How to test for neuromuscular diseases that can cause heart failure in young patients?

Testing for Neuromuscular Diseases Causing Heart Failure in Young Patients

All young patients with unexplained heart failure should undergo comprehensive cardiac evaluation including ECG, echocardiography, and genetic testing in blood samples, as cardiac involvement is a major cause of mortality in neuromuscular diseases and may present before or without significant skeletal muscle symptoms. 1, 2

Initial Diagnostic Approach

Clinical Assessment

• Obtain detailed family history focusing on sudden cardiac death, early-onset cardiomyopathy, progressive muscle weakness, and consanguinity 2, 3
• Look for specific neuromuscular signs including:
  • Proximal muscle weakness with Gowers' maneuver
  • Calf pseudohypertrophy (suggests Duchenne/Becker muscular dystrophy)
  • Scapular winging
  • Facial weakness or ptosis
  • Myotonia (inability to relax grip)
  • Progressive contractures
  • Exercise intolerance beyond cardiac symptoms 2, 4

Essential Cardiac Testing at Diagnosis

Electrocardiography should be performed immediately, looking for disease-specific patterns: 1, 5

• Duchenne/Becker muscular dystrophy: Short PR interval, right ventricular hypertrophy, prominent Q waves in leads I, aVL, V5-V6 or II, III, aVF, V5-V6, QRS duration ≥120 ms 1, 5
• Myotonic dystrophy: PR interval >240 ms, QRS duration >120 ms, any degree of atrioventricular block (high risk for sudden death) 1
• Friedreich ataxia: Lateral T-wave inversions, left-axis deviation, repolarization abnormalities 1
• Emery-Dreifuss/LMNA mutations: Conduction abnormalities, atrial fibrillation 1, 6

Echocardiography is the primary imaging modality and should be performed at diagnosis in all suspected cases (Class I; Level of Evidence B): 1

• Assess for dilated cardiomyopathy (most common in Duchenne/Becker, sarcoglycanopathies, LMNA mutations)
• Evaluate for left ventricular hypertrophy (Friedreich ataxia, some mitochondrial disorders)
• Measure left ventricular ejection fraction
• Look for left ventricular non-compaction (Barth syndrome) 1

Cardiac MRI with late gadolinium enhancement should be strongly considered when available (Class IIa; Level of Evidence B), as it provides superior assessment of: 1, 5

• Myocardial fibrosis patterns (characteristic inferolateral distribution in Duchenne/Becker)
• Chamber dimensions and function in patients with poor acoustic windows
• Early cardiac involvement before echocardiographic abnormalities appear
• Risk stratification for arrhythmias 5

Laboratory and Genetic Testing

Serum creatine kinase (CK) should be measured immediately: 2

• Markedly elevated (10-100x normal) suggests Duchenne/Becker muscular dystrophy
• Moderately elevated suggests limb-girdle muscular dystrophies
• Normal or mildly elevated does not exclude neuromuscular disease, particularly in myotonic dystrophy, Emery-Dreifuss, or Friedreich ataxia 2, 4

Genetic testing in blood samples is essential and should be performed in all suspected cases (Class I; Level of Evidence C): 2

• Provides definitive diagnosis without need for invasive muscle biopsy in most cases
• Guides mutation-specific therapies (e.g., exon-skipping in Duchenne)
• Enables family screening and genetic counseling
• Priority genes to test based on cardiac phenotype:
  • Dilated cardiomyopathy with heart failure: DMD (Duchenne/Becker), LMNA (Emery-Dreifuss/LGMD1B), sarcoglycan genes (LGMD2C-F), FKRP (LGMD2I), TAZ (Barth syndrome), mitochondrial DNA mutations 1, 2, 7
  • Hypertrophic cardiomyopathy: FXN (Friedreich ataxia), mitochondrial disorders, MYH7 (may cause both myopathy and cardiomyopathy) 1, 7
  • Arrhythmias/conduction disease: LMNA, DMPK (myotonic dystrophy type 1), DES (desminopathy) 1, 7, 6

Muscle biopsy should be reserved for cases where genetic testing is inconclusive and includes histochemical staining, immunohistochemistry, and electron microscopy 2

Disease-Specific Testing Algorithms

For Suspected Duchenne/Becker Muscular Dystrophy

Initial evaluation at diagnosis (Class I; Level of Evidence B): 1, 5

• Physical examination, ECG, echocardiography
• Serum CK (typically 10-100x normal)
• Genetic testing for DMD gene deletions/duplications/point mutations
• Consider cardiac MRI for baseline myocardial fibrosis assessment

Note: 78% of steroid-naive Duchenne patients <6 years have ECG abnormalities before clinical cardiac symptoms 1

For Suspected Myotonic Dystrophy

Urgent evaluation required due to high sudden death risk (Class I; Level of Evidence C): 1

• ECG looking specifically for PR >240 ms, QRS >120 ms, any AV block
• Echocardiography (though dilated cardiomyopathy is rare)
• Ambulatory ECG monitoring (at least 24-48 hours)
• Electrophysiology study should be strongly considered for PR >240 ms, QRS >120 ms, or any symptoms (syncope, palpitations, dizziness) for possible pacemaker/ICD placement 1
• Genetic testing for CTG repeat expansion in DMPK gene

For Suspected Friedreich Ataxia

Comprehensive cardiac evaluation (Class I; Level of Evidence C): 1, 8

• ECG (lateral T-wave inversions, left-axis deviation)
• Echocardiography assessing for ventricular hypertrophy (present in ~65%)
• Consider cardiac MRI to assess for iron overload and fibrosis
• Genetic testing for GAA repeat expansion in FXN gene
• Screen for diabetes mellitus (commonly associated) 8

Important: Cardiac involvement does not correlate with neurological severity, so cardiac screening is mandatory regardless of neurological status 1

For Suspected Emery-Dreifuss/LMNA-Related Disorders

Aggressive arrhythmia surveillance required (Class I; Level of Evidence C): 1, 6

• ECG and echocardiography at diagnosis
• Annual ambulatory ECG monitoring minimum (or more frequent if ICD not implanted)
• Consider electrophysiology study for any conduction abnormalities
• Genetic testing for LMNA, EMD, FHL1 genes
• Critical: Malignant arrhythmias can occur in 20% of pediatric patients, sometimes before dilated cardiomyopathy develops 6

For Suspected Barth Syndrome

Evaluate for metabolic crisis and cardiomyopathy: 1

• Echocardiography looking for left ventricular non-compaction or dilated cardiomyopathy
• ECG and ambulatory monitoring
• Genetic testing for TAZ gene mutations
• Metabolic workup including urine organic acids (elevated 3-methylglutaconic acid)

Ambulatory ECG Monitoring Strategy

Ambulatory monitoring frequency should be based on disease type and cardiac status (Class IIa; Level of Evidence C): 1

• Duchenne/Becker: Every 1-3 years based on age, ejection fraction, and clinical assessment 1
• Myotonic dystrophy: At least annually if no ICD, or with any new symptoms 1
• Emery-Dreifuss/LMNA: At least annually, consider implantable loop recorder in high-risk patients 1, 6
• Friedreich ataxia: Periodically, as arrhythmias increase with severity of hypertrophy 1

Critical Pitfalls to Avoid

• Do not wait for skeletal muscle symptoms to screen for cardiac involvement: Cardiac disease may present first or be the predominant feature, particularly in Becker muscular dystrophy, some limb-girdle dystrophies, and LMNA mutations 1, 3, 6
• Do not rely on normal ejection fraction to exclude arrhythmia risk: Life-threatening ventricular arrhythmias can occur with preserved LV function in Becker, desminopathy, and LMNA mutations 1, 7
• Do not assume normal CK excludes neuromuscular disease: Myotonic dystrophy, Emery-Dreifuss, and Friedreich ataxia often have normal or minimally elevated CK 2, 4
• Do not delay genetic testing: It provides definitive diagnosis, guides therapy, and enables family screening 2
• Do not underestimate sudden death risk in myotonic dystrophy: Physical exertion is proarrhythmic; serial exercise testing and aggressive monitoring are essential 1

Multidisciplinary Coordination

Establish care team at diagnosis including: 2

• Neuromuscular specialist
• Cardiologist experienced in neuromuscular diseases
• Genetic counselor
• Physical and occupational therapists
• Pulmonologist (for respiratory muscle involvement)

This coordinated approach is essential because cardiac management cannot be separated from skeletal muscle and respiratory considerations in these complex disorders 1, 2