Two of the congenital myasthenic diseases—fast channel syndrome and slow channel syndrome—are consequences of mutations in AChR subunits that accelerate (fast channel) and slow (slow channel) the kinetics of gating of receptor channel (Croxen et al). Another well-characterized type, usually causing arthrogryposis and recurrent apneic spells but occasionally having an adult onset (as late as 48 years) has been traced to mutations in the “rapsyn” gene. The rapsyn protein plays a role in maintaining the integrity of the postsynaptic membrane (see Burke et al). Deficiency of the enzyme required to synthesize and package ACh in vesicles (choline acetyltransferase) causes a congenital myopathy with episodes of stress-induced apnea. In another type, the synaptic vesicles form poorly and are reduced in number. Being largely presynaptic defects, both of these disorders respond to acetylcholine esterase (AChE) inhibitors. In comparison, children with congenital myasthenia as a result of deficiency of AChE deteriorate markedly if given AChE inhibitors. Three disorders affecting postsynaptic structures (the fast-channel syndrome, AChR deficiency, and the myasthenic syndromes associated with deficiencies of rapsyn and plectin) also respond to AChE inhibition and 3,4-DAP, although both agents are hazardous in individuals with the slow-channel syndrome.
Another recently discovered congenital myasthenia is caused by a recessive mutation in DOK-7 that causes a simplified structure of the synapse but no alteration in acetylcholine receptors (Beeson et al). The clinical features as described by Palace and colleagues (2007) are of a limb-girdle pattern of weakness that causes a delay in walking after the child has reached other normal motor milestones and of ptosis from an early age.
A further category of congenital syndromes of defects in the presynaptic quantal release of acetylcholine have been described by Milone and colleagues and an intriguing prenatal myasthenic disease called Escobar syndrome (arthrogryposis, pterygia, and respiratory distress) has been traced to mutations in the gamma subunit of the acetylcholine receptor, a component expressed only in fetal life and replaced with maturity by the epsilon subunit (see Hoffmann and coworkers).
The studies of A.G. Engel have systematically defined and classified these disorders in a series of extensive investigations of more than 100 cases. A detailed account of this work can be found in his review with Ohno and Sine and in the chapter on the subject in his monograph Myasthenia Gravis and Myasthenic Disorders.
Other Drugs and by Environmental Toxins (See Chap. 41 and Table 46-2)
Many drugs can cause a myasthenic syndrome or a worsening of myasthenia gravis by their action on preor postsynaptic structures. In the case of a nonmyasthenic patient, this is most likely to happen in the presence of hepatic or renal disease that allows excessive accumulation of the causative agent. The myasthenic state in these conditions is acute and lasts hours or days, with full recovery provided that the patient does not succumb to respiratory failure. The ocular, facial, and bulbar muscles are involved, just as in native myasthenia. The treatment is to provide respiratory support, discontinue the offending drug, and attempt to reverse the conduction block at the motor endplate by infusions of calcium gluconate, potassium, and anticholinesterases, along the lines suggested by Argov and Mastaglia.