This case report describes a novel mitochondrial metabolic myopathy (mtMM) caused by a variant in mitochondrial DNA. A 26-year-old male presented with episodic rhabdomyolysis and elevated creatine kinase. Genetic testing found a homoplasmic variant in the cytochrome c oxidase subunit III gene, encoding a defective protein. This pathogenic variant likely causes a defect in oxidative phosphorylation. Management focuses on diet, hydration and avoiding strenuous exercise to prevent rhabdomyolysis and damage to muscles, liver and kidneys. This condition represents a new mtMM identified through mitochondrial genome sequencing.

1. 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

2. 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

3. Laboratory and Imaging Studies
• Mild hepatic dysfunction (AST = 72/ALT = 71)
• Mild renal dysfunction (Creat = 1.3; eGFR = 76)
• CK = 1712 U/L (nl 24-204), 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.

5. 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.

6. 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

7. Differential diagnosis

8. Symptomatic Classification of MMs

10. 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

11. Mitochondrial Structure

12. ATP Production from Substrate

13. Oxidative Phosphorylation
• Defects in the enzymes of oxidative phosphorylation effect all
types of substrate utilization (glucose, fatty acids, amino acids)

14. Mitochondrial DNA (mtDNA)
• Only organelle other than nucleus with its own DNA
• Different structure than nuclear DNA - circular

15. Genes & Functions
• mtDNA encodes for 37 genes
– Peptides
• 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

17. 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

18. Inheritance of mtDNA
• Maternal (ovum)
• Paternal (sperm)
mtDNA actively
degraded
• Maternal mtDNA
mutations can be
amplified by the
“bottleneck effect”
of primary oocytes

19. 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

20. 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

22. Cytochrome c Oxidase (COX) subunit III

23. COX III Abnormality at Position 164 (L164F)
- Phenylalanine Substitutes Leucine
https://www.ebi.ac.uk/pdbe/entry/pdb/3abk/protein/3

24. 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

25. 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

26. 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.

27. Thank You for
Your Kind
Attention!