Congenital Myasthenic Syndromes
Congenital myasthenia syndrome (CMS) is a term used for a heterogenous group of disorders that are genetically determined rather than autoimmune-mediated. Patients may present in the neonatal period, later in childhood, or even in adult life.
Patients often exhibit ptosis, external ophthalmoparesis, facial weakness, general hypotonia, proximal greater than distal muscle weakness, and variable degrees of functional impairment. Patients show absence of anti-AChR antibodies. More than 20 subtypes have been described, and congenital myasthenia may be classified according to the following: 1) presynaptic defects (eg, choline acetyltransferese [CHAT] deficiency causing CMS with episodic apnea, paucity of synaptic vesicles and reduced quantal release, or congenital Lambert-Eatonlike syndrome), 2) synaptic basal lamina defects (eg, endplate acetylcholinesterase [AChE] deficiency at neuromuscular junctions [NMJs]), and 3) post- synaptic defects (eg, AChR disorders involving α, β, δ, e subunits; kinetic abnormalities in AChR function caused by AChR deficiency; slow AChR channel syndromes; fastchannel syndromes; endplate rapsyn deficiency, etc.).Several congenital myasthenic syndromes have been associated with arthrogryposis syndromes. For example, “multiple pterygium syndrome” (Escobar's syndrome) has been associated with AChR gamma, alpha 1, and delta subunit mutations.
For diagnostic workup, standard EMG with repetitive nerve stimulation is utilized initially, and subsequently stimulated single-fiber EMG may be useful. Ultrastructural evaluation of the neuromuscular junction with electron microscopy usually is performed on a biopsy of the deltoid or biceps, including the muscle region containing the neuromuscular junction (NMJ) or the “motor point.” For in vitro electrophysiologic and immunocytochemical studies of the neuromuscular junction, a short muscle usually is removed from origin to insertion along with its motor branch and NMJ (a “motor point biopsy”).
Muscles obtained have included the anconeus muscle near the elbow, the external intercostal muscle in the fifth or sixth intercostal space near the anterior axillary line, or the peroneus tertius muscle in the lower extremity. Such in vitro electrophysiologic studies allow specific delineation of the congenital myasthenic syndrome into one of the numerous specific subtypes. More recently, the diagnostic evaluation of CMS has increasingly relied upon molecular genetic studies.For treatment of a CMS subtype, a definitive diagnosis is important because some CMS syndromes deteriorate with empiric treatment with AChE inhibitors such as pyridostigmine (Mestinon). For example, slow channel syndromes may deteriorate on pyridostigmine and endplate acetylcholinesterase deficiency may deteriorate or show no response. Some presynaptic syndromes may show response to 3,4-diaminopyridine, which increases release of acetylcholine at the presynaptic terminal. This drug has been used in Lambert-Eaton syndrome and in presynaptic CMS on a compassionate-use basis.