Biallelic PIGB Variants Cause Motor Neuropathy with Conduction Blocks and Peripheral Nerve Hyperexcitability
Annals of Neurology, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Basım Tarihi: 2026
- Doi Numarası: 10.1002/ana.78358
- Dergi Adı: Annals of Neurology
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CINAHL, EMBASE, MEDLINE, Psycinfo, Academic Search Ultimate (EBSCO), Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Biomedical Reference Collection: Corporate Edition (EBSCO), Health Research Premium Collection (ProQuest)
- İstanbul Üniversitesi Adresli: Evet
Özet
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.