How to evaluate a patient for an inherited cause of rhabdomyolysis?

Evaluation for Inherited Causes of Rhabdomyolysis

The diagnostic evaluation for inherited causes of rhabdomyolysis should include a comprehensive three-generation family history, targeted genetic testing based on clinical presentation, and specific metabolic studies to identify underlying genetic disorders that may predispose to recurrent episodes of muscle breakdown.

Initial Assessment

• Family history: Obtain a detailed three-generation family history to identify possible inherited disease patterns 1, 2

  • Document any relatives with muscle disorders, exercise intolerance, or unexplained sudden death
  • Note consanguinity which increases risk of recessive disorders

• Clinical characteristics suggestive of genetic etiology:

  • Recurrent episodes of rhabdomyolysis
  • Episodes triggered by specific factors (fasting, exercise, fever)
  • Rhabdomyolysis occurring with minimal exertion
  • Onset during childhood or adolescence
  • Family history of similar episodes
  • Absence of common acquired causes

Laboratory Evaluation

First-tier Testing

1. Essential laboratory tests 2:

   • Serum creatine kinase (CK) - confirm elevation >5 times upper limit of normal
   • Plasma myoglobin - rises earlier than CK but has shorter half-life (2-3 hours)
   • Serum electrolytes (particularly potassium)
   • Renal function tests
   • Urinalysis (positive for blood on dipstick but negative for RBCs on microscopy)

2. Metabolic screening:

   • Fasting blood glucose
   • Lactate and pyruvate levels
   • Acylcarnitine profile
   • Urine organic acids
   • Plasma amino acids

Second-tier Testing

Based on clinical presentation and initial results, consider:

1. Disorders of glycogen metabolism:

   • Forearm ischemic exercise test
   • Muscle glycogen content analysis
   • Specific enzyme assays (phosphorylase, phosphofructokinase)

2. Fatty acid oxidation disorders:

   • Acylcarnitine profile (fasting and post-prandial)
   • Carnitine levels (total and free)
   • Fatty acid oxidation flux studies in fibroblasts

3. Mitochondrial disorders:

   • Lactate/pyruvate ratio
   • Mitochondrial DNA analysis
   • Respiratory chain enzyme analysis

Muscle Biopsy

Consider muscle biopsy when:

• Recurrent episodes without identified cause
• Strong suspicion of inherited myopathy
• Need for specific histological or biochemical analysis

Key analyses:

• Histology and immunohistochemistry
• Electron microscopy
• Biochemical enzyme assays
• Fresh tissue for metabolic studies

Genetic Testing

Targeted Gene Panels

Based on clinical presentation, consider specific gene panels for:

• Glycogen storage diseases (GSD) - especially GSD type V (McArdle disease)
• Fatty acid oxidation disorders
• Mitochondrial disorders
• Muscular dystrophies
• Ion channelopathies (periodic paralyses)

Comprehensive Genetic Testing

• Whole exome sequencing if targeted panels are negative
• Whole genome sequencing for complex cases

Clinical Scenarios and Specific Testing

1. Exercise-induced rhabdomyolysis:

   • Focus on glycogen storage disorders (especially McArdle disease)
   • Fatty acid oxidation disorders
   • Mitochondrial disorders

2. Fasting-induced rhabdomyolysis:

   • Prioritize fatty acid oxidation disorders
   • Carnitine metabolism disorders

3. Heat/fever-induced rhabdomyolysis:

   • Consider malignant hyperthermia susceptibility
   • RYR1 gene testing
   • Caffeine-halothane contracture test

4. Drug-induced rhabdomyolysis with minimal exposure:

   • Statin-associated autoimmune myopathy (test for HMGCR antibodies) 2
   • Underlying metabolic myopathies that increase susceptibility

Follow-up and Management

• Genetic counseling for patients with confirmed genetic diagnosis
• Family screening when hereditary disorder identified
• Avoidance of specific triggers based on diagnosis
• Prophylactic measures during high-risk situations (surgery, illness)
• Regular monitoring of renal function and CK levels

Common Pitfalls to Avoid

1. Missing the diagnosis:

   • Not considering genetic causes in adults with first-time rhabdomyolysis
   • Attributing recurrent episodes solely to exercise or dehydration

2. Inadequate testing:

   • Relying on single CK measurements
   • Failing to perform metabolic studies during acute episodes

3. Inappropriate management:

   • Delaying genetic consultation in recurrent cases
   • Not providing specific trigger-avoidance guidance based on diagnosis

By following this systematic approach, clinicians can effectively identify inherited causes of rhabdomyolysis, allowing for appropriate genetic counseling, preventive measures, and targeted management strategies to reduce morbidity and mortality associated with recurrent episodes.