Rhabdomyolysis is characterised by skeletal muscle damage which can present acutely, and when severe, if untreated in a timely manner, it can lead to acute kidney injury. The release of intracellular muscle components into the blood stream (associated with rising CK) results in myoglobinuria, which gives the urine a dark tea-coloured appearance. Although finding an underlying genetic defect in a patient presenting with rhabdomyolysis is an infrequent occurrence, it is of great clinical importance as diagnosis enables appropriate advice on its implications and will enable introduction of strategies to prevent future episodes, when due to a metabolic defect. Diagnosis of an inherited metabolic disorder will also guide testing of other family members to ascertain risk.

Episodes of rhabdomyolysis, particularly when recurrent or encountered in a patient with other similarly affected relatives, should raise the index of suspicion that there may be a causal genetic predisposition. Exploring the patient’s complaints, in relation to the timing and precipitating factor (eg. prolonged fasting, prolonged or burst of exercise) may provide a strong clue. Muscle contraction is heavily energy-dependent, starting with glucose utilisation on initiation of activity, and when physical activity is sustained metabolism switches to consumption of fatty acids (to spare essential glucose requirements of the brain).

Thus, in disorders of glucose metabolism (eg. glycogenolysis-McArdle disease, or glycolysis-Tarui disease), symptoms are induced within minutes by isometric muscle contraction (such as weight lifting) or intense activity (sprinting). Exercise intolerance can manifest as fatigue and/or discomfort and cramps. In contrast, in disorders of fatty acid metabolism symptoms develop after aerobic exercise or activity for a more prolonged period, and can be brought on by fever, fasting and stress. In these cases, recognition of provoking factors is a critical element in managing symptoms and preventing progression of further muscle damage. 

The majority of these conditions are inherited in an autosomal recessive manner, that is, in an individual born to unaffected (carrier) parents; therefore, information about whether siblings also have symptoms may be helpful.

McArdle disease or GSD type V

McArdle disease or GSD type V (deficiency of skeletal muscle glycogen phosphorylase) is the most common disorder of glycogen (glucose) metabolism; which is also often missed or diagnosis significantly delayed. Among Caucasians, around 55% of the defects (in the implicated PYGM gene) is due to the R50XA mutation. A recent report from a London metabolic clinic examined the patient experience in 50 genetically confirmed cases, noting a high frequency of misdiagnosis (90%, n = 45/50); indeed, the correct diagnosis of McArdle disease was rarely made before adulthood (median age of diagnosis 33 years).¹ The most common labels given to patients during their early years were ‘growing pains’ (40%, n = 20) and ‘laziness/being unfit’ (46%, n = 23).  Importantly, of the 45 patients who were misdiagnosed, 21 (47%) received incorrect management. A ‘second wind’ phenomenon, characterised by easing of symptoms and an associated decrease in heart rate with ongoing activity – occurring at around 8-10 minutes of exertion – is a key feature. Hyperuricaemia and gout are also seen frequently in affected individuals. Oral intake of glucose (sugary drinks) immediately prior to exercise can improve exercise tolerance.

Tarui disease or GSD type VII

Tarui disease or GSD type VII (deficiency of phosphofructokinase) – a rarer condition – shares similar manifestations with McArdle disease, except that patients have more severe exercise intolerance and do not experience the second wind phenomenon. Moreover, intake of glucose drinks prior to exercise can exacerbate exercise intolerance – an ‘out-of-wind’ phenomenon. Haemolytic anaemia can develop in severely affected cases, which can also be encountered in two other even more rare disorders of glycogen metabolism (ie. GSD type XII or aldolase A deficiency and phosphoglycerate kinase (PGK1) deficiency). Unlike the conditions mentioned thus far, phosphoglycerate kinase (PGK1) deficiency is transmitted as an x-linked trait. In these disorders, mildly raised serum bilirubin may suggest haemolysis.

The enzyme defects and evidence of glycogen storage may be demonstrated on muscle biopsy. However, non-ischaemic forearm (exercise) stress test – suboptimal rise in lactate level – may support the clinical diagnosis. A blood test, ie. a limited rhabdomyolysis gene panel testing, may be a more cost-effective (relatively non-invasive) approach that may be considered. These tests can be arranged by the Adult Metabolic Unit at the Mater Hospital for adults and through Temple Street Children’s University Hospital, Dublin.

Carnitine palmitoyl-transferase-II (CPT-II) and very long-chain acyl-CoA dehydrogenase (VLCAD) 

Deficiency of carnitine palmitoyl-transferase-II (CPT-II) and very long-chain acyl-CoA dehydrogenase (VLCAD) are two distinct disorders of fatty acid (oxidation) metabolism. Both are inherited in an autosomal recessive fashion, like most of the glycogen disorders of metabolism (ie. GSDs), noted above.

In contrast to assessment of suspected GSDs, a muscle biopsy is unhelpful and should not be performed if VLCAD is suspected; instead the most important first-line investigation is fasting blood acylcarnitine profile which can be undertaken on blood spotted filter paper (as done for newborn screening tests) and sent to the metabolic lab at Temple Street Children’s Hospital. CPT-II may also be detected by examining the acylcarnitine profile but this may necessitate a blood sample, which currently needs to be sent abroad. Although serum creatine kinase (CK) levels can be elevated during an attack, CK levels can be normal between episodes and thus does not exclude the diagnosis of a fatty acid oxidation (FAO) defect. 

Approximately 60% of affected people with CPT-II deficiency carry the common mutation (c.338C > T, p.Ser113Leu), thus, testing of this specific mutation is recommended as a second-line investigation. With both VLCAD and CPT-II deficiency, patients are advised regarding avoidance of fasting, excessive exercise, with modest dietary fat restriction and prescription of medium chain triglycerides supplements for emergency use. These patients may also develop secondary carnitine deficiency, and should be monitored appropriately so carnitine can be supplemented, as needed. Patients with FAO defects may also develop cardiac dysfunction and rhythm disturbances, and should be monitored accordingly during an acute illness.

Mitochondrial disorders

Defects of fatty acid oxidation are intrinsically mitochondrial disorders, as the relevant metabolic pathways can be found in the mitochondria, compromising the production of ATP production required to meet the high metabolic demand of skeletal muscle. Conditions classically classified as mitochondrial disorders also often manifest with involvement of other organs/tissues that have a high energy requirement, eg. brain, heart. As a consequence, there can be a range of problems, whose severity can be variable, resulting from cardiac complications, impairment of sensory organs (vision and hearing) and diabetes. 

Unfortunately, there are no specific therapies for mitochondrial disorders, although supplements such as co-enzyme Q may be prescribed. In patients with a particular mitochondrial disorder known as MELAS, which predisposes patients to stroke, the use of arginine may be beneficial in management to limit the damage during its evolution.

Early diagnosis

It is important not to miss the conditions mentioned and related diseases as they can be readily managed, with the exception of mitochondrial disorders. Furthermore, these patients can be at risk for decompensation during surgery, which can be mitigated by appropriate precautions, including ensuring adequate hydration. Some patients may also not tolerate certain anaesthetics and muscle relaxants that may be given in situations requiring sedation, whether for diagnostic or interventional purposes. In addition, these patients may be at risk of malignant hyperthermia, which manifests clinically as a hypermetabolic crisis (including features such as hypercapnia, masseter muscle and/or generalised muscle rigidity, acidosis, and peaked T-waves on ECG). 

Malignant hyperthermia susceptibility (MHS) is a particular concern for patients with disorders of intramuscular calcium release and excitation-contraction coupling, and those with exertional rhabdomyolysis. A retrospective Canadian study by Kraeva et al involving MHS patients showed that 10 out of 17 patients (58%) carried a ryanodine receptor (RYR1) or CACNA1S (which activates RYR1) defect.² Cognate genes encode proteins involved in the translation of an electrical neuronal impulse into muscle contraction, which entails the transport (capture and release) of calcium. 

Interestingly, recent case reports describe a malignant hyperthermia-like syndrome (ie. non anaesthetic-induced) in physically active individuals associated with exertional heat stroke (EHS) and exertional rhabdomyolysis (ER).³ It has been suggested that the first responder (eg. athletics coach, team physician) be trained to recognise signs and symptoms, and emergency management measures to reduce the likelihood of complications. In individuals at risk, mitigation would be advised by optimising hydration throughout exercise, providing athletes with acclimatisation periods before exercising in the heat for the first time, selecting exercise intensities that are appropriate for each individual, and avoiding physical activities when ill.

Statins

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are recommended in patients with established, or those at risk for, cardiovascular disease –to decrease the incidence of adverse cardiovascular events and mortality. Statin-associated adverse effects manifest primarily as muscle-related symptoms and are seen in up to one-third of patients in clinical practice. 

A thorough assessment of the patient’s clinical and laboratory history should be performed in any patient presenting with muscle symptoms on statin therapy. In practice, most patients with statin intolerance due to muscle symptoms will be able to tolerate another statin, when clinically indicated.

Propofol infusion syndrome

Propofol infusion syndrome must be kept in mind as inborn errors of mitochondrial fatty acid oxidation have been listed as a risk factor. Symptoms include a wide range of systemic complications such as cardiovascular, respiratory, metabolic and hepatic dysfunction. Typical features include an otherwise unexplained high anion gap metabolic acidosis, rhabdomyolysis, hyperkalaemia, acute kidney injury, elevated liver enzymes, and cardiac dysfunction. Young age, high dose of propofol and concomitant administration of vasopressor, and underlying critical illness are considered as major risk factors, necessitating adequate precautionary measures. 

Genetic screening

Increasingly, genetic screening tests are being undertaken to identify an underlying cause, primarily in individuals where a genetic/metabolic basis is suspected. About 60 different rare monogenic forms of rhabdomyolysis have been reported to date. A study undertaken in a cohort of 21 unrelated families (of Jewish and Arab ancestry) with rhabdomyolysis, in whom no underlying aetiology had been previously established, enabled diagnosis in nine (43%).⁴ All patients, except one, were children and or adolescents at presentation (ie. < 21 years of age). Disease-causing mutations identified could be grouped into the following categories:

• Disorders of fatty acid metabolism (CPT2) 

• Disorders of glycogen metabolism (PFKM and PGAM2) 

• Disorders of abnormal skeletal muscle relaxation and contraction (CACNA1S, MYH3, RYR1 and SCN4A) 

• Disorders of purine metabolism (AHCY), which is a rare disorder where most affected individuals exhibit delayed psychomotor development and hypotonia at birth, although disease severity can be variable. 

Genetic studies are increasingly available, but can be costly, and interpretation of gene sequence alterations (so-called variants) may not be straightforward in some cases. It is advised that opinion from a clinical geneticist be sought prior to testing.

References

1. Scalco RS et al. Misdiagnosis is an important factor for diagnostic delay in McArdle disease. Neuromuscul Disord 2017; 27(9): 852-855
2. Kraeva N et al. Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: a retrospective cohort study and updated systematic review. Can J Anaesth 2017; 64(7):736-743
3. Hosokawa Y et al. Round table on malignant hyperthermia in physically active populations: meeting proceedings. J Athl Train 2017; 52(4):377-383
4. Vivante A et al. Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases. Pediatr Nephrol 2017; 32(12): 2273-2282