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Diagnosis of congenital myasthenic syndrome with mutation of the RAPSN gene after general anaesthesia

Gentili, Andrea; Ansaloni, Stefania; Morello, William; Cecini, Maria T.; Cordelli, Duccio M.; Baroncini, Simonetta

Author Information
European Journal of Anaesthesiology: October 2011 - Volume 28 - Issue 10 - p 748-749
doi: 10.1097/EJA.0b013e3283453f4b
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This Correspondence accompanies the following articles:

• Veyckemans F. Sharing information on the anaesthetic management of patients with a rare disease. Eur J Anaesthesiol 2011; 28:680–681.

• Becke K, Aymé S, Strauß J, et al. The OrphanAnaesthesia Project. Eur J Anaesthesiol 2011; 28:678–679.


In congenital myasthenia syndrome (CMS), a genetic defect causes a disruption of the neuromuscular transmission. Symptoms start perinatally or in the first years of life and consist mainly of bilateral ptosis, dysarthria, weak cry, feeding difficulties and muscle weakness accentuated by exertion. Diaphragmatic involvement may eventually lead to respiratory failure. Reflexes and sensibility are generally unchanged.1

Case report

We report the case of a 4-year-old male child, weighing 16 kg. At 1 year, the patient underwent an inguinal herniorraphy with inhalation anaesthesia with sevoflurane at a concentration increasing from 1 to 4%. Midazolam (200 μg kg−1) was administered and caudal anaesthesia with ropivacaine 0.2% (2 mg kg−1) was done without problems. At 4 years of age, the patient underwent a tonsillectomy with anaesthesia with sevoflurane, fentanyl (3 μg kg−1) and succinylcholine (1 mg kg−1). Surgery lasted 35 min. The recovery room awakening was characterised by difficulties in coughing and weak spontaneous breathing. Four hours later the patient became hyperthermic (39°C). Intense shivering was followed by a marked hypotonia that ended in a progressive respiratory distress. The patient required re-intubation using propofol (2 mg kg−1) and topical administration of lidocaine (3 mg kg−1) to the larynx, without muscle relaxants. Intensive care was necessary. Post-operative creatine phosphokinase values were normal, white blood cells counts were 14 490 μl−1, blood culture was negative. Ceftriaxone (50 mg kg−1 per day) was given for 6 days. Fever resolved in 2 days with acetaminophen. A new deep anamnesis with parents revealed no family history for neuromuscular diseases, but transitory events of slight muscle weakness after hyperpyrexia in the last year. A myopathy was suspected. Electromyography showed a defect of the neuromuscular junction of post-synaptic type (myasthenic). Muscle biopsy showed no signs of primary muscle disease. Therapy with pyridostigmine (2.5 mg kg−1 per day) was started. After 3 days the child recovered good muscular strength. Respiratory weaning was, thus, possible and 6 days after Paediatric Intensive Care Unit admission, the patient was extubated. Non-invasive ventilation with a helmet mask was done for 2 days. After 8 days, the acute event resolved and the patient recovered respiratory autonomy. Genetic testing showed an N88K mutation in homozygosis in the RAPSN gene, confirming the diagnosis of CMS. Six months later the patient had no symptoms. Treatment with pyridostigmine (2 mg kg−1 per day) was maintained.


CMSs are rare and complex genetic disorders of neuromuscular transmission produced by mutations that alter the expression and function of ion channels, enzymes, receptors or other proteins necessary for neuromuscular transmission.1 The N88K mutation in the RAPSN gene impairs the function of rapsyn, a protein associated with the post-synaptic acetylcholine receptor (AChR).2,3 In patients harbouring this mutation, symptoms are usually evident at birth or in the first few years, but cases are described presenting later in life. Apart from severe clinical cases, others exist characterised by a soft and unknown symptomatology for long periods, worsened by acute events, such as stress, fever, infections and drug administration. Episodic crises of acute respiratory failure are described. Symptomatology may improve later in life.4 No cases of an undiagnosed form of CMS with sudden onset after general anaesthesia are reported in the literature.

The present case describes a patient who is a carrier of an unknown form of CMS with slow onset and who was submitted twice to general anaesthesia. The two anaesthesias were made at two different ages, with different modalities (without and with succinylcholine) and obtained opposing post-operative developments (without and with respiratory failure). The first was administered before the onset of symptomatology. The second was administered after clinical expression had already started to slightly manifest, although not emerging during pre-operative anamnesis.

The case suggests the following observations:

  1. First, in the case of symptoms suggesting a neuromuscular disease, further investigations should be performed, such as electromyography, muscle biopsy and genetic research, as part of pre-operative screening, especially in paediatric patients. Clinically and histopathologically oriented genetic testing allows the precise identification of several mutations responsible for the disease, such as the RAPSN N88K mutation.
  2. Apart from the more advanced stage of the disease, different factors in the second anaesthesia that may have precipitated the clinical situation probably include the use of succinycholine and the post-operative hyperpyrexia related to an infectious/inflammatory state. Succinycholine is a depolarising agent of the neuromuscular plaque. It stimulates cholinergic receptors, opening the ion channels in the neuromuscular junction. Hyperpyrexia and infection lead to increased breathing exertion, and an increment in metabolic and ventilatory requirements, resulting in muscular fatigue.4
  3. Owing to its rarity, little anaesthetic literature exists about CMS. Early diagnosis of the disease would allow the anaesthesiologist to develop a specially designed anaesthesia plan in order to avoid drugs that could either trigger or worsen CMS. The first anaesthesia seems to confirm the few reports in the literature that inhalation and loco-regional anaesthesia are well tolerated.5,6 Although the use of succinycholine has been reported in myasthenia gravis in adults,7 we believe it is useful to review its application, and probably also that of all muscle relaxants, in children with CMS. Unlike myasthenia gravis, in which the only pathogenetic mechanism is the destruction of AChRs by antibodies, CMS involves various processes of plaque malfunction (pre-synaptic, synaptic and post-synaptic), on which muscle relaxants and associated conditions, such as hyperpyrexia, can act in different ways. Succinycholine acts by blocking the post-synaptic response through desensitisation of the nicotinic AChR, drastically, though momentarily, changing the patient's neuromuscular transmission. From a pharmacological perspective, it would be interesting to study its impact on the specific situation of the post-synaptic membrane in CMS with the RAPSN mutation.
  4. The appropriateness of therapy with pyridostigmine was confirmed by the patient's clinical trend and the successive diagnosis of RAPSN mutations, sensitive to the drug. Use of succinylcholine and concomitant hyperpyrexia, both responsible for serious neuromuscular dysfunction, in association with a moderate dose of pyridostigmine, may explain the slow but efficient therapeutic response. Alternative therapy, as ephedrine, was not used on account of the unclear mode of action and its efficacy limited only to some forms. The main issue for this patient would be whether to suspend the pyridostigmine, administering it only in the case of acute events, or whether the post-operative hypotonia is a sign of overall worsening of the pathology requiring constant treatment.


Recent studies suggest considering CMS as a group of heterogeneous genetic disorders of neuromuscular transmission presenting different symptomatology and physiopathology. In the analysis of the difficult recovery of muscular function in this case, it would be interesting to consider the effect of the succinylcholine and the hyperpyrexia in relation to this particular post-synaptic form of CMS characterised by an AChR defect. Further studies combining genetic and pharmacological aspects would be useful to better associate the CMS mutations to the relative deficits of the neuromuscular transmission mechanism, to identify both the risk factors for patients suffering from this pathology and to optimise the most suitable pharmacological treatments for neuromuscular function.


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2. Müller JS, Mildner G, Müller-Felber W, et al. Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients. Neurology 2003; 60:1805–1810.
3. Engel AG, Ohno K, Shen XM, Sine SM. Congenital myasthenic syndromes: multiple molecular targets at the neuromuscular junction. Ann N Y Acad Sci 2003; 998:138–160.
4. Robb SA, Muntoni F, Simonds AK. Respiratory management of congenital myasthenic syndromes in childhood. Neuromuscul Disord 2010; 20:833–838.
5. McBeth C, Watkins TG. Isoflurane for sedation in a case of congenital myasthenia gravis. Br J Anaesth 1996; 77:672–674.
6. Calişkan E, Koçum A, Sener M, et al. Caudal epidural anesthesia for a 2-year old child with congenital myasthenia gravis. Agri 2008; 20:49–52.
7. Levitan R. Safety of succinylcholine in myasthenia gravis. Ann Emerg Med 2005; 45:225–226.
© 2011 European Society of Anaesthesiology