DOI: 10.1002/ana.78358 ISSN: 0364-5134

Biallelic PIGB Variants Cause Motor Neuropathy with Conduction Blocks and Peripheral Nerve Hyperexcitability

Gorka Fernández‐Eulate, Romain Duval, Marina Konyukh, Alessandro Bertini, Ayse Candayan, Albena Jordanova, Theresa Brunet, Wolfgang Müller‐Felber, Helena F. Pernice, Katrin Hahn, Nadja Ehmke, Juliane Beuschlein, Bertrand Isidor, Benjamin Cogné, Yann Péréon, Annabelle Chaussenot, John Rendu, Aysylu Murtazina, Dmitrii Subbotin, Artem Borovikov, Andrey Marakhonov, Chiara Pisciotta, Paola Saveri, Daniele Cazzato, Lucie Lemeray, Bérengère Koehl, Jean‐Madeleine de Sainte‐Agathe, Stefano Facchini, Ilaria Quartesan, Andrea Cortese, Yesim Parman, Arman Cakar, Davide Pareyson, Slim Azouzi, Tanya Stojkovic
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Objective

Glycosylphosphatidylinositol ( GPI )‐anchored proteins play critical roles in nervous system function. Pathogenic variants in genes involved in GPI ‐anchor biosynthesis cause early‐onset multisystem disorders known as inherited GPI deficiencies. We describe a novel neuromuscular phenotype associated with PIGB deficiency.

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

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