The slow-channel CMSs and sodium-channel myasthenia are transmitted by dominant inheritance. All other CMSs identified to date are transmitted by recessive inheritance.
Phenotypic Features and Pathological Mechanisms in the Different CMSs
This section considers the more frequently encountered CMSs before those identified in only a few kinships.
Choline Acetyltransferase Deficiency
Mutations in ChAT either reduce the expression or decrease the catalytic efficiency of the enzyme. This decreases the rate of ACh resynthesis and the ACh content of the synaptic vesicles during physiological activity. Consequently the amplitude of the synaptic response, reflected by the amplitude of the miniature EPP (MEPP) and EPP, also decrease. This disorder leaves no anatomic footprint.
Endplate AChE Deficiency
The endplate species of AChE is composed of catalytic subunits encoded by ACHET and a structural subunit encoded by COLQ. No spontaneous mutations have been observed in ACHET. ColQ anchors the enzyme complex in the synaptic basal lamina. Different mutations in different ColQ domains prevent its association with the catalytic subunits, reduce ColQ expression, or prevent ColQ from anchoring the enzyme in the synaptic basal lamina. Absence of AChE from the endplate prolongs the lifetime of ACh in the synaptic space so that each ACh can bind to a series of AChRs before leaving the synaptic space by diffusion, and this prolongs the decay phase of the MEPP and EPP. When the EPP outlasts the absolute refractory period of the muscle fiber, it generates a second or repetitive compound muscle action potential (CMAP). Cholinergic overactivity at the endplate results in cationic overloading of the postsynaptic region; this causes degeneration of the junctional folds with loss of AChR.
Perhaps to protect the endplate from overexposure to ACh, the nerve terminals are abnormally small; this reduces the number of readily releasable quanta and hence the quantal content of the EPP. Thus, the safety margin of neuromuscular transmission is compromised by the decreased quantal content of the EPP, loss of AChR from degenerating junctional folds, altered endplate geometry, and desensitization of AChR from overexposure to ACh.
Pathogenic Mutations in AChR
These can either decrease the expression of AChR at the endplate or alter the kinetic properties of the receptor, so as to shift the thermodynamic equilibrium to favor the open channel state and result in slowly decaying EPPs (slow-channel syndromes) or to favor the closed channel state and result in fast decaying EPPs (fast-channel syndromes).
Primary Endplate AChR Deficiency
Endplate AChR deficiency results from mutations in the α, β, δ, or ε subunits of the receptor. The types of identified mutations include frameshift, splice-site, or nonsense mutations, chromosomal microdeletions, or missense mutations in the promoter or signal peptide region, or in residues essential for assembly of the pentameric AChR. Morphological studies show an increased number of small endplate regions distributed over an increased span of the muscle fiber, and the distribution of AChRs on the junctional folds is patchy and attenuated. The structural integrity of the junctional folds is preserved but the postsynaptic region is simplified due to the decreased height and number of the folds. The safety margin is compromised by the AChR deficiency and the postsynaptic simplification that reduces the input resistance of the postsynaptic region. Both factors reduce the amplitude of the MEPPs and EPPs. Low-expressor or null mutations in the ε subunit are partially compensated for by expression of small amounts of AChR harboring the fetal γ subunit and this likely rescues the phenotype. Low-expressor or null mutations in non-ε subunits either are embryonic lethal or generate severe phenotypes with high mortality in early life. Consequently, most identified low-expressor or null mutations of AChR reside in the ε subunit.
Slow-Channel Syndrome
Pathogenic mutations occurring in different AChR subunits prolong the opening events of the AChR channel by increasing the rate at which the channel opens, decrease the rate at which it closes, or increase its affinity for ACh, resulting in repeated channel reopenings during the prolonged sojourn of ACh at the receptor-binding site. The prolonged channel-opening events prolong the duration of the EPP so that it outlasts the refractory period of the muscle fiber, and thereby eliciting a repetitive CMAP. The prolonged synaptic response also causes cationic overloading of the postsynaptic region and degeneration of the junctional folds with loss of AChR from the folds. The safety margin is compromised by loss of AChR, altered endplate geometry, and progressive depolarization block of the endplate at physiological rates of stimulation, as a result of each consecutive EPP arising in the wake of the preceding EPP before the postsynaptic membrane has repolarized.
Fast-Channel Syndrome
Pathogenic mutations residing in different subunits of the AChR curtail the duration of the channel-opening events by decreasing the rate at which the AChR channel opens, increasing the rate at which it closes, decreasing the affinity for ACh, or altering the fidelity of channel openings, which typically become briefer than normal. The kinetic mutations are generally accompanied by a null mutation in the second allele so that the kinetic mutation dominates the phenotype. Endplate structure is normal. The safety margin of neuromuscular transmission is compromised by a decreased probability of channel openings, which decreases the synaptic response to ACh and accelerates its decay.
Rapsyn Deficiency
Rapsyn, under the influence of agrin and MuSK, concentrates AChR on the terminal expansions of the junctional folds. Mutations in different domains of rapsyn cause endplate AChR deficiency. Nearly all white patients carry a common N88K mutation. The morphological features of the endplate and the factors that impair the safety margin are like those in primary AChR deficiency.
Dok-7 Myasthenia
Dok-7 is a muscle intrinsic activator of MuSK required for normal development and maintenance of the neuromuscular junction. The clinical hallmarks are limb–girdle weakness with lesser face, jaw, and neck muscle weakness. Mild ptosis is common but the ocular ductions are usually spared. The neuromuscular junctions are composed of single or multiple small regions. The postsynaptic membrane is less folded than normal and there is ongoing destruction of endplates and attempts to form new endplates. Different parameters of neuromuscular transmission (MEPP amplitude, quantal release, AChR content) are reduced to a different extent in different patients. The safety margin of neuromuscular transmission is likely impaired by a combination of factors that operate to a different extent in different patients.
Paucity of Synaptic Vesicles and Reduced Quantal Release
In a single investigated patient, the number of quanta released by nerve impulse was decreased due to a decreased number of readily releasable quanta. Electron microscopy revealed that the decrease in quantal content of the EPP was due to a decrease in the number of readily releasable quanta, and this was proportionate to a decreased density of synaptic vesicles in the nerve terminals.
Congenital Lambert–Eaton-Like Syndrome
A CMS in which the EMG features resembled those in the acquired autoimmune form of the disease was reported in a single patient. In another patient, the number of quanta released by nerve impulse was decreased due to a decreased probability of quantal release. Electron microscopy revealed no structural abnormality of the endplate.
β2-Laminin Myasthenia
β2-Laminin, encoded by LAMB2, is a component of the basal lamina of different tissues and is highly expressed in the kidney, eye, and neuromuscular junction. In vitro microelectrode studies revealed decreased quantal release by nerve impulse and decreased MEPP amplitude. The nerve terminals were abnormally small and often encased by Schwann cells, the synaptic space was widened, and the junctional folds were simplified.
CMSs Due to Defect in Agrin
Agrin, encoded by AGRN, is a multidomain proteoglycan secreted into the synaptic basal lamina by the nerve terminal. The muscle isoform of agrin harbors A and B regions near its C terminus. Agrin phosphorylates and thereby activates MuSK by way of its receptor, LRP4. Two siblings with eyelid ptosis but normal ocular ductions and only mild weakness of the facial and hip–girdle muscles carried a homozygous missense mutation in the agrin A region. Light microscopic preparations showed newly formed, partially denervated, and remodeled endplates. Electron microscopy revealed some abandoned and partially occupied postsynaptic regions. The aggregation of AChR at the endplates was not affected. The number of AChRs per endplate was not determined.
CMSs Due to Defects in MuSK
MuSK under the influence of agrin and LRP4 plays a role in maturation and maintenance of the synapse and in directing rapsyn to concentrate AChR in the postsynaptic membrane. In one kinship there was decreased expression and stability of the mutant protein, decreased AChR aggregation, and reduced AChR expression at simplified endplates. The safety margin is likely compromised by the AChR deficiency. Endplate fine structure was not examined.
Sodium-Channel Myasthenia
In the single patient observed to date, quantal release by nerve impulse and the amplitude of the EPPs were normal, but suprathreshold EPPs failed to generate muscle action potentials. This disease was traced to a p.V1442E mutation in an S4/S5 linker in domain IV of Nav1.4. This mutation enhances fast inactivation of Nav1.4 at a resting membrane potential, rendering a large fraction of the channels inexcitable at rest, and also enhances use-dependent inactivation of the channel. The endplates show no structural abnormality.
CMSs, Muscular Dystrophy, and Epidermolysis Bullosa Simplex Caused by Plectin Deficiency
Plectin is an intermediate filament-associated protein that orchestrates the internal cytoskeleton in a variety of cells and tissues in an isoform-dependent manner. Plectin deficiency in muscle results in impaired anchoring and defective function of the muscle fiber organelles, breaks in the sarcolemma, and degeneration of the junctional folds. Plectin deficiency in skin causes dermoepidermal disjunction and epidermolysis bullosa simplex. The safety margin of neuromuscular transmission is likely impaired by the abnormal endplate geometry and by loss of AChR and Nav1.4 from the postsynaptic membrane.
Prenatal CMS with Fetal Akinesia and Deformities
Fetal hypomotility can result in intrauterine growth retardation, multiple joint contractures, subcutaneous edema, pterygia (webbing of the neck, axilla, elbows, fingers, or popliteal fossa), lung hypoplasia, and other congenital malformations. The syndrome is often lethal; the nonlethal form is referred to as Escobar’s syndrome. Fetal akinesia has many causes. Those due to defects in neuromuscular transmission include transplacental transfer from mother to fetus of anti-AChR antibodies that contain a high titer of complement-fixing anti-γ subunit specificities. Mutations in the AChR gamma subunit and severe or null mutations in non-epsilon AChR subunits, RAPSN, and DOK7 can also cause fetal akinesia and congenital deformities.
Diagnosis of the CMSS
A generic diagnosis of a CMS can be made on the basis of fatigable weakness since birth or early childhood involving oculobulbar, axial, and limb muscles, similarly affected relatives, a decremental electromyographic (EMG) response of the evoked CMAP at 2- to 3-Hz stimulation, and negative tests for antibodies directed against AChR, MuSK, and P-/Q-type of calcium channels. There are exceptions, however. In some CMSs the onset is delayed, the weakness may not involve the oculobulbar muscles, often there are no similarly affected relatives, and the symptoms can be episodic. Further, the EMG abnormalities may not be present in all muscles, are present only intermittently, or are elicited only after a prolonged train of subtetanic stimuli. Box 19.1 summarizes the clinical clues pointing to the diagnosis of specific types of CMSs.
Box 19.1. Clinical clues pointing to specific types of congenital myasthenic syndromes
Low-expressor or null mutations in the AChR subunit
Early fixed ophthalmoparesis refractory to therapy
Mutations in non-ε subunits carry worse prognosis than mutations in ε subunit
Respond to cholinergic agonists
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