Rhabdomyolysis featuring muscular dystrophies
Introduction
Rhabdomyolysis is a potentially life threatening condition due to acute myofiber necrosis, characterized by a marked elevation in serum creatine kinase (CK) levels with or without myoglobinuria [1], [2]. Myoglobinuria indeed may go undetected if rhabdomyolysis is mild or urine myoglobin does not exceed 100 mg/dl [2]. The clinical presentation is variable with a combination of myalgia, muscle swelling and acute onset muscle weakness. Acute renal failure is the most serious complication occurring in approximately 15% to 50% of cases [3]. The etiologies of rhabdomyolysis are various and include acquired and inherited causes; genetic predisposition and environmental factors may be contributing factors. An isolated episode of rhabdomyolysis in an otherwise healthy individual, in the context of a clearly identifiable exogenous (e.g. drugs, trauma or infections [2], [4], [5]) or endogenous trigger (e.g. hypothyroidism [2]), may require no further diagnostic evaluation. Conversely, recurrent rhabdomyolysis, a history of preexisting symptoms such as exercise intolerance, exercise-induced muscle cramps, muscle weakness, or positive family history of myopathy are all concerns for an inherited muscle disorder [2], [6].
Recurrent rhabdomyolysis is the hallmark of many metabolic myopathies in which rhabdomyolysis is often precipitated by exercise or fever and followed by complete clinical recovery [2], [6], [7]. CK values may normalize in between episodes of rhabdomyolysis [e.g. in carnitine palmitoil transferase 2 (CPT2) deficiency] or may persist elevated (e.g. in myophosphorylase deficiency, McArdle disease) in metabolic myopathies [6], [7]. Rhabdomyolysis can also be a manifestation of the skeletal muscle ryanodine receptor 1 (RYR1) defect, often but not necessarily, occurring in the setting of malignant hyperthermia [2]. Progressive muscle weakness, muscle atrophy and persistently elevated CK values are classic features of muscular dystrophies. However, rhabdomyolysis can occur also in patients with muscular dystrophies and be precipitated by exercise or other etiologies, similarly to what observed in individuals with other types of myopathies [8], [9], [10]. Less frequently, rhabdomyolysis occurs spontaneously with no identifiable trigger in muscular dystrophies, or may be the initial manifestation of it in asymptomatic or mildly symptomatic patients [11], [12], [13], [14], [15], [16], [17].
The association between rhabdomyolysis and muscular dystrophies is less well recognized in clinical practice than the association between rhabdomyolysis and metabolic myopathies. This often leads to the misdiagnosis of metabolic myopathy or to delayed diagnosis, especially in the absence of anatomical footprint on muscle biopsy. For example, in a large retrospective study with 475 patients manifesting rhabdomyolysis, muscular dystrophy was suspected only in one patient on the basis of the muscle biopsy findings and was not confirmed genetically [4]. The unusual association between muscular dystrophy and rhabdomyolysis, frequently described in the form of case reports, could be due to the rarity or under-recognition of this phenomenon.
The aim of this study is to identify the most frequent muscular dystrophies presenting with rhabdomyolysis at onset or having rhabdomyolysis as predominant feature.
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Materials and methods
The Institutional Review Board of Mayo Clinic approved this study. An electronic record retrieval system was used to identify retrospectively patients evaluated by neuromuscular specialists at our institution between 1997 and 2014 for one or more episodes of rhabdomyolysis and whose evaluation confirmed a diagnosis of muscular dystrophy either through genetic testing, immunohistochemical analysis of muscle tissue or both. We searched the electronic medical records for the terms rhabdomyolysis
Patients with genetically confirmed diagnosis of a muscular dystrophy and rhabdomyolysis
Pertinent clinical and laboratory features of these patients are summarized in Table 1, Table 2. Thirteen unrelated patients, 6 males and 7 females, were identified (patients 1 and 3 were previously reported [13], [18]). The median age was 18 years (range, 2–47 years) at the time of the first episode of rhabdomyolysis and 23 years (range, 2–53 years) at the time of our clinical evaluation. Four patients reported recurrent rhabdomyolysis.
Exercise was the most common precipitant (n = 6), followed by
Discussion
This study underscores the occurrence of rhabdomyolysis in several muscular dystrophies, often as initial manifestation or predominant clinical feature that leads to the neurological evaluation. FKRP-muscular dystrophy (LMGD2I) was the most common muscular dystrophy manifesting or presenting at onset with rhabdomyolysis in our cohort. Anoctaminopathy-5, calpainopathy-3 and dystrophinopathy also presented with rhabdomyolysis in our patients. In addition, dysferlinopathy, caveolinopathy-3, and
Conflicts of interests
Rajat Lahoria and Margherita Milone report no conflicts of interests.
Acknowledgments
We are grateful to Dr. Steven Moore for performing calpain-3 Western blot in patient 5.
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2020, Environmental Toxicology and PharmacologyCitation Excerpt :There was a significant increase in serum myoglobin levels in rats treated with DS, yet no change in myoglobin levels were seen in the serum of animals treated with MZ (Fig. 2B). Rhabdomyolysis, a type of myopathy due to severe muscle damage, is characterized by acute myofiber necrosis, elevations of CK, myoglobinuria, myalgia, muscle swelling, and muscle weakness and can occur with or without the presence of muscular dystrophy (Lahoria and Milone, 2015; Percy, 2016). The mechanism by which rhabdomyolysis occurs is either through sarcolemmal injury or failure of energy supply to the muscle which leads to an increase of free intracellular calcium and therefore activation of calcium-dependent proteases resulting in myonecrosis, characterized by myofibril destruction and lysosomal digestion (Shelton, 2004).