GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity

Neurology. 2013 Jul 23;81(4):370-8. doi: 10.1212/WNL.0b013e31829c5e9c. Epub 2013 Jun 21.


Objective: To identify patients with GFPT1-related limb-girdle myasthenia and analyze phenotypic consequences of the mutations.

Methods: We performed genetic analysis, histochemical, immunoblot, and ultrastructural studies and in vitro electrophysiologic analysis of neuromuscular transmission.

Results: We identified 16 recessive mutations in GFPT1 in 11 patients, of which 12 are novel. Ten patients had slowly progressive limb-girdle weakness responsive to cholinergic agonists with onset between infancy and age 19 years. One patient (no. 6) harbored a nonsense mutation and a second mutation that disrupts the muscle-specific GFPT1 exon. This patient never moved in utero, was apneic and arthrogrypotic at birth, and was bedfast, tube-fed, and barely responded to therapy at age 6 years. Histochemical studies in 9 of 11 patients showed tubular aggregates in 6 and rimmed vacuoles in 3. Microelectrode studies of intercostal muscle endplates in 5 patients indicated reduced synaptic response to acetylcholine in 3 and severely reduced quantal release in patient 6. Endplate acetylcholine receptor content was moderately reduced in only one patient. The synaptic contacts were small and single or grape-like, and quantitative electron microscopy revealed hypoplastic endplate regions. Numerous muscle fibers of patient 6 contained myriad dilated and degenerate vesicular profiles, autophagic vacuoles, and bizarre apoptotic nuclei. Glycoprotein expression in muscle was absent in patient 6 and reduced in 5 others.

Conclusions: GFPT1-myasthenia is more heterogeneous than previously reported. Different parameters of neuromuscular transmission are variably affected. When disruption of muscle-specific isoform determines the phenotype, this has devastating clinical, pathologic, and biochemical consequences.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Acetylcholinesterase / metabolism
  • Action Potentials / physiology*
  • Adolescent
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • Genotype
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / genetics*
  • Humans
  • In Vitro Techniques
  • Infant
  • Male
  • Microscopy, Electron, Transmission
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Muscle, Skeletal / ultrastructure
  • Mutation / genetics
  • Myasthenia Gravis / drug therapy
  • Myasthenia Gravis / genetics*
  • Myasthenia Gravis / pathology*
  • Myasthenia Gravis / physiopathology*
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / genetics
  • Neuromuscular Junction / ultrastructure
  • Pyridostigmine Bromide / pharmacology
  • Pyridostigmine Bromide / therapeutic use
  • Receptors, Cholinergic / metabolism
  • Receptors, Cholinergic / ultrastructure
  • Sarcoplasmic Reticulum / pathology
  • Young Adult


  • Receptors, Cholinergic
  • GFPT1 protein, human
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
  • Acetylcholinesterase
  • Pyridostigmine Bromide
  • Acetylcholine