Neuromuscular hyperexcitability syndromes

To provide an update on recent developments regarding acquired, antibody-mediated, neuromuscular hyperexcitability syndromes, including Isaac's and Morvan's syndromes, cramp-fasciculation syndrome and rippling muscle disease, and their genetic differential diagnoses.

Antibodies in auto-immune peripheral nerve hyperexcitability syndromes (PNHS) are directed against CASPR2 and LGI1, proteins of the voltage-gated potassium channel (VGKC) complex. We discuss the significance of 'double-negative' VGKC antibodies in PNHS and the rationale for ceasing VGKC antibody testing (but testing CASPR2 and LGI1 antibodies instead) in clinical practice. Recent case reports also expand the possible clinical phenotypes related to CASPR2/LGI1 antibodies, but the interpretation of these findings is complicated by the frequent association of antibody-mediated neuromuscular hyperexcitability syndromes with other auto-immune disorders (e.g. myasthenia gravis).Finally, a hereditary origin of neuromuscular hyperexcitability should always be considered, even in non-VGKC-related genes, as evidenced by the recently discovered high frequency of HINT1 mutations in people of Slavic origin.

This review provides an update on recent clinical, immunological and genetic developments in neuromuscular hyperexcitability syndromes. We also provide a guide for the clinician for diagnosing and managing these disorders in clinical practice, with a special focus on the main differential diagnoses.