mitochondrial Disorders
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Differential diagnosis
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Symptomatic Classification of MMs
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Mitochondrial Metabolic Myopthy - mtMM
Mitochondrial DNA disease phenotypes are typically multisystemic Muscle, CNS, PNS, hepatic, GI, other tissues. Myopathy often involves key enzymes of energy metabolism Can cause disease early in life Mild cases may go unrecognized into adulthood
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Mitochondrial Structure
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ATP Production from Substrate
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Oxidative Phosphorylation
Lets make this background slide 2 Lets start with metabolic myopathies: CPT1/2, McArdles, GSDs, other IEOMs, MM Defects in the enzymes of oxidative phosphorylation effect all types of substrate utilization (glucose, fatty acids, amino acids)
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Mitochondrial DNA (mtDNA)
Find circular image Only organelle other than nucleus with its own DNA Different structure than nuclear DNA - circular
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Genes & Functions mtDNA encodes for 37 genes Peptides rRNAs: 2
Encodes 13 of mitochondrial peptide subunits All 13 peptides are in mitochondrial respiratory-chain complex (OXPHOS) Remaining > 67 OXPHOS subunits are nuclear encoded rRNAs: 2 tRNAs: 22; Located between every 2 rRNA or Protein coding genes Non coding region: Triple stranded (D) displacement-loop Produced from additional synthesis of a piece of mitochondrial DNA, 7s DNA Contains promoter region Origins of replication for H and L strand replication Contains elements for initiation of leading strand replication
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Find circular image
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Mitochondrial DNA variation
Homoplasmy; All copies of mtDNA are identical within cells Heteroplasmy: Cells contain varied mtDNA populations Occurs with some mtDNA mutations Due to presence of multiple mitochondria in one cell, each containing several mtDNA copies Produces tissue variation Post-mitotic tissues Usually contain highest levels of mutated mtDNA Neurons; Skeletal & Cardiac muscle; Endocrine tissue Mutations in mtDNA % vs normal in mtDNA can vary among tissues in an individual Mutational loads may change over time Tissues are differentially sensitive to levels of mtDNA mutations: ? Related to oxidative energy requirements
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Inheritance of mtDNA Maternal (ovum)
Paternal (sperm) mtDNA actively degraded Maternal mtDNA mutations can be amplified by the “bottleneck effect” of primary oocytes
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Case AR – Nuclear DNA Studies
Otherwise healthy 26 yo male with mild hepatic and renal dysfunction; persistent ↑CK/myoglobin Rhabdomyolysis genetic sequencing screen (Baylor/Miraca) - no known pathologic variants in 27 MM nuclear genes
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Case AR – mtDNA Genome Mitochondrial genome submitted and compared to the MITOMAP database Homoplasmic variant in cytochrome c oxidase (COX) subunit III (mt-CO3) gene found at position 9696 in which cytosine was substituted for thymine Pathologic variant encodes a defective COX III protein - phenylalanine substituted leucine at position 164 Patient’s mother shares the variant, without apparent symptoms
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Cytochrome c Oxidase (COX) subunit III
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COX III Abnormality at Position 164 (L164F) - Phenylalanine Substitutes Leucine
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Assessment We suspected MM clinically on the basis of persistent CK and myoglobin elevations We used a diagnostic algorithm and nuclear DNA testing to eliminate abnormalities of glycogen, lipid and purine biochemistry We then proceeded with mitochondrial DNA sequencing to reveal a genetic defect in COXIII
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Management and Follow-up
Complex carbohydrate, high protein diet Careful attention to fluid intake to reduce the impact of myoglobin on renal function Patient instructed to avoid heavy exertion CK, myoglobin, liver enzymes and renal function have improved with this approach Supplemental coQ10, creatine and alpha lipoic acid supplementation may be considered
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Discussion/Conclusions
The patient’s rhabdomyolysis is apparently due to defect in OXPHOS caused by a pathologic variant in the gene encoding his COXIII. He is clinically stable unless he undergoes extreme exertion. He has no evidence of neurological, ophthalmologic or cardiac dysfunction but hepatic, renal and endocrine systems may be compromised. This condition appears to represent a novel MM due to a maternally inherited pathologic variant in mtDNA.
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Thank You for Your Kind Attention!
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