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