Abstract
<title>Abstract</title> <p> <bold>Background</bold> : Dipeptidyl-peptidase-like protein-6 (DPPX/DPP6) autoimmunity is classically associated with central and enteric hyperexcitability, whereas acquired neuromyotonia (Isaacs syndrome) is a peripheral nerve hyperexcitability (PNH) disorder most often linked to CASPR2 but may be seronegative. Objective peripheral nerve abnormalities have only occasionally been documented in anti-DPPX-associated disease. <bold>Case presentation</bold> : A 34-year-old man had a 6-year peripheral-predominant course of lower-limb weakness, muscle twitching, hyperhidrosis, distal numbness, gluteal pain, and squatting difficulty, leading to an outside diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy. He later developed exaggerated startle, marked tension, tongue fasciculations, and one paroxysmal generalized tonic-stiffening episode during corticosteroid tapering. Electrophysiology confirmed PNH with fasciculation potentials and triplet discharges. Serum DPPX-IgG was positive at 1:10 by cell-based assay (CBA), whereas cerebrospinal fluid DPPX-IgG, CASPR2, and LGI1 antibodies were negative; VGKC-complex testing was negative on two occasions. Tongue fasciculations disappeared after corticosteroid treatment. At 3 months, repeat serum DPPX-IgG by CBA was negative while residual electrophysiological PNH persisted. A later low-titer P/Q-type VGCC-IgG result was interpreted as associated serology because high-frequency stimulation did not support Lambert-Eaton myasthenic syndrome. <bold>Conclusions</bold> : The combined central hyperexcitability features and electrophysiologically confirmed acquired neuromyotonia suggest a DPPX-IgG-associated CNS-PNS hyperexcitability overlap phenotype with predominant peripheral involvement. Previous reports of demyelinating sensorimotor polyneuropathy, active denervation, mixed axonal/demyelinating changes, and a DPPX/CASPR2 double-positive neuromyotonia phenotype support possible peripheral involvement, but direct pathogenicity of DPPX-IgG in peripheral motor axons remains unproven. </p>