Biallelic PIGB Variants Cause Motor Neuropathy with Conduction Blocks and Peripheral Nerve Hyperexcitability.
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Fernández-Eulate Gorka, Duval Romain, Konyukh Marina, Bertini Alessandro, Candayan Ayse, Jordanova Albena, Brunet Theresa, Müller-Felber Wolfgang, Pernice Helena F, Hahn Katrin, Ehmke Nadja, Beuschlein Juliane, Isidor Bertrand, Cogné Benjamin, Péréon Yann, Chaussenot Annabelle, Rendu John, Murtazina Aysylu, Subbotin Dmitrii, Borovikov Artem, Marakhonov Andrey, Pisciotta Chiara, Saveri Paola, Cazzato Daniele, Lemeray Lucie, Koehl Bérengère, de Sainte-Agathe Jean-Madeleine, Facchini Stefano, Quartesan Ilaria, Cortese Andrea, Parman Yesim, Cakar Arman, Pareyson Davide, Azouzi Slim, Stojkovic Tanya
Аннотация
METHODS: Patients with neuromuscular disease carrying PIGB variants were identified, and clinical data collected. GPI-anchored protein and free-GPI expression were assessed by flow cytometry and variants validated in a PIGB knockout cellular model.
RESULTS: Biallelic PIGB variants were identified in 12 patients (median age 32 years, range 15-52 years) from 9 independent families. Of 15 variants, 13 were novel, including a de novo inversion generating a PIGB::RAB27A gene fusion. Of 12 patients, 10 presented with distal lower-limb weakness, and neurophysiological studies demonstrated a motor-predominant neuropathy with frequent conduction blocks in all patients. Signs of nerve hyperexcitability were observed in 9 patients, with electromyography neuromyotonic discharges and myokymia compatible with peripheral nerve hyperexcitability in 6. A total of 3 patients showed a decremental response on repetitive nerve stimulation; 2 were symptomatic and responded to pyridostigmine, consistent with neuromuscular junction transmission defect. Neurodevelopmental features were inconsistent. Flow cytometry revealed variable reductions of GPI-anchored proteins, but consistent reduction of free GPI in blood cells. Novel variants impaired GPI-anchor expression in vitro.
INTERPRETATION: We expand the phenotypic spectrum of inherited GPI deficiencies with a novel neuromuscular syndrome encompassing motor neuropathy with conduction blocks, peripheral nerve hyperexcitability, and occasional neuromuscular junction defects associated with PIGB variants. PIGB and other GPI-anchor biosynthesis genes should be considered in motor neuropathy with conduction blocks. ANN NEUROL 2026.