SFEMG is the most sensitive test in detecting defects in the neuromuscular junction [5, 6]. A variant of this procedure, stimulated single-fiber EMG (SSFEMG), is much easier to perform in children compared to the traditional SFEMG approach. Details of this technique may be found in Chap. 10.

Congenital myasthenic syndromes are a heterogeneous group of disorders that classically present at birth, but may also present later in childhood [7–10]. These syndromes are typically classified according to the neuroanatomical localization of the defect: presynaptic, synaptic, and post synaptic. Infants usually present with various combinations of generalized hypotonia, weakness, respiratory distress, episodic apnea, and feeding difficulties. Symptoms are often exacerbated by crying and feeding, with improvement after sleeping. Respiratory symptoms may be intermittent, in some cases presenting as brief resolved unexplained events (BRUEs), previously known as acute life threatening events (ALTEs). Older children will classically present with a combination of fatiguable or fluctuating ptosis, ophthalmoplegia, and motor difficulties caused by muscle weakness. Prenatal symptoms may include reduced fetal movements and polyhydramnios due to dysphagia; the former may result in arthrogryposis that is apparent at birth. The range of clinical presentations is broad, from severe, life-threatening disease at birth to mild symptoms with onset later in childhood. The differential diagnosis for the presentations at both ends of the spectrum is broad and there are no easily detected serum biomarkers, in contrast to the antibody tests available for autoimmune disorders of the neuromuscular junction, often leading to difficulties in pinpointing the diagnosis. Distinctive clinical and electrophysiologic features may help the clinician distinguish between the different syndromes, as noted below.

Congenital myasthenic syndromes are caused by mutations in genes that are expressed at the neuromuscular junction. Such mutations disrupt the normal signaling that occurs between the motor axon and the muscle fiber. Mutations in CHRNE are responsible for more than half of the cases. Mutations in RAPSN, CHAT, COLQ, and DOK7 account for many of the others. As in other categories of inherited disorders associated with multiple genetic loci, there remain cohorts of patients who do not have mutations identified in the known causative genes. Table 21.2 shows a classification of known causative genes based on the neuroanatomical site of defect, and Table 21.3 correlates electrophysiologic and clinical findings with specific subtypes. Postsynaptic CMSs are more frequent than the presynaptic or synaptic CMSs, in large part due to the high incidence of CHRNE mutations. The inheritance of congenital myasthenic syndrome is usually autosomal recessive. Less commonly, these diseases may also be inherited in an autosomal dominant pattern, typically a result of de novo spontaneous mutations.

The hallmarks of presynaptic congenital myasthenic syndrome include episodic apnea resulting from respiratory distress and bulbar weakness. These episodes may be triggered by fever or intercurrent illness. Neonatal, infantile and juvenile forms have been described, primarily associated with mutations in CHAT [11–13].

Low frequency repetitive nerve stimulation at 3 Hz typically results in a significant decremental response (greater than 10%) (Fig. 21.1), though some patients may not manifest this classic electrophysiologic abnormality. A mild incremental response has also been reported in a small group of patients [12, 14].

Lambert Eaton-like congenital myasthenic syndrome is distinct from Lambert Eaton myasthenic syndrome in that the former is genetic in origin, albeit without identified mutations to date, while the latter is autoimmune in origin, as in adults. Both are extremely rare in childhood. The classical nerve conduction findings in both include a low compound muscle action potential at rest, with an incremental increase after high frequency repetitive stimulation or voluntary exertion [15, 16]. The genetic etiology of Lambert Eaton-like congenital myasthenic syndrome presumably affects the presynaptic region, though this will only be confirmed structurally when genetic mutations are confirmed for this disorder.

Endplate acetylcholinesterase deficiency of the motor plate and abnormal laminin β2 chain can each cause synaptic congenital myasthenic syndrome, with the former being more common.

Recessive mutations in COLQ cause defects in a subunit of acetylcholinesterase, leading to endplate acetylcholinesterase deficiency [17, 18]. Acetylcholinesterase hydrolyses acetylcholine after its action at the cholinergic synapse. Defective acetylcholinesterase is unable to bind to acetylcholine and its receptor, leading to prolonged exposure of the receptor to acetylcholine. This prolonged exposure results in several damaging consequences at the neuromuscular junction, including desensitization of the ACh receptor to acetylcholine [19].

In laminin β2 chain congenital myasthenic syndrome caused by mutations in LAMB2 [20], the pathophysiology has been postulated to be an abnormal formation of the neuromuscular junction.

Low frequency repetitive nerve stimulation at 3 Hz usually demonstrates a decremental response in the compound muscle action potential, with confirmation of the diagnosis by the identification of mutations in COLQ and LAMB2.

Mutations in the genes encoding the α, β, δ and ε subunits of the acetylcholine receptor and various proteins that interact with the acetylcholine receptor lead to postsynaptic defects of the neuromuscular junction. The other proteins include rapsyn, tyrosine kinase 7 and muscle-specific tyrosine kinase. Within this subgroup, there is significant heterogeneity and overlap in clinical presentations and electrophysiologic findings [7, 11, 21].

Mutations of genes causing defects in acetylcholine receptors can be classified into two subtypes: those that reduce the expression of AChR without altering its kinetic properties, and those that do alter its kinetic properties. The latter may be further subdivided into slow channel mutations and fast channel mutations. Slow channel mutations increase the synaptic response to acetylcholine while fast channel mutations decrease the synaptic response to acetylcholine [22]. More recently, it has been found that certain novel subtypes of postsynaptic congenital myasthenic syndrome do not fall into any of these three categories, including those associated with mutations in SCN4A (which encodes a sodium channel) [23], AGRIN (whose protein product aggregates ACh receptors) [24], CHRNG (which is associated with Escobar syndrome, recently confirmed to be caused by neuromuscular junction defects, but without ongoing postnatal weakness or fatigability as CHRNG is only expressed in the fetal form of the ACh receptor) [25, 26]; and PLEC1 (which is associated with concomitant muscular dystrophy and epidermolysis bullosa) [27, 28].

For those patients with postsynaptic disorders who have ACh receptor deficiency without altered ACh receptor kinetics, the most common mutations occur in CHRNE, which encodes the ε subunit of the acetylcholine receptor; mutations have also been reported in such a context for CHRNB, CHRND, RAPSN, DOK7, MUSK, and GFPT1. The clinical phenotype of this subgroup includes hypotonia, ptosis, ophthalmoplegia, fatiguable weakness, dysphagia, and respiratory difficulties. Skeletal deformities such as arthrogryposis and/or scoliosis are usually present [7, 11, 21]. The inheritance pattern is autosomal recessive. The primary electrophysiologic finding is a decremental response on low frequency repetitive stimulation, thus there is a not a distinct electrophysiologic signature for this subgroup.

Slow-channel CMS is an autosomal dominant disorder that is associated with mutations in CHRNA, CHRNB, CHRND, and CHRNE, and may present at any age [22, 29, 30]. Patients present with ptosis, ophthalmoplegia, neck weakness, and distal muscle weakness. The weakness tends to affect the upper limbs more than the lower limbs, and may be asymmetric after exertion [29, 31]. An electrophysiologic hallmark of slow-channel syndromes is a repetitive CMAP after single stimulation. Thus, the sweep speed should be adjusted after performing standard motor nerve conduction studies in children suspected of this diagnosis to seek cryptic second CMAPs that on first glance may not appear on the screen. In nerve conduction studies, there is a decremental response to both low and high frequency repetitive stimulation, with a greater decremental response to high frequency repetitive stimulation. Conventional needle EMG may show a myopathic pattern [11, 32]. As slow-channel CMS has distinct electrophysiologic findings, patients with a suggestive pattern of weakness along with a dominant pattern of inheritance should have the complete electrophysiologic evaluation that is described, when feasible.

Fast-channel CMS is an autosomal recessive condition that is associated with mutations in CHRNA, CHRND, and CHRNE, and presents in infancy. Clinical signs include ptosis, ophthalmoplegia, dysphagia, and muscle weakness [21, 31]. Repetitive stimulation studies demonstrate a decremental response, which improves with volitional muscle contractions [22, 31]. When it is feasible to stimulate voluntary contractions in patients under examination, it is worth re-checking repetitive stimulation studies after volitional movement in an attempt to find signs of fast-channel CMS.

Myasthenia gravis is an acquired autoimmune disorder, in contrast to the inherited congenital myasthenic syndromes. Autoimmune myasthenia gravis is caused by autoantibodies directed against different proteins at the motor end plate, most commonly the acetylcholine receptor (AChR). Other autoantibodies that have been associated with myasthenia gravis are IgG autoantibodies to muscle-specific kinase (MuSK), striated muscle protein, or low density lipoprotein receptor-related protein [33–35]. These autoantibodies disrupt the neuromuscular junction via various mechanisms. One mechanism is binding of the antibody to the acetylcholine receptor, decreasing the number of functional acetylcholine receptors and disrupting the normal function of the postsynaptic neuromuscular transmission by causing an accelerated degradation of the AChR. Another mechanism is blocking of the binding sites of the AChR by the antibody. A third is via deposition of complement. Some cases of myasthenia gravis are associated with antecedent infections, but many cases are not associated with a clear infectious trigger for the autoimmune reaction. In rare cases, drugs such as penicillamine may trigger autoimmune myasthenia gravis.