What are the causes of myopathy?

Causes of Myopathy

Myopathies are broadly classified into hereditary (congenital) and acquired categories, with hereditary forms more common in children and acquired forms predominating in adults. 1

Hereditary/Congenital Myopathies

Structural Myopathies

• Congenital myopathies include nemaline myopathies, central core and multiminicore diseases, centronuclear-myotubular myopathy, myosin storage myopathy, and congenital fiber type disproportion 1
• Muscular dystrophies encompass limb girdle muscular dystrophies, facioscapulohumeral muscular dystrophy, Duchenne and Becker muscular dystrophy, and proximal myotonic myopathy 2
• Myofibrillar myopathies (MFM) result from mutations in DES, MYOT, LDB3/ZASP, CRYAB, FLNC, BAG3, FHL1, DNAJB6, and TTN genes, typically presenting at 30-50 years with progressive distal-to-proximal weakness and cardiac conduction defects 3

Myotonic Disorders

• Myotonic dystrophy type 1 (DM1) is caused by CTG trinucleotide repeat expansion in the DMPK gene (>35 repeats), presenting with progressive facial, neck, and distal limb weakness, myotonia, and cardiac manifestations in approximately 80% of patients 3, 1
• Myotonic dystrophy type 2 (DM2) results from CCTG repeat expansion in CNBP, with more variable clinical manifestations and generally more favorable prognosis than DM1 3

Metabolic Myopathies

• Glycogen storage diseases such as McArdle disease cause rapid exhaustion, myalgia, and cramping in working muscles 2
• Lipid deposition myopathies lead to lipid accumulation in skeletal muscle fibers causing lesions and degeneration 2
• Mitochondrial disorders manifest during prolonged low-intensity activities or fasting, characterized by progressive fixed weakness and multisystem features 4
• Barth syndrome is an X-linked mitochondrial myopathy caused by TAZ gene mutations affecting cardiolipin remodeling 3
• Friedreich ataxia results from GAA repeat expansion (>70 copies) in the FXN gene, causing mitochondrial iron dysregulation 3

Hollow Visceral Myopathy

• Familial visceral myopathy is a rare congenital disorder presenting in the first or second decade with gross gastrointestinal and urinary tract dilatation, following autosomal dominant inheritance 3

Acquired Myopathies

Inflammatory/Autoimmune

• Idiopathic inflammatory myopathies include polymyositis (primary muscle inflammation without skin involvement) and dermatomyositis (with characteristic skin manifestations) 1, 5, 2
• Inclusion body myositis (IBM) is the most prevalent acquired myopathy above age 50 2
• Autoimmune myopathy can occur as a primary pathology or secondary to systemic lupus erythematosus, Sjögren's syndrome, and overlap syndromes 3, 1, 2
• Necrotizing autoimmune myopathy associated with anti-HMGCR antibodies is responsive to aggressive immunotherapy 6

Connective Tissue Disorders

• Systemic sclerosis (scleroderma) causes smooth muscle atrophy and gut wall fibrosis, starting with microvasculature damage from collagen deposits leading to neural damage, muscle dysfunction, and fibrosis 3, 1
• Other rheumatologic disorders including rheumatoid arthritis, Still's disease, dermatomyositis, and polyarteritis nodosa can cause myopathy through immune-mediated mechanisms, progressive fibrosis, or treatment-related effects 3

Infiltrative Diseases

• Amyloidosis (most commonly from myeloma producing lambda chains) can cause both myopathy and neuropathy, requiring duodenal sampling for diagnosis 3, 1
• Sarcoidosis can manifest as muscle weakness and myalgia 2

Toxic Myopathies

• Statins and fibrates are the most important iatrogenic causes, potentially causing severe necrotizing myopathy, acute rhabdomyolysis, and myoglobinuria 6, 7
• Corticosteroids are among the three main culprits of acquired myopathy alongside statins and alcohol 7
• Alcohol is a major cause of toxic myopathy 7
• Other medications include SGLT2 inhibitors, antimalarials, antiretroviral agents, pyrimidine nucleoside analogues (clevudine), and succinylcholine (which should be avoided in all metabolic myopathies due to rhabdomyolysis risk) 4, 2, 6
• Red yeast rice and toxic mushroom species have been reported to cause myopathy 6

Endocrine/Metabolic

• Adrenal dysfunction including both Cushing's syndrome (overproduction) and adrenal insufficiency can cause myopathy 2
• Thyroid disorders (both hyperthyroidism and hypothyroidism) directly contribute to muscle weakness 2
• Parathyroid disorders and pituitary gland dysfunction can indirectly contribute to myopathy 2

Infectious

• Viral causes include HIV, dengue virus, influenza virus, hepatitis B and C viruses, and SARS-CoV-2 2
• Chagas disease (Trypanosoma cruzi) causes progressive myocardial damage through parasite persistence and autoimmune responses, with 50% mortality within 4 years in patients with heart failure 3
• COVID-19 vaccination has been attributed to myopathy development 2

Radiation-Induced

• Chronic irradiation damage typically occurs after pelvic irradiation (>45 Gy) for gynecological or genitourinary cancers, affecting gut permeability, secretion, motility, and blood supply, with problems manifesting months to years later 3

Critical Diagnostic Considerations

Most toxic myopathies are potentially reversible if diagnosed early, making rapid identification crucial to avoid serious permanent muscle damage 7. The classification can be challenging because some conditions (systemic sclerosis, vasculitis, amyloid) can present as both myopathy and neuropathy 3, 1. Primary myopathies often have multivisceral involvement with relatively high mortality, while secondary myopathies in adults may have better outcomes if the underlying cause is addressed 1.