Presynaptic congenital myasthenic syndrome due to quantal release deficiency

Objective: To provide clinical, electrophysiologic, and ultrastructural fin dings in three patients with a presynaptic congenital myasthenic syndrome ( CMS). Background: Familial infantile myasthenia and paucity of synaptic ves icles are the only two fully characterized CMS. We are describing here thre e patients with another form of presynaptic CMS characterized by deficiency of the action potential-dependent release without reduction of the spontan eous release of neurotransmitter from the nerve terminal. Methods: The auth ors performed electromyography and anconeus muscle biopsies that included i ntracellular recordings and electron microscopy of the neuromuscular juncti on in three patients with presynaptic CMS. They also sequenced part of the P/Q-calcium alpha (1)-subunit gene (CACNA1A) and the acetylcholine receptor subunit (AChR) genes in these patients. Results: In these patients there w ere additional neurologic findings including nystagmus and ataxia. In all t hree patients the end-plate potential quantal content (m) was markedly redu ced but neither the amplitudes nor the frequencies of miniature end-plate p otentials were diminished. Ultrastructurally, postsynaptic end-plate folds, nerve terminal size, and synaptic vesicle number were normal but double-me mbrane-bound sacs containing synaptic vesicles were present in the nerve te rminal of all three patients. The screening of reported pathogenic mutation s in the CACNA1A and a mutational analysis of AChR subunit genes were negat ive. Conclusion: This form of CMS appears to result only from a deficiency of the quantal release of neurotransmitter that may be due to an abnormal c alcium mechanism or impaired endocytosis and recycling of synaptic vesicles .