**6. Conclusions**

188 Neuromuscular Disorders

Choline acetyltransferase (ChAT) is the only presynaptic molecule that is known to be

ACh released from the nerve terminal is hydrolyzed into choline and acetate by AChE at the synaptic basal lamina. Choline is taken up by the nerve terminal by a high-affinity choline transporter on the presynaptic membrane (Apparsundaram *et al.*, 2000; Okuda *et al.*, 2000). ChAT resynthesizes ACh from choline and acetyl-CoA (Oda *et al.*, 1992). After the synaptic vesicles are acidified by the vesicular proton pump (Reimer *et al.*, 1998), the resynthesized cationic ACh is packed into a synaptic vesicle by the vesicular ACh transporter (vAChT) in

**5.1 CMS with episodic apnea due to defects in choline acetyltransferase (ChAT)** 

Fig. 5. Choline acetyltransferase (ChAT). (A) Genomic structure of *CHAT* and identified mutations. A gene for vesicular acetylcholine transporter (vAChT) is in the first intron of

acetylcholine using choline and acetyl-CoA. L210P abrogates an affinity of ChAT for acetyl-

We determined the complete genomic structure of *CHAT* encoding ChAT, and identified ten mutations in five CMS patients with the characteristic clinical features of sudden episodes of apnea associated with variable myasthenic symptoms (Ohno *et al.*, 2001). Additional *CHAT* mutations were later reported by other groups (Maselli *et al.*, 2003; Schmidt *et al.*, 2003; Barisic *et al.*, 2005; Mallory *et al.*, 2009; Yeung *et al.*, 2009; Schara *et al.*, 2010). All of our patients showed a marked decrease of the endplate potential after subtetanic stimulation that recovered slowly over 5 to 10 min, which pointed to a defect in the resynthesis or

*CHAT*. (B) Kinetics of wild-type and mutant ChAT enzymes. ChAT synthesizes

CoA (AcCoA), and R560H abolishes an affinity of ChAT for choline.

**5. Presynaptic CMS** 

exchange for protons (Erickson *et al.*, 1994).

defective in CMS.

We reviewed the clinical and molecular consequences of defects in 11 genes associated with CMS. Molecular studies of CMS began with identification of a missense mutation in the AChR subunit in a SCCM patient (Ohno *et al.*, 1995). Since then, mutations in seven postsynaptic, three synaptic, and one presynaptic proteins have been discovered. In some CMS the disease gene has been elusive and await discovery. Resequencing analysis with the next generation sequencers may speed this effort.
