Biallelic PIGB Variants Cause Motor Neuropathy with Conduction Blocks and Peripheral Nerve Hyperexcitability
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.
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BibTeX
@article{fernandezeulate2026biallelic,
title = {{Biallelic PIGB Variants Cause Motor Neuropathy with Conduction Blocks and Peripheral Nerve Hyperexcitability}},
author = {Gorka Fernández-Eulate and Romain Duval and Marina Konyukh and Alessandro Bertini and Ayse Candayan and Albena Jordanova and Theresa Brunet and Wolfgang Müller-Felber and Helena Pernice and Katrin Hahn and Nadja Ehmke and Juliane Beuschlein and Bertrand Isidor and Benjamin Cogné and Yann Péréon and Annabelle Chaussenot and John Rendu and Aysylu Murtazina and Dmitrii Subbotin and Artem Borovikov and Andrey Marakhonov and Chiara Pisciotta and Paola Saveri and Daniele Cazzato and Lucie Lemeray and Bérengère Koehl and Jean‐madeleine de Sainte-Agathe and Stefano Facchini and Ilaria Quartesan and Andrea Cortese and Yesim Parman and Arman Cakar and Davide Pareyson and Slim Azouzi and Tanya Stojkovic},
journal = {Annals of Neurology},
year = {2026},
month = sep,
doi = {10.1002/ana.78358},
url = {https://hal.science/hal-05786132v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Biallelic PIGB Variants Cause Motor Neuropathy with Conduction Blocks and Peripheral Nerve Hyperexcitability
AU - Gorka Fernández-Eulate
AU - Romain Duval
AU - Marina Konyukh
AU - Alessandro Bertini
AU - Ayse Candayan
AU - Albena Jordanova
AU - Theresa Brunet
AU - Wolfgang Müller-Felber
AU - Helena Pernice
AU - Katrin Hahn
AU - Nadja Ehmke
AU - Juliane Beuschlein
AU - Bertrand Isidor
AU - Benjamin Cogné
AU - Yann Péréon
AU - Annabelle Chaussenot
AU - John Rendu
AU - Aysylu Murtazina
AU - Dmitrii Subbotin
AU - Artem Borovikov
AU - Andrey Marakhonov
AU - Chiara Pisciotta
AU - Paola Saveri
AU - Daniele Cazzato
AU - Lucie Lemeray
AU - Bérengère Koehl
AU - Jean‐madeleine de Sainte-Agathe
AU - Stefano Facchini
AU - Ilaria Quartesan
AU - Andrea Cortese
AU - Yesim Parman
AU - Arman Cakar
AU - Davide Pareyson
AU - Slim Azouzi
AU - Tanya Stojkovic
PY - 2026
DA - 2026/09/30
JO - Annals of Neurology
DO - 10.1002/ana.78358
UR - https://hal.science/hal-05786132v1
AB - 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.
SN - 0364-5134
SN - 1531-8249
ER -