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Systemic, Inflammatory, and Inherited Causes of

Myopathy, and Relevant Differential Diagnosis

Irvin Calderon
University of California Riverside
School of Medicine - Class of 2021

Mrs. B. was a patient who demonstrated chronic and progressive daytime fatigue. Her electrolyte panel, thyroid function tests, ESR, creatine kinase serum level, and CBC were all within normal limits. Most of her physical exam was unremarkable, except for the musculoskeletal exam in which she demonstrated bilateral tenderness of the deltoid, supraspinatus, paracervical, and upper trapezius muscles with no edema and a full range of motion. She did not demonstrate the cardinal signs of an inflammatory response, nor did she appear to have a systemic endocrine disorder. Given these results, it is unlikely that she has an inherited or acquired myopathy. Thus, the differential diagnosis may not be myopathy-associated.

Myopathies are defined as a group of diseases of muscle tissue. The most common symptoms of skeletal myopathy include, but are not limited to, proximal skeletal muscle weakness, myotonia, fatigue, and dark-colored urine(1). Myopathy can either be acquired or inherited; if acquired, the most common etiologies include endocrine, metabolic, or an inflammatory cause, but if inherited, then the etiology can either point to a deficiency of a metabolic enzyme (e.g. glycogen storage disorders) or a problem with the structural proteins of skeletal muscle (e.g. Duchene’s muscular dystrophy). Thus, the range of diagnoses will commonly fall into one of these categories.

Endocrine causes of myopathy are typical in their presentation and usually share a common lab result: a normal, although sometime elevated, creatine kinase (CK) serum level. Hyperthyroidism, hypothyroidism, hyperparathyroidism, and Cushing’s syndrome collectively cause proximal muscle weakness(2). In hypothyroidism, CK levels are often elevated 10-fold. To illustrate how myopathy can be induced by an electrolyte imbalance, proximal muscle weakness observed in primary aldosteronism is due to hypokalemia. It is also worth mentioning that in uncontrolled diabetes, myopathy can result from an ischemia induced infarction of thigh muscles.

Inflammatory myopathies, that are not associated with infection, include dermatomyositis, polymyositis,and inclusion body myositis(3). Dermatomyositis is very distinct in its presentation because of characteristic rashes that develop prior to the onset of the myopathic symptoms. The characteristic rashes can include heliotropic rashes (purple discolorations on the eyelid), Gottron’s papules (scale-like rashes on dorsal aspect of fingers), and a shawl sign (red-colored rashes on shoulders and back). Polymyositis presents with an inflammatory response against the extremity muscles that are closest to the trunk; arthralgia also tends to be an exclusive symptom of polymyositis. Lastly, inclusion body myositisis caused by an inflammatory response against the quadriceps muscle and the muscles of the distal extremities; another associated symptom that is more exclusive to inclusion body myositis is the degeneration and clumping of muscle cells within the tissue.

The most commonly inherited myopathy disorders include dystrophinopathies, inborn errors of metabolism, mitochondrial myopathies, and congenital myopathies(4).The two common examples of a dystrophinopathy are Duchenne muscular dystrophy and the milder Becker muscular dystrophy, which are caused by a frameshift or deletion mutation of the dystrophin gene on the X chromosome. Dystrophin is an important protein that normally plays a role in anchoring the myofibrils of muscle cells to cytoskeleton and extracellular matrix. In its absence, muscle atrophy and necrosis manifest gradually, with symptoms afflicting the pelvic girdle muscles first. Symmetric limb weakness with preserved reflexes are often exhibited in these diseases(5). Like the dystrophinopathies that result from a mutation on a structural protein, mutations in metabolic enzyme genes can also cause myopathy. McArdle disease (a glycogen storage disorder) can exemplify such a phenomenon. In McArdle disease, there is a deficiency in muscle glycogen phosphorylase. Glycogen collects in skeletal muscle with the inability of degradation for fuel, leading to painful muscle cramps and myoglobinuria during exercise(6).Unlike mutations that occur in the chromosomes, mutations can also occur in mitochondrial DNA, resulting in several forms of inherited mitochondrial diseases. The accumulation of deleterious mutations in mitochondria will often cause the patient to present with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. One common sign is the presence of “ragged red fibers” on a biopsy of the afflicted muscle(7). No doubt, a differential diagnosis that includes an inherited disease is a necessity when determining the cause of myopathies.

Undoubtedly, if a clinician suspects that their patient is demonstrating symptoms of myopathy, one of the first questions that should be addressed is whether the myopathy is acquired or inherited, which a thorough history can accomplish. If the myopathy is suspected to be inherited, then the clinician must continue to ask if it is a congenital problem that arose during development, or whether the problem is associated with an inherited deficiency of an important metabolic enzyme or structural protein, such as in McArdle’s disease or Duchenne muscular dystrophy respectively; mitochondrial inherited diseases are prevalent among siblings because of the maternal inheritance pattern. Conversely, if the myopathy is suspected to be acquired, then the evaluation for systemic endocrine diseases (e.g. thyroid disorders) and inflammatory myopathies (e.g. dermatomyositis) becomes paramount; the physical examination and lab workup become more important to guide the clinician in the right direction. Remarkably, although myopathy can result from various etiologies, it is most often secondary to other diseases, and thus, the best way to treat myopathy is by addressing the source.

Funding: None.
Conflict of Interest: None.
Authorship: Author is entirely responsible for the content of this manuscript.
Requests for reprint should be addressed to Irvin Calderon, University of California School of Medicine, 900 University Ave., Riverside, CA 92507

1. Myopathies. (2017, December 28). https://emedicine.medscape.com/article/759487-overview

2. Chawla J. Stepwise Approach to Myopathy in Systemic Disease. Frontiers in Neurology. 2011;2:49. doi:10.3389/fneur.2011.00049.

3. Dalakas MC. Polymyositis, Dermatomyositis, and Inclusion Body Myositis. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e New York, NY: McGraw-Hill; 2014.

4. Muthusamy P, Tavee J. Myopathy. Current Clinical Medicine. 2010:904-908. doi:10.1016/b978-1-4160-6643-9.00234-4.

5. Amato AA, Brown RH, Jr.. Muscular Dystrophies and Other Muscle Diseases. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e New York, NY: McGraw-Hill; 2014.

6. Kishnani PS, Chen Y. Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e New York, NY: McGraw-Hill; 2014.

7. Skorecki K, Behar D. Mitochondrial DNA and Heritable Traits and Diseases. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e New York, NY: McGraw-Hill; 2014.