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

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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Journal
Annals of Neurology
Published
2026-09-30
DOI
https://doi.org/10.1002/ana.78358
Primary Topic
Trypanosoma species research and implications
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Biallelic PIGB Variants Cause Motor Neuropathy with Conduction Blocks and Peripheral Nerve Hyperexcitability

Arman Çakar, Bérengère Koehl, Alessandro Bertini, Theresa Brunet et al.
Annals of Neurology
Trypanosoma species research and implications
article

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

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

Abstract

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.

Annals of Neurology
Centre National de la Recherche Scientifique (FR), University of Antwerp (BE), Inserm (FR), University of Milan (IT), Université Paris-Est Créteil (FR), Université Paris Cité (FR), Medical University of Sofia (BG), Sorbonne Université (FR), Institut de Myologie (FR), Hôpital l'Archet (FR), Institute of Human Genetics (PL), Pitié-Salpêtrière Hospital (FR), Research Centre for Medical Genetics (RU), Hôpitaux Universitaires Henri-Mondor (FR), VIB-UAntwerp Center for Molecular Neurology (BE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Institut du Thorax (FR), Grenoble Institute of Neurosciences (FR), Génétique Médicale & Génomique Fonctionelle (FR), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), UCL Queen Square Institute of Neurology (GB), University College London (GB), Istanbul University (TR), Charité - Universitätsmedizin Berlin (DE), Ludwig-Maximilians-Universität München (DE), Nantes Université (FR)
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Openalex Percentile: Top 11%
Trypanosoma species research and implications
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