Congenital Myasthenic Syndrome: Clinical Presentation
Congenital myasthenic syndromes (CMS) present with fatigable or fluctuating muscle weakness affecting ocular, facial, bulbar, limb, and respiratory muscles, typically manifesting from birth through childhood, though diagnosis is frequently delayed into adulthood. 1, 2, 3
Core Clinical Features
Muscle Weakness Patterns
CMS manifests with exercise-induced weakness and abnormal fatigability as the hallmark feature, distinguishing it from static myopathies 1, 2. The specific pattern depends on the genetic subtype:
Ocular symptoms: Ptosis and double vision (diplopia) are common presenting features, particularly in CHRNE-low expressor, CHRND, and fast-channel CMS variants 4, 3
Bulbar dysfunction: Dysphagia, dysarthria, facial muscle weakness, and head drop or neck weakness occur frequently 4, 2
Limb-girdle pattern: Proximal muscle weakness affecting shoulder and hip girdle muscles, particularly prominent in DOK7, RAPSN, COLQ, GFPT1, and GMPPB mutations 1, 3. Notably, limb-girdle CMS may present WITHOUT ptosis or ophthalmoparesis, making diagnosis particularly challenging 1
Distal weakness: Slow-channel CMS (SCCMS) characteristically presents with distal muscle involvement 3
Respiratory Involvement
Respiratory muscle weakness represents a critical and potentially life-threatening manifestation requiring vigilant monitoring 2, 3:
- RAPSN patients have the highest risk of intensive care unit admission (54.8%), predominantly before age 18 3
- DOK7 patients show 38.6% ICU admission rate, often occurring at or after age 18, with 36.3% requiring ventilation at long-term follow-up 3
- SCCMS patients have particularly high ventilatory needs, with 55% requiring ventilation at last follow-up 3
Additional Clinical Features
- Hypotonia may be present, particularly in infantile presentations 2
- Developmental delay can occur in some subtypes 2
- Cognitive disability, dysmorphism, neuropathy, or epilepsy are rare but have been reported 2
Diagnostic Approach
Electrophysiological Testing
Repetitive nerve stimulation (RNS) and single-fiber EMG are essential diagnostic tools 1, 2:
- Low- or high-frequency RNS may demonstrate abnormal decrement or increment 2
- Single-fiber EMG shows increased jitter or blocking 2
- Neuromuscular junction testing with repetitive stimulation and/or jitter studies should be performed under neurologic consultation 4
Laboratory Evaluation
The following workup is mandatory when CMS is suspected 4, 5:
- Antibody testing: AChR and anti-striated muscle antibodies; if negative, test for MuSK and LRP4 antibodies (approximately 50% of seronegative myasthenia patients have MuSK antibodies) 4, 5
- Muscle enzyme markers: CPK, aldolase to evaluate for concurrent myositis 4, 5
- Inflammatory markers: ESR and CRP 4, 5
- Pulmonary function: Negative inspiratory force (NIF) and vital capacity (VC) to assess respiratory muscle strength 4, 5
Cardiac Evaluation
Cardiac screening is essential, as cardiac involvement can occur 4:
- Troponin and ECG 4
- Consider transthoracic echocardiography and/or cardiac MRI to evaluate for concomitant myocarditis 4
Genetic Testing
Genetic confirmation is ultimately required to identify the specific mutation and guide treatment optimization 1, 2, 6:
- Currently, mutations in 32 genes are responsible for CMS, affecting presynaptic (8 genes), synaptic (4 genes), postsynaptic (15 genes), and glycosylation (5 genes) proteins 2
- Most common causative genes: CHAT, COLQ, RAPSN, CHRNE, DOK7, and GFPT1 2
- CHRNE-low expressor variants are most common (23.8%), followed by DOK7 (18.7%) and RAPSN (14%) 3
Treatment Strategies
Acetylcholinesterase Inhibitors
Pyridostigmine is the first-line treatment for most CMS subtypes 1, 2:
- Start at 30 mg orally three times daily, gradually titrate to maximum 120 mg four times daily based on symptoms 4, 5
- Critical exception: Pyridostigmine is NOT effective or is even detrimental in DOK7- and COLQ-related limb-girdle CMS 1
Beta-Adrenergic Agonists
Ephedrine, salbutamol, and albuterol show sustained benefit, particularly in DOK7 and COLQ mutations 1, 2:
- These agents are preferred over pyridostigmine in DOK7-related CMS 1
Additional Therapeutic Options
- 3,4-diaminopyridine enhances neuromuscular transmission in selected cases 2
- Fluoxetine has shown benefit in some CMS subtypes 2
- Corticosteroids: Prednisone 0.5 mg/kg orally daily may be added if symptoms persist despite maximum pyridostigmine dosing 4, 5
- IVIG (2 g/kg IV over 5 days) or plasmapheresis can be considered as steroid-sparing alternatives 4, 5
Medications to Avoid
The following medications can worsen myasthenic symptoms and must be avoided 4, 7, 5:
- Beta-blockers 4, 5
- IV magnesium 4, 5
- Fluoroquinolones (norfloxacin, ofloxacin, pefloxacin, moxifloxacin) 4, 7, 5
- Aminoglycosides (streptomycin, amikacin, kanamycin, gentamicin) - absolute contraindication 4, 7, 5
- Macrolide antibiotics (azithromycin, erythromycin) 4, 7, 5
Vancomycin is safe to use in CMS patients but requires renal function monitoring 7
Long-Term Prognosis
The long-term prognosis for most CMS patients is favorable, with appropriate treatment showing striking positive impact even in severely affected patients 3:
- Mean follow-up data from 235 adult patients showed 34 years from first symptoms to last visit 3
- Most patients do not require ventilation or wheelchair at long-term follow-up 3
- CHRNE-low expressor patients typically do not worsen during adulthood 3
- RAPSN patients, though often severely affected in early childhood, subsequently improve 3
- Progressive deterioration can occur in DOK7, SCCMS, and GFPT1 patients: 36.3% of DOK7 patients become wheelchair-bound, and both DOK7 and SCCMS patients have high ventilatory requirements 3
Disease Course Patterns
Different patterns (stability, improvement, progressive worsening) may succeed one another throughout life, particularly in AGRN, DOK7, and COLQ mutations 3, emphasizing the need for ongoing neurologic monitoring and treatment adjustment.