[MIM 254 200]

Muscle weakness and fatigue following exercise. 

In children, the causes are: 

(a) juvenile myasthenia gravis, (autoimmune origin). Autoantibodies are directed against the muscle receptors for acetylcholine (85 %), the muSK protein (muscle-specific receptor tyrosine kinase) (4 %) or the LRP4 protein (lipoprotein-related protein 4 which is the receptor for agrin) (2 %). These serum autoantibodies are absent in cases called seronegative: they are IgG1 antibodies directed against the cellular form of the ACh receptor and therefore undetectable with conventional biological methods.

Seronegative forms usually develop oculobulbar symptoms and respond poorly to anticholinesterases; thymectomy is unnecessary in these cases. 

Histologically, there is a widening of the synaptic cleft and disappearance of the postsynaptic folds. Onset before the age of 15 years in 10 to 15 % of the cases and important female predominance. The cause is unknown, but genetic predisposition is not excluded (familial cases, frequency of HLA-B8 and HLA-DR3 for women). Histological abnormalities of the thymus are frequent (hyperplasia or thymoma) and thymectomy is often beneficial. 

Symptomatology: variable involvement in intensity and topography of the voluntary muscles: oculomotor muscles are usually the first affected: ptosis, diplopia and intermittent strabismus, that are classically more important in the evening than in the morning: unpredictable evolution, sometimes outbreaks favored by infection; in general, the involvement is progressing from the oculomotor muscles to the bulbar muscles (swallowing), and later thoracic muscles. The main complication is respiratory decompensation which can be brutal. The differential diagnosis between myasthenic crisis and cholinergic crisis (by overdose of anticholinesterase) is difficult: in general,.

-        the myasthenic crisis is triggered by a respiratory infection, stress, or surgical intervention: increased muscle weakness, respiratory distress;

-        cholinergic crisis: salivation and excessive sweating, cramps, bradycardia.

Mydriasis is present in a myasthenic crisis and miosis in a cholinergic crisis.

Treatments: anticholinesterase by the IV route then by mouth (pyridostigmine): they are the basis of the treatment; if they are insufficient: corticosteroids, plasmapheresis, thymectomy (sternotomy or video-assisted thoracic surgery), immunosuppression: azathioprine, cyclosporine.

Intermittent IV administration of Inebilizumab (B-cell anti-CD19 antibody) is successful in adult patients with generalized myasthenia gravis associated with the presence of antibodies to muscle acetylcholine receptors or MuSK protein.

Cases of severe autoimmune generalized myasthenia gravis are sometimes treated with zilucoplan (peptide inhibiting the C5 fraction of the complement) subcutaneously (1x/day) or efgartigimod alpha (neonatal Fc receptor antagonist) IV in patients with anti-acetylcholine receptor antibodies.

Clinical classification of myasthenia gravis severity

Anesthetic implications: 

if possible, stop the anticholinesterase treatment the night preceding the intervention and plan for the child to be operated in the first place. If a temporary interruption of the treatment is not possible (danger of myasthenic crisis), continue the treatment according to the regular schedule and add an anticholinergic in premedication. In case of important muscle weakness, it may be useful to perform a preoperative plasmapheresis. IV induction or by inhalation. The intrinsic muscle relaxing effect of the halogenated agents is usually sufficient to allow for intubation and surgery; if important muscle relaxation is necessary, titrate the dose of non-depolarizing muscle relaxant, starting with a dose equal to 10 % of the usual dose and titrate according to the child's response to neuromuscular stimulation (TOF). The agents of choice are: atracurium, cis-atracurium or rocuronium that can  be antagonized with sugammadex (which allows avoiding neostigmine and its disadvantages in this context: already maximal inhibition ? cholinergic crisis ? However a few cases of incomplete reversal with sugammadex have been reported). The duration of action of mivacurium may be prolonged if the child received some anticholinesterase on the day of the procedure. For maintenance of anesthesia: a halogenated agent, or TIVA: the duration of action of remifentanil is not changed by the anticholinesterase but a case of delayed awakening has been described in a patient treated with pyridostigmine . Before extubating the child, make sure that it has regained enough muscle strength to ensure control of the airway and ventilation: eye opening, normal mobility, swallowing, lack of additional fading at the monitoring of the decurarization (TOF and DBS). Some recommend stimulating the facial nerve rather than the ulnar since the oculomotor muscles are more sensitive to myorelaxants in case of myasthenia gravis. Postoperative monitoring is carried out in intensive care unit and anticholinesterase therapy is adapted to the child's muscle strength.

References : 

• White MC, Stoddart PA. 
  Anesthesia for thymectomy in children with myasthenia gravis. 
  Pediatr Anesth 2004;14:625-35.
• Baraka A, Haroun-Bizri ST, Gerges FJ. 
  Delayed postoperative arousal following remifentanil-based anesthesia in a myasthenic patient undergoing thymectomy. 
  Anesthesiology 2004; 100: 460-1.
• Rangasamy V, Kumar K, Rai A, Baidya DK. 
  Sevoflurane and thoracic epidural anesthesia for trans-sternal thymectomy in a child with juvenile myasthenia gravis. 
  J Anaesthesiol Clin Pharmacol 2014 ; 30 : 276-8
• De Boer HD, Shields MO, Booij LHDJ. 
  Reversal of neuromuscular blockade with sugammadex in patients with myasthenia gravis: a case series of 21 patients and review of the literature. 
  Eur J Anaesthesiol 2014; 31: 715-21. 
• Sugi Y, Nitahara K, Shiroshita T, Higa K.
  Restoration of train-of-four ration with neostigmine after insufficient recovery with sugammadex in a patient with myasthenia gravis.
  A&A Case reports 2013; 1: 43-5.
• Dos Santos Fernandes H, Saraiva Jimnez JL, Ibanhes Nunes D, Ashmawi HA, Vieira JE.
  Failure of reversion of neuromuscular block with sugammadex in patient with myasthenia gravis: case report and brief review of literature.
  BMC Anesthesiology 2019; 19: 160
• Nowak RJ, Benatar M, Ciafaloni E,  Howard JF Jr.,  Leite I et al. 
  Phase 3 trial of Inebilizumab in generalized Myasthenia Gravis.
  N Engl J Med 2025;392:2309-20

b) transient neonatal myasthenia, of maternal origin;

Caused by the transplacental passage of anti-ACh receptor antibodies of maternal origin, it is found in 10-25 % of the newborns from mothers suffering myasthenia gravis. It begins within 48 hours following birth: hypotonia, weak cry, swallowing disorders, sometimes respiratory distress. A treatment with anti-cholinesterase eliminates muscle weakness. Healing without sequelae occurs 3 to 6 weeks after birth.

c) congenital, hereditary myasthenia gravis is very rare (1/250,000). It may manifest itself as arthrogryposis but its early signs  appear in the neonatal period or in early childhood or in adulthood. These signs are: localized or generalized muscle weakness, that increases with exercice. The following are often present: ptosis, ophthalmoplegia, swallowing disorders, or even bilateral vocal cords paralysis.  Sudden respiratory failure can also be observed in case of infection. The diagnosis is based on EMG: decreasing (decrement) motor response following repetitive stimulation. Muscle biopsy sometimes shows signs of myopathy with variations of the size or proportion of I and II muscle fibers. The response to treatment is very variable.

At the present time, mutations of 32 genes have been identified as potential causes of congenital myasthenia: 8 at the presynaptic level, 4 at the synaptic level, 15 at the postsynaptic level and 5 concern the glycolysation of some proteins.

The usual classification is based on the location of the defect at the level of the neuromuscular junction. 

• presynaptic problem (5 %): formerly called familial infant myasthenia or congenital myasthenia with episodic apneas:

1)        disorder of the axonal transport of choline: mutation of the LC5A7 gene (2q12.3) [MIM 617 143] coding for CHT (choline transporter 1) protein

2)        disorder of the synthesis and recycling of ACh due to a deficiency in acetylcholinetransferase (mutations of the CHAT gene (10q11.23)) [MIM 254 210] (type 6)

3)        disorder of the intravesicular transport of the ACh synthetized in the cytoplasm due to a mutation of the SLC18A3 gene (10q11.23) [MIM 617 239] (type 20) or of the SLC25A1 gene (22q11.21) [MIM 618 197] (type 23) coding for a mitochondrial transporter of citrate

4)        disorder of the synaptic vesicles exocytosis due to a mutation of the

-  SNAP25 gene (20p12.2) [MIM 616 330] (type 18) coding for the SNARE protein.
-  VAMP1 gene (12p13.31) [MIM 618 823]
                  (type 25) coding for the protein 1 associated with the vesicular membrane
-  SYB1 gene
-  SYT2 gene (1q32.1) [MIM 616 040] (type 7) coding for synaptotagmin 2
-  MUNC13-1 gene (19p13.11) leading to the congenital presynaptic myasthenia associated with the MUNC13-1 gene

           -  RPH3A gene (12q24.13) coding for rabphilin 3A

5)        deficiency in laminin 5 which plays an important role in the composition of the extracellular matrix (LAMA5 gene (20q13.33))

However, postsynaptic disorders (fast channel and RAPSN) can cause a similar clinical picture. Transmission is autosomal recessive. One can observe a fluctuating ptosis, feeding difficulties, sometimes sudden death by respiratory failure. Treatment: anticholinesterase: oral pyridostigmine 30 to 300 mg/day in 4-6 doses; and sometimes oral salbutamol: 0.1 mg/kg/day (max 2 mg) in 3 doses in children less than 6 years of age, 2 mg 2 to 3 times per day from 6 to 12 years, and 4 mg 1-3 times/day for adults

• synaptic problem (10 %): 

1)  acetylcholinesterase deficiency due to the autosomal recessive transmission of a mutation of the COLQ gene (3p24.2) [MIM 603 034] (type 5) coding for the collagen Q linking acetylcholinesterase to the basal membrane of the neuromuscular junction);. Early death in the neonatal period.

2) deficiency in laminin β2: it is a basal membrane protein specific of the neuromuscular junction (LAMB2 gene (3p21.31)) that is also present in the kidney and the eye, causing congenital myasthenia with nephrotic syndrome. This deficiency can also cause Pierson syndrome combining eye and kidney malformations.

3) deficiency in the α chain of the non fibrillar collagen, playing a key role in the agglomeration of the ACh receptors during the differentiation of the myotube (COL13A1 gene (2q32.2)) [MIM 120 350] (type 19)

The usual treatment is ephedrine 2 to 3 mg/kg/day in 3 doses.

• postsynaptic problem (85 %): this is the most common cause of congenital myasthenia; there are different clinical  presentations depending on the protein that is deficient. Some mutations affect the genes regulating the synthesis of the different subunits of the ACh receptor:

• mutation of the CHRNA1 gene (2q31.1) coding for the α1-subunit of the nicotinic cholinergic receptor: congenital myasthenia 1A [MIM 601 462] in case of autosomal dominant transmission and 1B [MIM 608 930] in case of autosomal  recessive transmission
• mutation of the CHRNB1 gene (17p13.1) coding for the β1-subunit of the nicotinic cholinergic receptor: congenital myasthenia 2A [MIM 613 313]  in case of autosomal dominant transmission and 2C [MIM 616 314]  in case of autosomal  recessive transmission
• mutation of the CHRND gene (2q37.1) coding for the δ-subunit of the nicotinic cholinergic receptor : congenital myasthenia 3A [MIM 616 321]  in case of autosomal dominant transmission and 3B [MIM 616 322] or 3C [MIM 616 323]  in case of autosomal  recessive transmission
• mutation of the CHRNE gene (17p13.2) coding for the ε-subunit of the nicotinic cholinergic receptor : congenital myasthenia 4A [MIM 605 809]  in case of autosomal dominant or recessive transmission, and 4B [MIM 616 324] ou 4C [MIM 608 931]  in case of autosomal  recessive transmission
• Escobar or multiple pterygium syndrome (see those terms): autosomal recessive transmission of the CHRNG gene (2q37.1) [MIM 265 000] coding for the γ-subunit of the nicotinic cholinergic receptor. This subunit is only present during  the fetal period and is progressively replaced by the ε-subunit after birth: the muscle weakness fades out progressively  after birth.

These mutations can cause:

1) a decrease in acetylcholine receptors: forms 2C, 3C et 4C, but also congenital myasthenia type 9 [MIM 616 325] caused  by a mutation of the MUSK gene (9q31.3) coding for the MUSK protein, a co-receptor for agrin and proteine LRP4, and congenital myasthenia type 11 [MIM 616 326] due to a mutation of the RAPSN gene (11p11.2) ] controlling the synthesis of   rapsyn, the protein that links the nicotinic receptors of ACh at the level of the motor plate.  The first signs may appear in the neonatal period. Treatment: an anticholinesterase and 3.4 diaminopyridine at a dose of 1 mg/kg/day in 4 doses.

2) a "slow channel syndrome": forms 1A to 4A. The opening time of the ACh receptor is increased. The first signs appear in childhood or in adulthood: it involves mainly the neck and the shoulder girdle muscles. It is important to avoid anticholinesterases as they may aggravate the situation. Treatment: quinidine (15-6 mg/kg/day in 4-6 doses) or fluoxetine (80 to 120 mg/d in 1 dose; therapeutic level between 8 and 11 µM/l)

3) "fast channel syndrome": forms 1B, 3B and 4B, due to a too rapid closure of the ACh receptor. The first signs may appear in the neonatal period. Treatment: the anti-cholinesterases and 3.4 diaminopyridine can partly improve muscle function.

Mutation of the following genes involves the agregation of the  post-synaptic ACh receptors and leads to an alteration of the  signalling pathway between the  ionic channel of the ACh receptor and the contractile unit in the muscle fibers. 

·       AGRN gene (1p36.33) [MIM 615 120] (type 8) coding for agrin, a proteoglycan secreted in the synaptic cleft by the nerve ending. It plays an important role in the development of the neuromuscular junction

·       DOK7 gene (4p16.3) [MIM 254 300] (type 10) coding for the DOK7 protein that activates the MUSK protein: it may present as a congenital vocal cords paralysis

·       SCN4A gene (17q23.3) [MIM 614 198] (type 16) coding for a Na channel responsible for the genesis of the post-synaptic  action potentials

·             LRP4 gene (11p11.2) [MIM 616 304] (type 17) coding for the LRP4 protein, the receptor for agrin

·             PREPL gene (2p21) [MIM 616 224] (type 22) coding for propyl-endopeptidase, an effector of the protein associated to clathrin

·              MYO9A gene (15q23) [MIM 618 198] (type24) coding for a form of myosin (IXA)

·       PLEC gene (8q24.3) coding for plectin, linking intermediate filaments to their targets; other mutations can lead to limb girdle  dystrophy (LGMD2Q), with sometimes pyloric atresia or epidermolysis bullosa 

 

The protein under the control of MUSK and DOK-7 genes are necessary for the action of rapsin . DOK - 7 mutations generally result in a weakness of the girdle muscles but can cause stridor in infants. 

Treatments: ephedrine is effective in the forms associated with deficiency in DOK - 7; the 3,4 diaminopyridine is effective in MUSK and RAPSN deficiencies. The limb girdle dystrophy with tubular aggregates syndrome has long been attributed to a mutation of the DOK - 7 gene but is due to other still undetermined mutations anticholinesterases are useful in this case.

-     problem with the glycosylation of proteins:

The glycosylation of proteins takes place at the level of the endoplasmic reticulum and is essential to the proper functioning of the neuromuscular junction. A mutation of one of the following genes can cause a congenital myasthenia sometimes called, because of its clinical presentation and histological picture: limb girdle myasthenia gravis with tubular aggregates

*         mutation of the GFPT1 gene (2p13.3) [MIM 610 542] (type 12) coding for glutamine-fructose-6-phosphate,

*         GMPPB gene coding for the protein synthesizing GDP mannose; the clinical picture may look like a limb girdle myopathy or congenital muscular dystrophy

*         mutation of the ALG2 gene (9p22.33) [MIM 616 228] (type 14) coding for α1, 3-mannosyl-transferase

*         mutation of the DPAGT1 gene (11q23.3) [MIM 614 750] (type 13) catalyzing the first step of the N-glycosylation and thus reducing the number of the ACh receptors.

There exist other forms without tubular aggregates:

*         mutation of the ALG14 gene (1p21.3) [MIM 607 227] (type15) that could form a complex with the ALG13 and DPAGT1 proteins

*         mutation of the GMPPB (3q21.31) coding for the GDP-mannose pyrophosphorylase B and causing congenital myasthenia associated with GPPMB.

The response to treatment is very variable and must be individualized.
A few cases of congenital myopathy with pseudo-myasthenic onset have been observed. This is a non-dystrophic congenital myopathy linked to variants in the RYR1 gene. Patients present with axial hypotonia, a poorly expressive face with variable ptosis (fatigability), feeding difficulties, delayed gross motor development and proximal muscle weakness (severe involvement of the soleus muscle, sparing the right femoral muscle and the sartorius, gracilis and semitendinosus muscles). Scoliosis and recurrent respiratory tract infections are common. On muscle biopsy, atrophic type I fibers predominate.

 

Anesthetic implications: 

• avoid using non-depolarizing muscle relaxants if they are not necessary; otherwise, titrate small doses according to neuromuscular monitoring as in case of myasthenia gravis
• measure the basal response to neuromuscular stimulation: TOF
• if a treatment with anti-cholinesterases has been administered within 6 h before surgery, anticipate for:

1)  a prolonged action of succinylcholine and mivacurium; the duration of action of remifentanil is not changed

2)  an anticholinergic premedication to decrease oral and bronchial secretions

• avoid medications that can have an effect on the neuromuscular junction: aminoglycoside antibiotics, for example.
• before extubating the child, ensure that it has regained enough muscle strength to control its upper airway and ventilation: eye opening, normal mobility, swallowing, lack of fading on the monitoring of the decurarization (TOF = 1).
• good indication for locoregional anesthesia
• no risk of malignant hyperthermia except in cases of congenital myopathy with pseudo-myasthenic onset associated with a risk of malignant hyperthermia (RYR1 mutation).

References : 

• Regenbaum S, Sidhu K, Smith CE 
  Transient neonatal myasthenia gravis and pyloric stenosis. 
  J Clin Anesth 1995;7:515-8.
• Rubin JE, Ramamurthi RJ
  The role of sugammadex in symptomatic transient neonatal myasthenia gravis : a case report.
  A&A Case Reports 2017; 9:271-3.
• McConkey PP, Mullens AJ. 
  Congenital myasthenic syndrome: a rare, potentially treatable cause of respiratory failure in a "floppy" infant. 
  Anaesth Intensive Care 2000;28:82-6.
• McBeth C, Watkins TGL. 
  Isoflurane for sedation in a case of congenital myasthenia gravis. 
  Br J Anaesth 1996;77:672-4.

• Palace J, Beeson D.  
  The congenital myasthenic syndromes. 
  J Neuroimmunol 2008 ; 201-202 :2-5.

• Gentili A, Ansaloni S, Morello W, Cecini MT, Cordelli DM, Baroncini S. 
  Diagnosis of congenital myasthenic syndrome with mutation of the RAPSN gene after general anaesthesia. 
  Eur J Anaesthesiol 2011 ; 28 : 748-9. 

• de la Vaissière S, Toutain A, Chêne M-A, Lagrue E et al. 
  Syndromes myasthéniques congénitaux de l’enfant : stratégies thérapeutiques médicamenteuses. 
  Arch Fr Pédiatr 2015 ; 22 : 724-8.
• Finsterer J.
  Congenital myasthenic syndromes.
  Orphanet J Rare Dis 2019 ; 14 : 57, doi : 10.1186/s13023-019-1025-5
• Benarroch L, Bonne G, Rivier F, Hamroun D.
  The 2020 version of the gene table of neuromuscular disorders. 
  Neuromusc Dis 2019 ; 29 : 980-1018 or  http://www.musclegenetable.fr. 

• Pappy AL II, Sirmon CAF, Mukkamala SG.
  Administration of sugammadex intraoperatively in a patient with a congenital myasthenic syndrome: a case report.
  A & A Practice 2021 ; 15(3):p e01437
• Yamashita A , Muramatsu Y, Matsuda H,  Okamoto H .
  General anesthesia for treating scoliosis with congenital myasthenia syndrome: a case report.
  JA Clinical Reports 2022 ; 8:70 doi.org/10.1186/s40981-022-00560-1.
• Kuo W, Le S, Kim E, Lo C.
  Congenital Myasthenic syndrome with Malignant Hyperthermia susceptibility in a child undergoing adenotonsillectomy for obstructive sleep apnea: a case report.
  A & A Practice 2023; 17(10):e01723
• Illingworth MA, Maina M, Pitt M, Manzura A, Muntonia F. et al.
  RYR1-related congenital myopathy with fatigable weakness, responding to pyridostigimine.
  Neuromuscular Disorders 2014;  24:707-12
• Boye Lester E, Larsen MJ, Laulund LW, Illum N, Dunkhase-Heinl U,Schrøder HD, Ringmann Fagerberg R. 
  Ryanodine receptor 1 related myasthenia like myopathy responsive to pyridostigmine.
  Eur J Med Genet 2023 ; 66 :104706.  doi: 10.1016/j.ejmg.2023.104706

d) Eaton-Lambert syndrome : rare in children, it is a presynaptic block of paraneoplastic origin (antibodies agianst voltage-dependent anticalcic channel)

e) a  neuromuscular block of toxic origin: botulism (see this term)

Updated: June 2025