The neurobiology of congenital myasthenic syndromes (CMS).

The CMS are heterogeneous and disabling disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanism(s). The CMS are not uncommon but are commonly not diagnosed or treated correctly. Clinical, morphologic, and electrophysiologic analysis can determine whether a CMS is presynaptic, synaptic, or postsynaptic in origin and point to a defect in an endplate (EP) specific protein, such as the acetylcholine receptor (AChR), acetylcholinesterase (AChE), or choline acetyltransferase. The CMS are investigated by the following:

• Clinical assessment, including electromyography and tests for anti-AChR antibodies.
• Morphologic assessment, including immunocytochemical localization of AChR, AChE, and other EP-specific proteins, estimate of the number of AChR per EP, ultrastructural analysis of the EP, and evaluation of the density and distribution of AChR on the junctional folds.
• Electrophysiologic assessment, consisting of conventional microelectrode studies of EP potentials and currents, estimates of parameters of quantal release, and evaluation of AChR channel kinetics through single channel patch-clamp recordings.
• Mutation analysis when the preceding studies point to an EP-specific protein.
• Expression studies using genetically engineered mutants.

The CMS studies are important for diagnosis and prevention of the CMS, for investigating disease pathophysiology, for developing strategies for therapy, and for gaining insights into structure-function relationships of EP-specific proteins.

Collaborative studies are ongoing with Steven Sine at Mayo on the kinetic analysis of mutaions involving AChR.

Myofibrillar and related congenital myopathies. The myofibrillar myopathies (MFMs) have a characteristic morphological signature: at the light microscopic and immunocytochemical level they are associated with progressive myofibrillar destruction and the deposition of composite protein aggregates that immunoreact for desmin, alphaB-crystallin, myotilin, dystrophin, CDC2 kinase, prion proteins, and other proteins as well. At the ultrastructural level, the myofibrillar degeneration begins at the Z-disk. The elemental change is like that observed in minimulticore disease. The ultrastructural findings provide a clue that the MFMs are caused by mutations in Z-disk related proteins. The investigation tests the hypothesis that mutations in Z-disk related proteins cause MFM and that appropriate expression studies can provide insights into the pathogenesis of the disease. Sofar mutations in desmin, alphaB-crystallin and in another key Z-disk-associated structural protein have been detected in the MFM patients.