**7. Acknowledgments**

Works in our laboratories were supported by Grants-in-Aid from the MEXT and the MHLW of Japan to K.O., and by NIH Grant NS6277 and a research Grant from Muscular Dystrophy Association to A.G.E.

### **8. References**

Abicht, A., Stucka, R., Schmidt, C., Briguet, A., Höpfner, S., Song, I.-H., Pongratz, D., Müller-Felber, W., Ruegg, M. A. & Lochmüller, H. (2002). A newly identified chromosomal microdeletion and an N-box mutation of the AChR gene cause a congenital myasthenic syndrome. *Brain*, Vol. 125, No., pp. 1005-1013, ISSN 0006-8950

Congenital Myasthenic Syndromes – Molecular Bases

pp. 144-146, ISSN 0028-3878

61, No., pp. 826-828, ISSN 0028-3878

No. 6, pp. 782-789, ISSN 0364-5134

pp. 548-553, ISSN 0960-8966

0021-9525

0006-8950

of Congenital Defects of Proteins at the Neuromuscular Junction 191

Breningstall, G. N., Kurachek, S. C., Fugate, J. H. & Engel, A. G. (1996). Treatment of

periodic paralysis. *Neurology*, Vol. 53, No. 9, pp. 1932-1936, ISSN 0028-3878 Burke, G., Cossins, J., Maxwell, S., Owens, G., Vincent, A., Robb, S., Nicolle, M., Hilton-

Byring, R. F., Pihko, H., Tsujino, A., Shen, X.-M., Gustafsson, B., Hackman, P., Ohno, K.,

Cai, Y., Cronin, C. N., Engel, A. G., Ohno, K., Hersh, L. B. & Rodgers, D. W. (2004). Choline

Cartaud, A., Strochlic, L., Guerra, M., Blanchard, B., Lambergeon, M., Krejci, E., Cartaud, J.

Chevessier, F., Faraut, B., Ravel-Chapuis, A., Richard, P., Gaudon, K., Bauche, S., Prioleau,

Chevessier, F., Girard, E., Molgo, J., Bartling, S., Koenig, J., Hantai, D. & Witzemann, V.

*Human Molecular Genetics*, Vol. 17, No. 22, pp. 3577-3595, ISSN 0964-6906 Cole, R. N., Reddel, S. W., Gervasio, O. L. & Phillips, W. D. (2008). Anti-MuSK patient

Cossins, J., Burke, G., Maxwell, S., Spearman, H., Man, S., Kuks, J., Vincent, A., Palace, J.,

Croxen, R., Hatton, C., Shelley, C., Brydson, M., Chauplannaz, G., Oosterhuis, H., Vincent,

disorders. *EMBO Journal*, Vol. 23, No. 10, pp. 2047-2058, ISSN 0261-4189 Cartaud, A., Coutant, S., Petrucci, T. C. & Cartaud, J. (1998). Evidence for in situ and in vitro

*Chemistry*, Vol. 273, No. 18, pp. 11321-11326, ISSN 0021-9258

*Journal of Child Neurology*, Vol. 11, No. 4, pp. 345-346, ISSN 0883-0738 Bulman, D. E., Scoggan, K. A., van Oene, M. D., Nicolle, M. W., Hahn, A. F., Tollar, L. L. &

acetylcholinesterase deficiency responsive to ephedrine. *Neurology*, Vol. 65, No. 1,

congenital endplate acetylcholinesterase deficiency by neuromuscular blockade.

Ebers, G. C. (1999). A novel sodium channel mutation in a family with hypokalemic

Jones, D., Newsom-Davis, J., Palace, J. & Beeson, D. (2003). Rapsyn mutations in hereditary myasthenia: Distinct early- and late-onset phenotypes. *Neurology*, Vol.

Engel, A. G. & Udd, B. (2002). Congenital myasthenic syndrome associated with episodic apnea and sudden infant death. *Neuromuscular Disorders*, Vol. 12, No. 6,

acetyltransferase structure reveals distribution of mutations that cause motor

association between beta-dystroglycan and the subsynaptic 43k rapsyn protein consequence for acetylcholine receptor clustering at the synapse. *Journal of Biological* 

& Legay, C. (2004). MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. *Journal of Cell Biology*, Vol. 165, No. 4, pp. 505-515, ISSN

C., Herbst, R., Goillot, E., Ioos, C., Azulay, J. P., Attarian, S., Leroy, J. P., Fournier, E., Legay, C., Schaeffer, L., Koenig, J., Fardeau, M., Eymard, B., Pouget, J. & Hantai, D. (2004). MUSK, a new target for mutations causing congenital myasthenic syndrome. *Human Molecular Genetics*, Vol. 13, No. 24, pp. 3229-3240, ISSN 0964-6906

(2008). A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions.

antibodies disrupt the mouse neuromuscular junction. *Annals of Neurology*, Vol. 63,

Fuhrer, C. & Beeson, D. (2006). Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations. *Brain*, Vol. 129, No. Pt 10, pp. 2773-2783, ISSN

A., Newsom-Davis, J., Colquhoun, D. & Beeson, D. (2002). Recessive inheritance


Anderson, J. A., Ng, J. J., Bowe, C., McDonald, C., Richman, D. P., Wollmann, R. L. &

Apparsundaram, S., Ferguson, S. M., George, A. L., Jr. & Blakely, R. D. (2000). Molecular

nomenclature. *Matrix Biology*, Vol. 24, No. 5, pp. 326-332, ISSN 0945-053X Banwell, B. L., Russel, J., Fukudome, T., Shen, X. M., Stilling, G. & Engel, A. G. (1999).

Banwell, B. L., Ohno, K., Sieb, J. P. & Engel, A. G. (2004). Novel truncating RAPSN

Barisic, N., Muller, J. S., Paucic-Kirincic, E., Gazdik, M., Lah-Tomulic, K., Pertl, A., Sertic, J.,

Bartoli, M., Ramarao, M. K. & Cohen, J. B. (2001). Interactions of the rapsyn RING-H2

Beeson, D., Higuchi, O., Palace, J., Cossins, J., Spearman, H., Maxwell, S., Newsom-Davis, J.,

Bergamin, E., Hallock, P. T., Burden, S. J. & Hubbard, S. R. (2010). The cytoplasmic adaptor

Bestue-Cardiel, M., Saenz de Cabezon-Alvarez, A., Capablo-Liesa, J. L., Lopez-Pison, J.,

*Molecular Cell*, Vol. 39, No. 1, pp. 100-109, ISSN 1097-2765

*Muscle and Nerve*, Vol. 37, No. 4, pp. 448-456, ISSN 0148-639X

8, pp. 832-846, ISSN 0022-3069

24911-24917, ISSN 0021-9258

766, ISSN 0340-5354

8966

9639

Maselli, R. A. (2008). Variable phenotypes associated with mutations in DOK7.

cloning of a human, hemicholinium-3-sensitive choline transporter. *Biochemical and Biophysical Research Communications*, Vol. 276, No. 3, pp. 862-867, ISSN 0006-291X Aumailley, M., Bruckner-Tuderman, L., Carter, W. G., Deutzmann, R., Edgar, D., Ekblom,

P., Engel, J., Engvall, E., Hohenester, E., Jones, J. C., Kleinman, H. K., Marinkovich, M. P., Martin, G. R., Mayer, U., Meneguzzi, G., Miner, J. H., Miyazaki, K., Patarroyo, M., Paulsson, M., Quaranta, V., Sanes, J. R., Sasaki, T., Sekiguchi, K., Sorokin, L. M., Talts, J. F., Tryggvason, K., Uitto, J., Virtanen, I., von der Mark, K., Wewer, U. M., Yamada, Y. & Yurchenco, P. D. (2005). A simplified laminin

Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. *Journal of Neuropathology and Experimental Neurology*, Vol. 58, No.

mutations causing congenital myasthenic syndrome responsive to 3,4 diaminopyridine. *Neuromuscular Disorders*, Vol. 14, No. 3, pp. 202-207, ISSN 0960-

Zurak, N., Lochmuller, H. & Abicht, A. (2005). Clinical variability of CMS-EA (congenital myasthenic syndrome with episodic apnea) due to identical CHAT mutations in two infants. *Eur J Paediatr Neurol*, Vol. 9, No. 1, pp. 7-12, ISSN 1570-

domain with dystroglycan. *Journal of Biological Chemistry*, Vol. 276, No. 27, pp.

Burke, G., Fawcett, P., Motomura, M., Muller, J. S., Lochmuller, H., Slater, C., Vincent, A. & Yamanashi, Y. (2006). Dok-7 mutations underlie a neuromuscular junction synaptopathy. *Science*, Vol. 313, No. 5795, pp. 1975-1978, ISSN 0036-8075 Ben Ammar, A., Petit, F., Alexandri, N., Gaudon, K., Bauche, S., Rouche, A., Gras, D.,

Fournier, E., Koenig, J., Stojkovic, T., Lacour, A., Petiot, P., Zagnoli, F., Viollet, L., Pellegrini, N., Orlikowski, D., Lazaro, L., Ferrer, X., Stoltenburg, G., Paturneau-Jouas, M., Hentati, F., Fardeau, M., Sternberg, D., Hantai, D., Richard, P. & Eymard, B. (2010). Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7. *J Neurol*, Vol. 257, No. 5, pp. 754-

protein Dok7 activates the receptor tyrosine kinase MuSK via dimerization.

Pena-Segura, J. L., Martin-Martinez, J. & Engel, A. G. (2005). Congenital endplate

acetylcholinesterase deficiency responsive to ephedrine. *Neurology*, Vol. 65, No. 1, pp. 144-146, ISSN 0028-3878


Congenital Myasthenic Syndromes – Molecular Bases

*Neurology*, Vol. 48, No., pp. A72, ISSN 0028-3878

Vol. 9, No. 8, pp. 1907-1911, ISSN 0959-4965

283, No. 9, pp. 5518-5524, ISSN 0021-9258

No. Pt 3, pp. 729-760, ISSN 0022-3751

365-368, ISSN 1078-8956

*Neurology*, Vol. 69, No. 2, pp. 418-422, ISSN 0364-5134

0021-9738

ISSN 0364-5134

ISSN 0028-3878

of Congenital Defects of Proteins at the Neuromuscular Junction 193

Fucile, S., Sucapane, A., Grassi, F., Eusebi, F. & Engel, A. G. (2006). The human adult

Fukudome, T., Ohno, K., Brengman, J. M. & Engel, A. G. (1998). Quinidine normalizes the

Groshong, J. S., Spencer, M. J., Bhattacharyya, B. J., Kudryashova, E., Vohra, B. P., Zayas, R.,

Hallock, P. T., Xu, C. F., Park, T. J., Neubert, T. A., Curran, T. & Burden, S. J. (2010). Dok-7

Hamuro, J., Higuchi, O., Okada, K., Ueno, M., Iemura, S., Natsume, T., Spearman, H.,

Harper, C. M. & Engel, A. G. (1997). Quinidine sulfate in the treatment of the slow channel congenital myasthenic syndrome. *Neurology*, Vol. 48, No., pp. A72, ISSN 0028-3878 Harper, C. M. & Engel, A. G. (1998). Quinidine sulfate therapy for the slow-channel

Harper, C. M., Fukodome, T. & Engel, A. G. (2003). Treatment of slow-channel congenital

Hatton, C. J., Shelley, C., Brydson, M., Beeson, D. & Colquhoun, D. (2003). Properties of the

Higuchi, O., Hamuro, J., Motomura, M. & Yamanashi, Y. (2011). Autoantibodies to low-

Hoch, W., McConville, J., Helms, S., Newsom-Davis, J., Melms, A. & Vincent, A. (2001).

Huze, C., Bauche, S., Richard, P., Chevessier, F., Goillot, E., Gaudon, K., Ben Ammar, A.,

*Development*, Vol. 24, No. 21, pp. 2451-2461, ISSN 0890-9369

subtype ACh receptor channel has high Ca2+ permeability and predisposes to endplate Ca2+ overloading. *J Physiol*, Vol. 573, No. Pt 1, pp. 35-43, ISSN 0022-3751 Fukudome, T., Ohno, K., Brengman, J. M. & Engel, A. G. (1997). Quinidine sulfate

normalizes the open duration of slow channel congenital myasthenic syndrome acetylcholine receptor channels expressed in human embryonic kidney cells.

open duration of slow-channel mutants of the acetylcholine receptor. *Neuroreport*,

Wollmann, R. L., Miller, R. J. & Gomez, C. M. (2007). Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome. *Journal of Clinical Investigation*, Vol. 117, No. 10, pp. 2903-2912, ISSN

regulates neuromuscular synapse formation by recruiting Crk and Crk-L. *Genes &* 

Beeson, D. & Yamanashi, Y. (2008). Mutations causing DOK7 congenital myasthenia ablate functional motifs in Dok-7. *Journal of Biological Chemistry*, Vol.

congenital myasthenic syndrome. *Annals of Neurology*, Vol. 43, No. 4, pp. 480-484,

myasthenic syndrome with fluoxetine. *Neurology*, Vol. 60, No. 10, pp. 1710-1713,

human muscle nicotinic receptor, and of the slow-channel myasthenic syndrome mutant epsilonL221F, inferred from maximum likelihood fits. *J Physiol*, Vol. 547,

density lipoprotein receptor-related protein 4 in myasthenia gravis. *Annals of* 

Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. *Nature Medicine*, Vol. 7, No. 3, pp.

Chaboud, A., Grosjean, I., Lecuyer, H. A., Bernard, V., Rouche, A., Alexandri, N., Kuntzer, T., Fardeau, M., Fournier, E., Brancaccio, A., Ruegg, M. A., Koenig, J., Eymard, B., Schaeffer, L. & Hantai, D. (2009). Identification of an agrin mutation

and variable penetrance of slow-channel congenital myasthenic syndromes. *Neurology*, Vol. 59, No. 2, pp. 162-168, ISSN 0028-3878


Dechiara, T. M., Bowen, D. C., Valenzuela, D. M., Simmons, M. V., Poueymirou, W. T.,

Deprez, P., Inestrosa, N. C. & Krejci, E. (2003). Two different heparin-binding domains in the

Di Castro, A., Martinello, K., Grassi, F., Eusebi, F. & Engel, A. G. (2007). Pathogenic point

Donger, C., Krejci, E., Pou Serradell, A., Eymard, B., Bon, S., Nicole, S., Chateau, D., Gary, F.,

Dunne, V. & Maselli, R. A. (2003). Identification of pathogenic mutations in the human rapsyn gene. *Journal of Human Genetics*, Vol. 48, No. 4, pp. 204-207, ISSN 1434-5161

Engel, A. G., Lambert, E. H. & Gomez, M. R. (1977). A new myasthenic syndrome with end-

Engel, A. G., Ohno, K., Bouzat, C., Sine, S. M. & Griggs, R. C. (1996). End-plate acetylcholine

Engel, A. G., Ohno, K., Milone, M., Wang, H. L., Nakano, S., Bouzat, C., Pruitt, J. N., 2nd,

Erickson, J. D., Varoqui, H., Schafer, M. K., Modi, W., Diebler, M. F., Weihe, E., Rand, J.,

Fidzianska, A., Ryniewicz, B., Shen, X. M. & Engel, A. G. (2005). IBM-type inclusions in a

*Neurology*, Vol. 59, No. 2, pp. 162-168, ISSN 0028-3878

*J Hum Genet*, Vol. 63, No., pp. 967-975, ISSN 0002-9297

*Neurology*, Vol. 40, No. 5, pp. 810-817, ISSN 0364-5134

*Neuron*, Vol. 5, No. 4, pp. 403-410, ISSN 0896-6273

85, No. 4, pp. 501-512, ISSN 0092-8674

23242, ISSN 0021-9258

671-677, ISSN 0022-3751

pp. 1217-1227, ISSN 0964-6906

9258

and variable penetrance of slow-channel congenital myasthenic syndromes.

Thomas, S., Kinetz, E., Compton, D. L., Rojas, E., Park, J. S., Smith, C., Distefano, P. S., Glass, D. J., Burden, S. J. & Yancopoulos, G. D. (1996). The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. *Cell*, Vol.

triple-helical domain of ColQ, the collagen tail subunit of synaptic acetylcholinesterase. *Journal of Biological Chemistry*, Vol. 278, No. 26, pp. 23233-

mutations in a transmembrane domain of the epsilon subunit increase the Ca2+ permeability of the human endplate ACh receptor. *J Physiol*, Vol. 579, No. Pt 3, pp.

Fardeau, M., J., M. & Guicheney, P. (1998). Mutation in the human acetylcholinesterase-associated collagen gene, *COLQ*, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic). *Am* 

plate acetylcholinesterase deficiency, small nerve terminals, and reduced acetylcholine release. *Annals of Neurology*, Vol. 1, No. 4, pp. 315-330, ISSN 0364-5134

receptor deficiency due to nonsense mutations in the epsilon subunit. *Annals of* 

Hutchinson, D. O., Brengman, J. M., Bren, N., Sieb, J. P. & Sine, S. M. (1996). New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slowchannel congenital myasthenic syndrome. *Human Molecular Genetics*, Vol. 5, No. 9,

Eiden, L. E., Bonner, T. I. & Usdin, T. B. (1994). Functional identification of a vesicular acetylcholine transporter and its expression from a "cholinergic" gene locus. *Journal of Biological Chemistry*, Vol. 269, No. 35, pp. 21929-21932, ISSN 0021-

patient with slow-channel syndrome caused by a mutation in the AChR epsilon subunit. *Neuromuscular Disorders*, Vol. 15, No. 11, pp. 753-759, ISSN 0960-8966 Froehner, S. C., Luetje, C. W., Scotland, P. B. & Patrick, J. (1990). The postsynaptic 43K

protein clusters muscle nicotinic acetylcholine receptors in Xenopus oocytes.


Congenital Myasthenic Syndromes – Molecular Bases

Vol., No., pp., ISSN 0964-6906

ISSN 0188-4409

759, ISSN 0006-8950

0028-3878

0896-6273

*Genetics*, Vol. 46, No. 3, pp. 203-208, ISSN 0022-2593

*Genetics*, Vol. 82, No. 2, pp. 464-476, ISSN 0002-9297

of Congenital Defects of Proteins at the Neuromuscular Junction 195

Maselli, R. A., Arredondo, J., Cagney, O., Ng, J. J., Anderson, J. A., Williams, C., Gerke, B. J.,

McClatchey, A. I., McKenna-Yasek, D., Cros, D., Worthen, H. G., Kuncl, R. W., DeSilva, S.

Michalk, A., Stricker, S., Becker, J., Rupps, R., Pantzar, T., Miertus, J., Botta, G., Naretto, V.

Mihailescu, S. & Drucker-Colin, R. (2000). Nicotine, brain nicotinic receptors, and

Mihaylova, V., Muller, J. S., Vilchez, J. J., Salih, M. A., Kabiraj, M. M., D'Amico, A., Bertini,

Mihaylova, V., Salih, M. A., Mukhtar, M. M., Abuzeid, H. A., El-Sadig, S. M., von der

Milone, M. & Engel, A. G. (1996). Block of the endplate acetylcholine receptor channel by the

Milone, M., Wang, H. L., Ohno, K., Fukudome, T., Pruitt, J. N., Bren, N., Sine, S. M. & Engel,

Milone, M., Wang, H.-L., Ohno, K., Prince, R., Fukudome, T., Shen, X.-M., Brengman, J. M.,

Milone, M., Shen, X. M., Selcen, D., Ohno, K., Brengman, J., Iannaccone, S. T., Harper, C. M.

*Research*, Vol. 740, No. 1-2, pp. 346-352, ISSN 0006-8993

No. 15, pp. 5651-5665, ISSN 0270-6474

channel. *Nature Genetics*, Vol. 2, No. 2, pp. 148-152, ISSN 1061-4036

severe form of synaptic congenital myasthenic syndrome. *Journal of Medical* 

Soliven, B. & Wollmann, R. L. (2010). Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. *Human Molecular Genetics*,

M., Cornblath, D. R., Gusella, J. F. & Brown, R. H., Jr. (1992). Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium

G., Janetzki, C., Yaqoob, N., Ott, C. E., Seelow, D., Wieczorek, D., Fiebig, B., Wirth, B., Hoopmann, M., Walther, M., Korber, F., Blankenburg, M., Mundlos, S., Heller, R. & Hoffmann, K. (2008). Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. *American Journal of Human* 

neuropsychiatric disorders. *Archives of Medical Research*, Vol. 31, No. 2, pp. 131-144,

E., Wolfle, J., Schreiner, F., Kurlemann, G., Rasic, V. M., Siskova, D., Colomer, J., Herczegfalvi, A., Fabriciova, K., Weschke, B., Scola, R., Hoellen, F., Schara, U., Abicht, A. & Lochmuller, H. (2008). Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes. *Brain*, Vol. 131, No. Pt 3, pp. 747-

Hagen, M., Huebner, A., Nurnberg, G., Abicht, A., Muller, J. S., Lochmuller, H. & Guergueltcheva, V. (2009). Refinement of the clinical phenotype in musk-related congenital myasthenic syndromes. *Neurology*, Vol. 73, No. 22, pp. 1926-1928, ISSN

sympathomimetic agents ephedrine, pseudoephedrine, and albuterol. *Brain* 

A. G. (1997). Slow-channel myasthenic syndrome caused by enhanced activation, desensitization, and agonist binding affinity attributable to mutation in the M2 domain of the acetylcholine receptor alpha subunit. *Journal of Neuroscience*, Vol. 17,

Griggs, R. C., Sine, S. M. & Engel, A. G. (1998). Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor epsilon subunit. *Neuron*, Vol. 20, No. 3, pp. 575-588, ISSN

& Engel, A. G. (2009). Myasthenic syndrome due to defects in rapsyn: Clinical and

that causes congenital myasthenia and affects synapse function. *American Journal of Human Genetics*, Vol. 85, No. 2, pp. 155-167, ISSN 0002-9297


Keramidas, A., Moorhouse, A. J., Schofield, P. R. & Barry, P. H. (2004). Ligand-gated ion

Kim, N., Stiegler, A. L., Cameron, T. O., Hallock, P. T., Gomez, A. M., Huang, J. H.,

Kimbell, L. M., Ohno, K., Engel, A. G. & Rotundo, R. L. (2004). C-terminal and heparin-

Krejci, E., Thomine, S., Boschetti, N., Legay, C., Sketelj, J. & Massoulié, J. (1997). The

Lang, B. & Vincent, A. (2009). Autoimmune disorders of the neuromuscular junction. *Curr* 

Lee, W. Y., Free, C. R. & Sine, S. M. (2009). Binding to gating transduction in nicotinic

Lee, Y., Rudell, J., Yechikhov, S., Taylor, R., Swope, S. & Ferns, M. (2008). Rapsyn carboxyl

Lerche, H., Heine, R., Pika, U., George, A. L., Jr., Mitrovic, N., Browatzki, M., Weiss, T.,

Liewluck, T., Selcen, D. & Engel, A. G. (in press). Beneficial effects of albuterol in congenital

Mallory, L. A., Shaw, J. G., Burgess, S. L., Estrella, E., Nurko, S., Burpee, T. M., Agus, M. S.,

Maselli, R. A., Chen, D., Mo, D., Bowe, C., Fenton, G. & Wollmann, R. L. (2003). Choline

resynthesis. *Muscle and Nerve*, Vol. 27, No. 2, pp. 180-187, ISSN 0148-639X Maselli, R. A., Dunne, V., Pascual-Pascual, S. I., Bowe, C., Agius, M., Frank, R. & Wollmann,

clustering. *Muscle and Nerve*, Vol. 28, No. 3, pp. 293-301, ISSN 0148-639X Maselli, R. A., Ng, J. J., Anderson, J. A., Cagney, O., Arredondo, J., Williams, C., Wessel, H.

*Human Genetics*, Vol. 85, No. 2, pp. 155-167, ISSN 0002-9297

*Molecular Biology*, Vol. 86, No. 2, pp. 161-204, ISSN 0079-6107

*Chemistry*, Vol. 272, No. 36, pp. 22840-22847, ISSN 0021-9258

*Opin Pharmacol*, Vol. 9, No. 3, pp. 336-340, ISSN 1471-4892

*Neuroscience*, Vol. 29, No. 10, pp. 3189-3199, ISSN 0270-6474

III-IV linker. *J Physiol*, Vol. 470, No., pp. 13-22, ISSN 0022-3751

pp. 10997-11005, ISSN 0021-9258

Vol., No., pp., ISSN 0148-639X

1188, ISSN 0148-639X

0306-4522

that causes congenital myasthenia and affects synapse function. *American Journal of* 

channels: mechanisms underlying ion selectivity. *Progress in Biophysics and* 

Hubbard, S. R., Dustin, M. L. & Burden, S. J. (2008). Lrp4 Is a Receptor for Agrin and Forms a Complex with MuSK. *Cell*, Vol. 135, No. 2, pp. 334-342, ISSN 0092-8674

binding domains of collagenic tail subunit are both essential for anchoring acetylcholinesterase at the synapse. *Journal of Biological Chemistry*, Vol. 279, No. 12,

mammalian gene of acetylcholinesterase-associated collagen. *Journal of Biological* 

receptors: Cys-loop energetically couples to pre-M1 and M2-M3 regions. *Journal of* 

terminal domains mediate muscle specific kinase-induced phosphorylation of the muscle acetylcholine receptor. *Neuroscience*, Vol. 153, No. 4, pp. 997-1007, ISSN

Rivet-Bastide, M., Franke, C., Lomonaco, M. & et al. (1993). Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the

endplate acetylcholinesterase deficiency and DOK-7 myasthenia. *Muscle and Nerve*,

Darras, B. T., Kunkel, L. M. & Kang, P. B. (2009). Congenital myasthenic syndrome with episodic apnea. *Pediatric Neurology*, Vol. 41, No. 1, pp. 42-45, ISSN 0887-8994 Maselli, R. A. & Soliven, B. C. (1991). Analysis of the organophosphate-induced

electromyographic response to repetitive nerve stimulation: paradoxical response to edrophonium and D-tubocurarine. *Muscle & Nerve*, Vol. 14, No. 12, pp. 1182-

acetyltransferase mutations in myasthenic syndrome due to deficient acetylcholine

R. L. (2003). Rapsyn mutations in myasthenic syndrome due to impaired receptor

B., Abdel-Hamid, H. & Wollmann, R. L. (2009). Mutations in *LAMB2* causing a

severe form of synaptic congenital myasthenic syndrome. *Journal of Medical Genetics*, Vol. 46, No. 3, pp. 203-208, ISSN 0022-2593


Congenital Myasthenic Syndromes – Molecular Bases

(abstract), ISSN 0028-3878

No., pp. 162-170, ISSN 0364-5134

Vol. 70, No. 4, pp. 875-885, ISSN 0002-9297

No. 2, pp. 120-125, ISSN 1097-6256

2022, ISSN 0027-8424

ISSN 0960-8966

of Congenital Defects of Proteins at the Neuromuscular Junction 197

*the United States of America*, Vol. 95, No. 16, pp. 9654-9659, ISSN 0027-8424 Ohno, K., Milone, M., Brengman, J. M., LoMonaco, M., Evoli, A., Tonali, P. A. & Engel, A. G.

Ohno, K., Anlar, B. & Engel, A. G. (1999). Congenital myasthenic syndrome caused by a

Ohno, K., Brengman, J. M., Felice, K. J., Cornblath, D. R. & Engel, A. G. (1999). Congenital

Ohno, K., Engel, A. G., Brengman, J. M., Shen, X.-M., Heidenrich, F. R., Vincent, A., Milone,

Ohno, K., Tsujino, A., Brengman, J. M., Harper, C. M., Bajzer, Z., Udd, B., Beyring, R., Robb,

Ohno, K., Engel, A. G., Shen, X.-M., Selcen, D., Brengman, J., Harper, C. M., Tsujino, A. &

Ohno, K., Sadeh, M., Blatt, I., Brengman, J. M. & Engel, A. G. (2003). E-box mutations in the

Okada, K., Inoue, A., Okada, M., Murata, Y., Kakuta, S., Jigami, T., Kubo, S., Shiraishi, H.,

Okuda, T., Haga, T., Kanai, Y., Endou, H., Ishihara, T. & Katsura, I. (2000). Identification and

Patton, B. L., Chiu, A. Y. & Sanes, J. R. (1998). Synaptic laminin prevents glial entry into the synaptic cleft. *Nature*, Vol. 393, No. 6686, pp. 698-701, ISSN 0028-0836 Peng, H. B., Xie, H., Rossi, S. G. & Rotundo, R. L. (1999). Acetylcholinesterase clustering at

*Human Molecular Genetics*, Vol. 12, No. 7, pp. 739-748, ISSN 0964-6906 Ohno, K. & Engel, A. G. (2004). Lack of founder haplotype for the rapsyn N88K mutation:

*Medical Genetics*, Vol. 41, No. 1, pp. e8, ISSN 0022-2593

*Science*, Vol. 312, No. 5781, pp. 1802-1805, ISSN 0036-8075

*Biology*, Vol. 145, No., pp. 911-921, ISSN 0021-9525

*Human Genetics*, Vol. 65, No. 3, pp. 635-644, ISSN 0002-9297

(ColQ) of the asymmetric enzyme. *Proceedings of the National Academy of Sciences of* 

(1998). Slow-channel congenital myasthenic syndrome caused by a novel mutation in the acetylcholine receptor subunit. *Neurology*, Vol. 50 (Suppl. 4), No., pp. A432

mutation in the Ets-binding site of the promoter region of the acetylcholine receptor epsilon subunit gene. *Neuromuscular Disorders*, Vol. 9, No. 3, pp. 131-135,

end-plate acetylcholinesterase deficiency caused by a nonsense mutation and an A- ->G splice-donor-site mutation at position +3 of the collagenlike-tail-subunit gene (COLQ): how does G at position +3 result in aberrant splicing? *American Journal of* 

M., Tan, E., Demirci, M., Walsh, P., Nakano, S. & Akiguchi, I. (2000). The spectrum of mutations causing endplate acetylcholinesterase deficiency. *Annals of Neurology*, Vol. 47,

S., Kirkham, F. J. & Engel, A. G. (2001). Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. *Proceedings of the National Academy of Sciences of the United States of America*, Vol. 98, No. 4, pp. 2017-

Milone, M. (2002). Rapsyn mutations in humans cause endplate acetylcholinereceptor deficiency and myasthenic syndrome. *American Journal of Human Genetics*,

*RAPSN* promoter region in eight cases with congenital myasthenic syndrome.

N88K is an ancient founder mutation or arises from multiple founders. *Journal of* 

Eguchi, K., Motomura, M., Akiyama, T., Iwakura, Y., Higuchi, O. & Yamanashi, Y. (2006). The muscle protein Dok-7 is essential for neuromuscular synaptogenesis.

characterization of the high-affinity choline transporter. *Nature Neuroscience*, Vol. 3,

the neuromuscular junction involves perlecan and dystroglycan. *Journal of Cell* 

molecular findings in 39 patients. *Neurology*, Vol. 73, No. 3, pp. 228-235, ISSN 0028- 3878


Mishina, M., Takai, T., Imoto, K., Noda, M., Takahashi, T., Numa, S., Methfessel, C. &

Muller, J. S., Mildner, G., Muller-Felber, W., Schara, U., Krampfl, K., Petersen, B., Petrova, S.,

Muller JS, Abicht A, Burke G, Cossins J, Richard P, Baumeister SK, et al. The congenital

Muller, J. S., Baumeister, S. K., Rasic, V. M., Krause, S., Todorovic, S., Kugler, K., Muller-

Muller, J. S., Herczegfalvi, A., Vilchez, J. J., Colomer, J., Bachinski, L. L., Mihaylova, V.,

Oda, Y., Nakanishi, I. & Deguchi, T. (1992). A complementary DNA for human choline

Ohno, K., Hutchinson, D. O., Milone, M., Brengman, J. M., Bouzat, C., Sine, S. M. & Engel, A.

Ohno, K., Quiram, P. A., Milone, M., Wang, H.-L., Harper, M. C., Pruitt, J. N., 2nd,

Ohno, K., Brengman, J., Tsujino, A. & Engel, A. G. (1998). Human endplate

*Molecular Genetics*, Vol. 6, No. 5, pp. 753-766, ISSN 0964-6906

3878

No. 7245, pp. 451-454, ISSN 0028-0836

European founder. J Med Genet 2004; 41: e104.

*Nature*, Vol. 374, No., pp. 258-262, ISSN 0028-0836

Vol. 92, No. 3, pp. 758-762, ISSN 0027-8424

No. 7, pp. 1159-1164, ISSN 0028-3878

1810, ISSN 0028-3878

ISSN 0006-8993

molecular findings in 39 patients. *Neurology*, Vol. 73, No. 3, pp. 228-235, ISSN 0028-

Sakmann, B. (1986). Molecular distinction between fetal and adult forms of muscle acetylcholine receptor. *Nature*, Vol. 321, No. 6068, pp. 406-411, ISSN 0028-0836 Mukhtasimova, N., Lee, W. Y., Wang, H. L. & Sine, S. M. (2009). Detection and trapping of

intermediate states priming nicotinic receptor channel opening. *Nature*, Vol. 459,

Stucka, R., Mortier, W., Bufler, J., Kurlemann, G., Huebner, A., Merlini, L., Lochmuller, H. & Abicht, A. (2003). Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients. *Neurology*, Vol. 60, No. 11, pp. 1805-

myasthenic syndrome mutation RAPSN N88K derives from an ancient Indo-

Felber, W., Abicht, A. & Lochmuller, H. (2006). Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations. *Neurology*, Vol. 67,

Santos, M., Schara, U., Deschauer, M., Shevell, M., Poulin, C., Dias, A., Soudo, A., Hietala, M., Aarimaa, T., Krahe, R., Karcagi, V., Huebner, A., Beeson, D., Abicht, A. & Lochmuller, H. (2007). Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. *Brain*, Vol. 130, No. Pt 6, pp. 1497-1506, ISSN 0006-8950 Noakes, P. G., Gautam, M., Mudd, J., Sanes, J. R. & Merlie, J. P. (1995). Aberrant

differentiation of neuromuscular junctions in mice lacking s-laminin laminin beta 2.

acetyltransferase induces two forms of enzyme with different molecular weights in cultured cells. *Brain Research Molecular Brain Research*, Vol. 16, No. 3-4, pp. 287-294,

G. (1995). Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. *Proceedings of the National Academy of Sciences of the United States of America*,

Brengman, J. M., Pao, L., Fischbeck, K. H., Crawford, T. O., Sine, S. M. & Engel, A. G. (1997). Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of six new mutations. *Human* 

acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit

(ColQ) of the asymmetric enzyme. *Proceedings of the National Academy of Sciences of the United States of America*, Vol. 95, No. 16, pp. 9654-9659, ISSN 0027-8424


Congenital Myasthenic Syndromes – Molecular Bases

8950

ISSN 1059-1524

0896-6273

0022-1295

pp. 229-239, ISSN 0896-6273

*Genetics*, Vol. 88, No. 2, pp. 162-172, ISSN 0002-9297

*Genetics*, Vol. 13, No. 4, pp. 450-457, ISSN 1061-4036

*America*, Vol. 100, No., pp. 7377-7382, ISSN 0027-8424

Vol. 2, No. 3, pp. 226-233, ISSN 1097-6256

of Congenital Defects of Proteins at the Neuromuscular Junction 199

Shen, X.-M., Ohno, K., Sine, S. M. & Engel, A. G. (2005). Subunit-specific contribution to

Shen, X. M., Ohno, K., Milone, M., Brengman, J. M., Tsujino, A. & Engel, A. G. (2003). Effect

Sine, S. M., Ohno, K., Bouzat, C., Auerbach, A., Milone, M., Pruitt, J. N. & Engel, A. G.

Smith, F. J., Eady, R. A., Leigh, I. M., McMillan, J. R., Rugg, E. L., Kelsell, D. P., Bryant, S. P.,

Tsujino, A., Maertens, C., Ohno, K., Shen, X.-M., Fukuda, T., Harper, C. M., Cannon, S. C. &

Valenzuela, D. M., Stitt, T. N., DiStefano, P. S., Rojas, E., Mattsson, K., Compton, D. L.,

Vogt, J., Morgan, N. V., Marton, T., Maxwell, S., Harrison, B. J., Beeson, D. & Maher, E. R.

Wang, H.-L., Milone, M., Ohno, K., Shen, X.-M., Tsujino, A., Batocchi, A. P., Tonali, P.,

Wang, H.-L., Ohno, K., Milone, M., Brengman, J. M., Evoli, A., Batocchi, A. P., Middleton, L.

B., Schoser, B., Kirschner, J., Herrmann, R., Voit, T., Oldfors, A., Lindbergh, C., Urtizberea, A., von der Hagen, M., Hubner, A., Palace, J., Bushby, K., Straub, V., Beeson, D., Abicht, A. & Lochmuller, H. (2011). Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. *American Journal of Human* 

agonist binding and channel gating revealed by inherited mutation in muscle acetylcholine receptor M3-M4 linker. *Brain*, Vol. 128, No., pp. 345-355, ISSN 0006-

of residue side-chain mass on channel kinetics in second transmembrane domain of muscle AChR. *Molecular Biology of the Cell*, Vol. 14 (Suppl), No., pp. 223a (abstract),

(1995). Mutation of the acetylcholine receptor alpha subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. *Neuron*, Vol. 15, No. 1,

Spurr, N. K., Geddes, J. F., Kirtschig, G., Milana, G., de Bono, A. G., Owaribe, K., Wiche, G., Pulkkinen, L., Uitto, J., McLean, W. H. & Lane, E. B. (1996). Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. *Nature* 

Engel, A. G. (2003). Myasthenic syndrome caused by mutation of the SCN4A sodium channel. *Proceedings of the National Academy of Sciences of the United States of* 

Nunez, L., Park, J. S., Stark, J. L., Gies, D. R. & et al. (1995). Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. *Neuron*, Vol. 15, No. 3, pp. 573-584, ISSN

(2009). Germline mutation in DOK7 associated with fetal akinesia deformation sequence. *Journal of Medical Genetics*, Vol. 46, No. 5, pp. 338-340, ISSN 0022-2593 Wang, H.-L., Auerbach, A., Bren, N., Ohno, K., Engel, A. G. & Sine, S. M. (1997). Mutation in

the M1 domain of the acetylcholine receptor alpha subunit decreases the rate of agonist dissociation. *Journal of General Physiology*, Vol. 109, No. 6, pp. 757-766, ISSN

Brengman, J., Engel, A. G. & Sine, S. M. (1999). Acetylcholine receptor M3 domain: stereochemical and volume contributions to channel gating. *Nature Neuroscience*,

T., Christodoulou, K., Engel, A. G. & Sine, S. M. (2000). Fundamental gating mechanism of nicotinic receptor channel revealed by mutation causing a congenital


Ptacek, L. J., George, A. L., Jr., Griggs, R. C., Tawil, R., Kallen, R. G., Barchi, R. L., Robertson,

Ptacek, L. J., George, A. L., Jr., Barchi, R. L., Griggs, R. C., Riggs, J. E., Robertson, M. &

Ramarao, M. K., Bianchetta, M. J., Lanken, J. & Cohen, J. B. (2001). Role of rapsyn

Ramarao, N. K. & Cohen, J. B. (1998). Mechanism of nicotinic acetylcholine receptor cluster

Reimer, R. J., Fon, E. A. & Edwards, R. H. (1998). Vesicular neurotransmitter transport and

Richard, P., Gaudon, K., Andreux, F., Yasaki, E., Prioleau, C., S, B., Barois, A., Ioos, C.,

Sanes, J. R. (1997). Genetic analysis of postsynaptic differentiation at the vertebrate

Schara, U., Christen, H. J., Durmus, H., Hietala, M., Krabetz, K., Rodolico, C., Schreiber, G.,

Schmidt, C., Abicht, A., Krampfl, K., Voss, W., Stucka, R., Mildner, G., Petrova, S., Schara,

Selcen, D., Milone, M., Shen, X. M., Harper, C. M., Stans, A. A., Wieben, E. D. & Engel, A. G.

Selcen, D., Juel, V. C., Hobson-Webb, L. D., Smith, E. C., Stickler, D. E., Bite, A. V., Ohno, K.

Senderek, J., Muller, J. S., Dusl, M., Strom, T. M., Guergueltcheva, V., Diepolder, I., Laval, S.

*Annals of Neurology*, Vol. 64, No. 1, pp. 71-87, ISSN 0364-5134

Vol. 76, No. 4, pp. 327-336, ISSN 0028-3878

*States of America*, Vol. 95, No. 7, pp. 4007-4012, ISSN 0027-8424

ISSN 0896-6273

0022-2593

1090-3798

0960-8966

ISSN 0959-4388

7475-7483, ISSN 0021-9258

No. 3, pp. 405-412, ISSN 0959-4388

M. & Leppert, M. F. (1991). Identification of a mutation in the gene causing hyperkalemic periodic paralysis. *Cell*, Vol. 67, No. 5, pp. 1021-1027, ISSN 0092-8674

Leppert, M. F. (1992). Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita. *Neuron*, Vol. 8, No. 5, pp. 891-897,

tetratricopeptide repeat and coiled-coil domains in self-association and nicotinic acetylcholine receptor clustering. *Journal of Biological Chemistry*, Vol. 276, No. 10, pp.

formation by rapsyn. *Proceedings of the National Academy of Sciences of the United* 

the presynaptic regulation of quantal size. *Current Opinion in Neurobiology*, Vol. 8,

Mayer, M., Routon, M. C., Mokhtari, M., Leroy, J. P., Fournier, E., Hainque, B., Koenig, J., Fardeau, M., Eymard, B. & D, H. (2003). Possible founder effect of rapsyn N88K mutation and identification of novel rapsyn mutations in congenital myasthenic syndromes. *Journal of Medical Genetics*, Vol. 40, No. 6, pp. 81e, ISSN

neuromuscular junction. *Current Opinion in Neurobiology*, Vol. 7, No. 1, pp. 93-100,

Topaloglu, H., Talim, B., Voss, W., Pihko, H., Abicht, A., Muller, J. S. & Lochmuller, H. (2010). Long-term follow-up in patients with congenital myasthenic syndrome due to *CHAT* mutations. *Eur J Paediatr Neurol*, Vol. 14, No. 4, pp. 326-333, ISSN

U., Mortier, W., Bufler, J., Huebner, A. & Lochmuller, H. (2003). Congenital myasthenic syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase. *Neuromuscular Disorders*, Vol. 13, No. 3, pp. 245-251, ISSN

(2008). Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients.

& Engel, A. G. (2011). Myasthenic syndrome caused by plectinopathy. *Neurology*,

H., Maxwell, S., Cossins, J., Krause, S., Muelas, N., Vilchez, J. J., Colomer, J., Mallebrera, C. J., Nascimento, A., Nafissi, S., Kariminejad, A., Nilipour, Y., Bozorgmehr, B., Najmabadi, H., Rodolico, C., Sieb, J. P., Steinlein, O. K., Schlotter, B., Schoser, B., Kirschner, J., Herrmann, R., Voit, T., Oldfors, A., Lindbergh, C., Urtizberea, A., von der Hagen, M., Hubner, A., Palace, J., Bushby, K., Straub, V., Beeson, D., Abicht, A. & Lochmuller, H. (2011). Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. *American Journal of Human Genetics*, Vol. 88, No. 2, pp. 162-172, ISSN 0002-9297


**1. Introduction** 

amyotrophic lateral sclerosis.

later. (Allum and Shaw 2010).

**3. Epidemiology of motor neuron disease** 

**11** 

*Egypt* 

**Motor Neuron Disease** 

Neurologists in the 19th century recognized that muscle weakness could be due to primary disorders of muscle or secondary to loss of neuromuscular integrity, as happens when peripheral nerves are cut or when motor neurons degenerate. Furthermore, it was observed that there are forms of motor neuron degeneration which selectively affect upper motor neurons or lower motor neurons. A combination of upper and lower motor neuron dysfunction was named amyotrophic lateral sclerosis (ALS) by Charcot and Joffroy (Ringel, et al 1993). Jean-Martin Charcot first characterized the disease in 1874, naming the illness Amyotrophic lateral sclerosis (ALS) (Swash, 2001). In USA, ALS or Lou Gehrig's disease are terms used to describe all forms of the disease, whatever the combination of upper and lower motor neuron involvement (Ringel, et al 1993). ALS is now a term which classifies the most common form of the illness and is often used synonymously with MND (Swash, 2001). In the UK the umbrella term motor neuron disease (MND) is more common. MND is a

disease of middle to late life with a mean age of onset of 58 years, (Ringel, et al 1993).

**2. Definitions and terminology of motor neuron disease (MND)** 

weakness of bulbar, limbs and respiratory musculature, in different combination.

Actually, motor neuron diseases (MND) are a group of degenerative disorders that selectively affect motor neurons in the brain and spinal cord. Two groups of motor neurons are involved, lower motor neurons located in ventral horns of the spinal cord and brainstem motor nuclei, and upper motor neurons located in the cerebral cortex together with pyramidal tracts in spinal cord. The term MND is a broad spectrum term including

MND is a group of incurable progressive neurodegenerative disorders in which degeneration involves upper and lower motor neurons in different body regions, resulting in progressive

MND is an adult onset neurodegenerative disease which leads inexorably via weakness of limb, bulbar and respiratory muscles to death from respiratory failure three to five years

The prevalence of MND is 4-6 per 100,000 in most parts of the world, except the Western Pacific foci, (Leigh, 1991). However, its annual incidence is between 1.5 and 2/100,000 and

Hamdy N. El Tallawy

*Assiut University* 

myasthenic syndrome. *Journal of General Physiology*, Vol. 116, No. 3, pp. 449-462, ISSN 0022-1295

