Presentation: Adult with rhabdomyolysis

A 25-year-old man decides to take up cycling, having never done it before. He goes for a five-mile ride. The next day, his leg muscles feel swollen and painful and his urine looks dark brown, almost black. Investigations show that his creatine kinase (CK) levels are 100,000IU/L. He has experienced exercise intolerance since his teens, with previous episodes of dark urine, and now rarely does any exercise beyond daily activity.

• A single episode of rhabdomyolysis after unaccustomed exercise is rarely indicative of a genetic condition. However, genomic testing should be considered in anyone with:
  • recurrent episodes of rhabdomyolysis;
  • persistently elevated CK more than four months after the initial event;
  • a family history of similar symptoms or known metabolic myopathy;
  • associated symptoms, such as exertional intolerance from childhood or progressive weakness;
  • a single episode with no obvious trigger (for example, no unaccustomed exercise or drug history); and
  • very high CK during the episode, typically greater than 20,000IU/L (relative indication by itself).
• Unaffected individuals may present with a family history of an adult-onset genetic condition. Where signs and/or symptoms suggestive of that condition are not present in the patient, they should be offered referral to a local clinical genetics service to discuss testing as part of a predictive (presymptomatic) testing pathway.
• A genetic diagnosis may have implications for other family members, and can be particularly relevant during a pregnancy. If the patient or a close relative is pregnant, please discuss the case with your local clinical genetics service.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria document for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient and/or their family.
  • R419 Acute rhabdomyolysis. This panel tests for single-gene causes of rhabdomyolysis by medium gene panel and multiplex ligation-dependent probe amplification (MLPA).
  • R73 Duchenne or Becker muscular dystrophy. This panel involves single gene sequencing and MLPA of the DMD gene, looking for copy number variants and sequencing variants. Becker muscular dystrophy can present with exertional limitation, recurrent episodes of myoglobinuria or rhabdomyolysis and persistently raised CK levels. Testing for Becker muscular dystrophy is included in the R419 panel (above), but can be requested as a standalone test if the diagnosis is strongly suspected.
  • R273 Glycogen storage disease V (also known as McArdle disease). This panel involves single gene sequencing of PYGM. It can be used as a standalone test if there is a family history of glycogen storage disease V or characteristic history, biochemical or biopsy findings. The PYGM gene is also included in the R419 panel.
• Mitochondrial conditions can cause or be associated with rhabdomyolysis. In a patient with clinical, biochemical or histological features suggestive of a mitochondrial condition, consider further investigation using the panels listed below.
  • R300 Possible mitochondrial disorder. This panel involves whole mitochondrial genome sequencing.
  • R299 Possible mitochondrial disorder – mitochondrial DNA rearrangement testing. Consider this panel, which tests blood-derived DNA, in people under the age of 20, because rearrangements in most adults over that age can only be detected in muscle DNA.
  • R274 Glycogen storage disease. This panel involves whole exome sequencing or medium panel and MLPA testing. You may wish to consider it if there are clinical and biochemical features that indicate a different type of glycogen storage disease beyond glycogen storage disease V; alternatively, you may wish to refer the patient to a metabolic specialist. Note that genes causing glycogen storage disease with potential for rhabdomyolysis are included in R419, but selecting R273 or R274 in isolation can miss other potential causes of rhabdomyolysis.
• For tests that do not include whole genome sequencing, including all of the above:
  • you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms; and
  • bear in mind that, when testing in children, parental samples may be needed for interpretation of the proband’s result (samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed).
• For DNA-based tests, an EDTA sample (purple-topped tube) is required.
• Information about patient eligibility and test indications were correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory
• Scottish Muscle Network: Investigation pathway: Single episode of rhabdomyolysis in adults (PDF, seven pages)

References:

• Davenport RJ and Fernandes PM. ‘How to do it: Investigate exertional rhabdomyolysis (or not)’. Practical Neurology 2019: volume 19, issue 1, pages 43–48. DOI: 10.1136/practneurol-2018-002008