NEWLY RECOGNIZED CONGENITAL MYASTHENIC SYNDROME-ASSOCIATED WITH HIGH-CONDUCTANCE AND FAST CLOSURE OF THE ACETYLCHOLINE-RECEPTOR CHANNEL

We describe here a new congenital myasthenic syndrome associated with a kinetic abnormality of the acetylcholine receptor (AChR) channel. Th e propositus had poor suck and cry after birth. Subsequently, she had intermittent ocular symptoms and fatigued abnormally on exertion. At a ge 9 years, significant weakness was detected only in the frontalis, l evator palpebrae, and neck flexor muscles. Electromyography showed no decrement in limb muscles but single-fiber examination of the facial m uscles was consistent with a neuromuscular transmission defect. The oc ular symptoms responded partially to pyridostigmine, but the abnormal fatigability did not. Tests for anti-AChR antibodies were negative. A younger sister had elements of the same disease. An intercostal muscle specimen was obtained from the propositus at age 9 years for endplate studies. The quantal content of the endplate potential was normal. Mi niature endplate currents were abnormally large and their decay time c onstant was abnormally short. AChR channel properties were studied by analysis of acetylcholine-induced current noise. The mean single-chann el conductance was increased 1.7-fold and the mean channel open time w as 30% shorter than normal. The number of AChR per endplate was normal . Electron microscopy of most endplates showed no abnormality, but a f ew were degenerating or simplified. The channel abnormality may stem f rom a point mutation in an AChR subunit affecting a single amino acid residue lining the pore of the AChR channel. The mechanism by which th e physiological abnormality produces clinical symptoms is not known, b ut possible explanations are considered.