When should a rheumatologist suspect a mitochondrial myopathy?



Metabolic myopathies consist of inborn errors of glycogen, lipid, and mitochondrial respiratory chain enzymes (1). They result in weakness with or without muscle breakdown and in the case of mitochondrial disease, a bewildering array of multisystem abnormalities. Rheumatologists are usually comfortable with the diagnosis and management of dermatomyositis, polymyositis, connective tissue disease–associated myositis, malignancy-associated myositis, and inclusion body myositis. Because the signs and symptoms that distinguish the metabolic myopathies are less common, the recognition of these myopathies is more difficult and the diagnosis is often missed or delayed. These disorders are easily confused with other rheumatic diseases or neurologic conditions, including functional disorders, and are therefore difficult to diagnose. Since this heterogeneous group of diseases with protean manifestations is relatively common (between 1 in 11,000 and 1 in 24,000, although there are estimates as frequent as 1:8,000) (2), and because rheumatologists see patients with diagnostic dilemmas, we suspect that most rheumatologists encounter several such cases over years of practice.

The mitochondrial myopathies fall into 4 different categories of clinical presentation, 3 of which we will demonstrate with case reports. The fourth, infantile hypotonia, is a complex syndrome that presents most frequently in early infancy and is usually fatal by 1 year of age. It presents with severe hypotonia (floppy infant syndrome) as well as brain, heart, and kidney disease that lead to a fatal outcome. This disorder is very rare in later childhood and it is unlikely that a rheumatologist would see this condition. The other syndromes discussed below may be seen by rheumatologists.

Significance & Innovations

  • Mitochondrial myopathies are more common than currently appreciated.

  • Rheumatologists are likely to see patients with mitochondrial myopathies.

  • Patients with mitochondrial myopathies present with different syndromes.

  • Certain features of the presentation should trigger a diagnostic evaluation for a mitochondrial myopathy.

Case Reports

Case 1.

A 32-year-old woman presented with a history of migraine headaches that were treated with letriptan hydrobromide and atenolol and depression treated with mirtazapine. She also had anorexia with weight as low as 60 lbs and a Caesarean section for poor progression of labor. The patient presented with symptoms of generalized weakness and cramps in her legs, with difficulty walking upstairs and reaching for objects over her head. She related that these problems were present since her teens. The patient also reported difficulty swallowing liquids, especially when reclining.

The initial examination revealed weakness proximally of the upper and lower extremities and nasal speech. There was a suggestion of facial weakness and mild ptosis. She experienced double vision on the extremes of lateral gaze. The evaluation included a creatinine kinase (CK) 3181 and an electromyogram (EMG), which demonstrated myopathic motor unit potentials present in the proximal muscles. Genetic testing was negative for oculopharyngeal muscular dystrophy.

A muscle biopsy was performed (Figures 1 and 2). The sample revealed ragged-red fibers. The patient was diagnosed with Kearns-Sayre syndrome (KSS) with mitochondrial gene mutation at position 3243 (1, 3–7). There was a reduction in mitochondrial respiratory chain complexes I and III. Treatment consisted of coenzyme Q10, thiamine, lipoic acid, idebenone, and riboflavin, with marginal improvement.

Figure 1.

Trichrome-stained sections from case 1 showing the classic “ragged-red” morphology but slightly different in appearance characteristically seen in mitochondrial myopathies.

Figure 2.

Electron micrographs from case 1 illustrating the presence of ultra structurally abnormal mitochondria with intramitochondrial paracrystalline inclusions. Note also the accumulations of lipid droplets as can be seen in a variety of metabolic myopathies.

KSS often has variable myopathic and neuropathic phenomena. It can present as an idiopathic proximal myopathy with very subtle neuropathic features. Alternately, it can present with ophthalmoplegia with very subtle myopathic changes. Often there is a family history of a neurologic or myopathic disorder and the manifestations can be similar among family members. If a patient has external ophthalmoplegia as the predominant feature, then they would most likely present to an ophthalmologist or neurologist with a differential diagnosis that would include myasthenia gravis and certain muscular dystrophies such as oculopharyngeal muscular dystrophy. Occasionally, these patients will present with predominant proximal myopathy and relatively spared ocular involvement, and for this reason they may present to a rheumatologist.

Case 2.

A 39-year-old man presented with a 7-year history of progressive muscle weakness, pain and spasms in his muscles with exertion, and decreased stamina. Prior to onset, he had been a semiprofessional football player, and at onset, he was a competitive bodybuilder. Despite a high-caloric, high-protein diet, he was losing weight and muscle mass. He briefly tried anabolic steroids, without effect. He gave up weight lifting, and over time had difficulty maintaining employment as his weakness and muscle pain progressed. Extensive evaluations (including serology for autoimmune and inflammatory myopathy) were negative except for an intermittently mildly elevated creatine phosphokinase (CPK) level. EMG findings were normal. He denied fasciculations, difficulty swallowing, or respiratory compromise. He was found to have mild hypotestosteronism, with no evidence of a pituitary tumor. Testosterone-replacement therapy had no effect on his symptoms. His family history is notable for a 16-year-old daughter with muscle pain, but no definitive diagnosis. A brother had a neurologic disease believed to be multiple sclerosis (although this was not confirmed).

On examination, he had normal vital signs and a normal cutaneous examination. His neurologic examination was notable for normal extraocular movements, and he had 5/5 strength (Medical Research Council scale), normal reflexes, and sensation.

A repeat EMG examination showed mild myopathic motor unit change in the anterior tibialis. His CPK level increased from 121 units (normal) to 546 units (elevated). A muscle biopsy sample (Figure 3) showed myopathic changes with sarcolemma aggregates and ragged-red fibers. The presence of ragged-red fibers in the absence of inflammation or serologic evidence for autoimmunity suggested a mitochondrial disorder. Mitochondrial enzyme activity was requested and revealed decreased activity of complexes 1, 4, and 5; borderline decrease in 2; and reduced ratio of complex 5 to citrate synthase activity. Acetylcarnitine level was 3 mmoles/liter with a normal range of 5–30, but a mitochondrial mutation analysis was negative. He was given a trial of coenzyme Q10 with no discernable improvement.

Figure 3.

A, Variable fiber size and shape, some central nuclei, abnormal internal architecture in some fibers in case 2 (paraffin-embedded, formalin-fixed muscle, hematoxylin and eosin [H&E] stained, original magnification × 125). B, Early ragged-red fibers with subsarcolemmal aggregates (frozen muscle, trichrome stained, original magnification × 250). C, Early ragged-red fibers with subsarcolemmal aggregates (frozen muscle, trichrome stained, original magnification × 500). D, Fiber with central nuclei and prominent subsarcolemmal aggregates (frozen muscle, trichrome stained, original magnification × 250). E, Variable fiber size and shape, some central nuclei, vaguely seen subsarcolemmal accumulations (frozen muscle, H&E stained, original magnification × 250). F, Abnormal internal architecture of some fibers and some with subsarcolemmal aggregates (frozen muscle, NADH stained, original magnification × 250).

The second syndrome that is likely to be seen by a rheumatologist is that of isolated myopathy. These patients have a proximal myopathy with or without exercise intolerance. In addition, myoglobinuria may be present as well as constitutional symptoms such as fatigue. As a result, these patients may be evaluated for polymyositis, dermatomyositis, inclusion body myositis, paraneoplastic myositis, or a collagen vascular myositis. CK values may be normal or mildly elevated. Occasionally, these individuals would be considered for other metabolic myopathies such as a glycogen storage disease or carnitine deficiency. Interestingly, male patients with mitochondrial myopathies are frequently found to have hypogonadism (5).

Case 3.

A 44-year-old woman with a history of migraine headaches, vulvodynia, and irritable bowel presented with waxing and waning numbness and paresthesias of the roof of her mouth, tongue, and extremities, as well as dysgeusia, dysarthria, and blurry vision. In addition, she had a 9-lb weight loss and 2 episodes of retropulsion resulting in falls without injury. At that time she was evaluated by a neurologist and found to have a normal neurologic examination. Testing included brain magnetic resonance imaging (MRI) that revealed a mild type I Arnold-Chiari malformation without ischemic changes or demyelination. Subsequently, she underwent further MRI evaluation of her cervical, thoracic, and lumbar spine that demonstrated only mild degenerative joint disease. A lumbar puncture was performed and the cerebrospinal fluid studies were normal. B12, folate, glycosylated hemoglobin, thyroid function, and Lyme tests were unremarkable.

Six months later she was evaluated by 2 neurologists and found to have a normal neurologic examination. The patient underwent evoked potential studies of EMG and nerve conduction study, both of which were normal.

The patient presented again within 7 months with a repeat lumbar puncture that was again within normal limitations. A rheumatologic examination showed a normal joint examination along with a normal serologic evaluation, including antinuclear antibodies, rheumatoid factor, anticardiolipin antibody, antineutrophil cytoplasmic antibody, and erythrocyte sedimentation rate.

Symptoms persisted and 3 courses of high-dose oral pulse methylprednisolone (96 mg twice a day for 2 days) offered the patient partial relief from her symptoms for the next 3–4 days before all symptoms returned with the same intensity. 5-hydroxyindoleacetic acid was normal and a toxicology screen for heavy metals was normal. A second rheumatologist familiar with mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS) syndrome saw the patient and recognized the unusual feature of retropulsion, suggested the diagnosis, and ordered diagnostic genetic testing.

These tests revealed the patient to have MELAS syndrome. She was started on a treatment regimen of coenzyme Q10, menadione, idebenone, riboflavin, nicotinamide, creatine monohydrate, and L-arginine (4), with moderate improvement.

Patients with multisystem disease, including myopathy, can present with a host of varying manifestations suggesting a systemic vasculitis or one of the vasculitic mimics, such as antiphospholipid syndrome, fibromuscular dysplasia, or cholesterol emboli. Most of the individuals with multisystem disease as a consequence of mitochondrial myopathy will present with MELAS syndrome. The others are more likely to be seen by a neurologist or an ophthalmologist.

MELAS syndrome is a progressive neurodegenerative disorder that may present sporadically or as members of maternal pedigrees. Stroke-like episodes occur in conjunction with other features that may include the possibility of seizures, diabetes mellitus, hearing loss, short stature, and exercise intolerance. There is multiorgan involvement: central nervous system, skeletal and cardiac muscle, ophthalmologic, gastrointestinal, and renal. The MELAS syndrome is particularly difficult to diagnose.

Genetic studies reveal that 80% of patients diagnosed with MELAS syndrome have heteroplasmic A- to G-point mutation in dihydrouridine loop of transfer RNA at bp 3243. Although up to 62% do not have a clear maternal inheritance, family history, if positive, can be a major clue to the diagnosis. Mutations may affect transfer RNA, leading to disruption of global intramitochondrial protein synthesis. More than 50% have decreased respiratory enzyme activity (complex I and IV) resulting in decreased respiratory chain activity by reduced translation of UUG-rich genes (complex I). The stroke pathogenesis is not clear but may be due to transient oxygen phosphorylation dysfunction within the brain or alterations in nitrous oxide homeostasis displacing heme-bound oxygen and resulting in decreased oxygen availability. Mitochondrial angiopathy of small vessels or oxygen phosphorylation defects of parenchyma and vasculature may contribute to multiorgan symptoms. Increased production of free radicals in association with the oxygen phosphorylation defect can also cause vasoconstriction.

The treatment consists of antioxidants and various vitamins, including coenzyme Q10, menadione (vitamin K3, donates electrons to cytochrome c), idebenone, riboflavin (if complex I deficient), nicotinamide, creatine monohydrate (potential increase in muscle strength reported), and L-arginine (8).

There are no estimates of MELAS syndrome prevalence in the US, except that it appears to be less common in African Americans and is not sex specific. MELAS syndrome has a high overall morbidity and mortality rate. Encephalomyopathy with stroke-like episodes followed by hemiplegia and hemianopia can occur. The development of focal and general seizures can occur. Patients may manifest psychiatric abnormalities (schizophrenia and cognitive decline). This cognitive impairment may progress to dementia. It is important to remember that cardiac involvement with atrioventricular blocks, Wolff-Parkinson-White syndrome, and hypertrophic cardiomyopathy occurs. Renal failure and focal segmental glomerulosclerosis may also be features of MELAS syndrome.


Mitochondria are intracellular organelles responsible for energy production and to some extent operate independently but cooperatively with their host cells. They are thought to be an evolutionary parasitic photosynthetic bacterium that invaded early eukaryotic cells approximately 1 billion years ago as the earth's environment became more oxidative. This symbiotic relationship permitted enhanced aerobic ATP production. The mitochondrial respiratory chain consists of 5 protein complexes that generate ATP through oxidative phosphorylation. The complexity of this process is highlighted by the presence of components that are encoded by either mitochondrial genes or nuclear DNA. Defects in either of them can cause mitochondrial myopathies. Although a total of approximately 100 genes have been found defective in one or another type of mitochondrial myopathy, only approximately 50% of patients have an identifiable genetic defect. The inheritance is similarly complex, with autosomal dominant, autosomal recessive, x-linked, and maternal inheritance patterns. In addition, in contrast to genes that segregate by Mendelian genetics, the inheritance of mitochondrial disorders results in a pattern called heteroplasmy that refers to the ratio of normal to abnormal mitochondria per cell. Since this can occur at more than 100-fold, the severity of presentation is similarly large. There is variability across tissue types and need for oxidative respiration (brain, heart, and skeletal muscle being especially at risk), resulting in vastly different clinical presentations. Lastly, there is poor phenotypic/genotypic correlation resulting in families with the same genetic defect and widely variable phenotypic variation. Therefore, there may be a family history of a neurologic disorder but it may have been mislabeled myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis, or another neurologic disorder.

Other mitochondrial disorders that are not predominantly myopathic present with a wide range of manifestations, including peripheral neuropathies, cranial neuropathies, cardiomyopathies, and encephalomyelopathies, as well as hematologic, gastrointestinal, nephrologic, and endocrinologic issues (especially diabetes mellitus). Discussion of these syndromes (including neuropathy, ataxia, and retinitis pigmentosa; Leigh's syndrome; myoclonus epilepsy with ragged fibers; Pearson syndrome; mitochondrial neurogastrointestinal encephalopathy; Leber's hereditary optic neuropathy; and others) are beyond the scope of this review.

These 3 cases represent very different presentations of mitochondrial myopathies. The first is a typical presentation of the KSS with bilateral ptosis, ophthalmoplegia, and a noninflammatory myopathy. The second is a slowly progressive isolated proximal myopathy. The third is a chronic multiorgan system failure syndrome progressing over years. The previous case reports serve to demonstrate that because mitochondrial myopathies present with proximal muscle weakness, they can be mistaken for inflammatory myopathies. Clues that the patient has a mitochondrial myopathy are shown in Table 1.

Table 1. Clues that the patient has a mitochondrial myopathy
Family history
Associated neurologic findings
Exercise-induced exacerbation
Rhabdomyolysis, particularly with exercise
Lack of electromyogram findings of membrane instability
Biopsy sample that lacks inflammation
Ragged-red fibers
Nonresponse to corticosteroids and/or immunosuppressive
Multiorgan system disease
Absent or very low creatine kinase elevations

An algorithmic approach to diagnosis of metabolic myopathies that includes the mitochondrial diseases has been published (6), although a more detailed approach that only focuses on mitochondrial myopathies might be more helpful (7). Alternatively, an approach that tries to link the genetic defect to the multisystem manifestations is also insightful (9). A limited differential diagnostic list for these presentations can be helpful and is shown in Table 2.

Table 2. Differential diagnosis of mitochondrial myopathies*
  • *

    MELAS = mitochondrial encephalopathy, lactic acidosis, and stroke; CNS = central nervous system; SLE = systemic lupus erythematosus.

Kearns-Sayre presentation
 Myasthenia gravis
 Oculopharyngeal muscular dystrophy
 Paraneoplastic neuromyopathy
 Granulomatosis with polyangiitis (Wegener's)
Proximal myopathy
 Inclusion body myopathy
 Drug-induced (e.g., statin) myopathy
 Paraneoplastic myopathy
MELAS syndrome
 Granulomatous angiitis of the CNS
 Sjögren's syndrome
 Antiphospholipid syndrome
 Polyarteritis nodosa
 Granulomatosis with polyangiitis (Wegener's)

Laboratory studies (Table 3) and other tests that can be performed to support a diagnosis of mitochondrial myopathy, including lactic acid (serum and cerebral spinal fluid [CSF]), CSF pyruvic acid, CK (serum), muscle biopsy (with testing of respiratory chain enzymatic activity), mitochondrial DNA mutation analysis (on skeletal muscle, hair follicles, or buccal mucosa), and computed tomography/MRI scanning of the brain, can demonstrate lucencies consistent with infarction, later cerebral atrophy (also calcifications in the basal ganglia), and proton MR spectroscopy (used to identify metabolic abnormalities), including lactate/creatinine ratio in muscle or the brain (while serum lactate is low). MR spectroscopy has also been found to be useful in the centers that can perform these studies. Centers that are specially equipped to evaluate patients for these disorders are shown in Table 4.

Table 3. Tests that may be useful to evaluate for possible mitochondrial myopathy*
  • *

    In addition to a complete history, physical examination, neurologic examination, and family history. CPK = creatine phosphokinase; EMG = electromyogram; NCV = nerve conduction velocity; CSF = cerebrospinal fluid; EEG = electroencephalogram; MR = magnetic resonance; H&E = hematoxylin and eosin.

Renal function
Plasma and/or CSF lactic acid/pyruvate
Ketone bodies
Plasma acetylcarnitine
Urinary organic acids
MR spectroscopy
Mitochondrial genetic testing
Exercise testing with lactic/pyruvate
Muscle biopsy sample for H&E stain and assessment of respiratory chain enzymes
Table 4. Specialized testing and treatment facilities
Gene Dx
 207 Perry Parkway
 Gaithersburg, MD 20877
Athena Diagnostics
 Four Biotech Park
 377 Plantation Street
 Worcester, MA 01605
Center for Human Genetics & Center for Inherited Diseases in Metabolism, University Hospitals, Case Medical Center, Cleveland,  Ohio
Cleveland Clinic Neurometabolism & Neurogenetics & Center for Inherited Diseases in Metabolism, Cleveland, Ohio
Medical Neurogenetics
 5424 Glenridge Drive
 Atlanta, GA 30392
Mitochondrial & Metabolic Disease Center, University of California, San Diego, California
Baylor College of Medicine Medical Genetics Laboratories, Baylor, Texas
Columbia Merritt Center Laboratory for Medical Neurogenetics, Columbia, New York
Neurometabolic Clinic, McMaster University Medical Center, Hamilton, Ontario, Canada
Robert Guthrie Genetics Laboratory, Buffalo, NY

In conclusion, presentations of the mitochondrial disorders can be obscure. A significant number of patients who present with symptom complexes are directed to see an ophthalmologist or neurologist; however, some will present with features suggesting a rheumatic disease. There is treatment available (Table 5) and family counseling is important. Large amounts of time and money can be expended in fruitless and potentially dangerous diagnostic procedures. For these reasons, it is important for rheumatologists to be aware of these conditions. Online resources are also available (Table 6).

Table 5. Potential therapeutic agents
Electron donors and acceptors
 Coenzyme Q10
  Key component of the mitochondrial chain with antioxidant properties. It plays a major role in transporting electrons from   complexes I and II to complex III
  Coenzyme Q10 analog
  Converted to thiamine pyrophosphate, which is a cofactor for the enzyme reaction that catalyzes the conversion of   pyruvate to acetyl-coenzyme A and α-ketoglutarate to succinyl-coenzyme A
  Precursor of riboflavin cofactors used in the electron-transport chain and reduces lactic acid
  Vitamin B7 cofactor for several carboxylase enzymes
Lactic acid reduction strategies
  Inhibits pyruvate dehydrogenase kinase and thus reduces lactic acid formation
  Increases nicotinamide adenine dinucleotide by reducing serum lactate and pyruvate
 Menadione (vitamin K3)
  Increases NADH oxidase activity and reduces lactic acid
  Increases tricarboxylic acid cycle activity, thus reducing anaerobic metabolism and lactic acid production
 Vitamin E (α-tocopherol)
  Scavenges free radicals
 α-lipoic acid
  Binds free radicals
 Vitamin C
  Ascorbic acid
Alternative energy source
 Creatine monohydrate
  Increases muscle creatine and phosphocreatine
Table 6. Online resources
The Mitochondrial Medicine Societyhttp://mitosoc.org/blogs/diagnosis/tissue/
National Institutes of Health Office of Rare Diseases ResearchRarediseases.info.nih.gov
United Mitochondrial Disease Foundationwww.umdf.org/
Muscular Dystrophy Associationwww.mdausa.org


All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.