TY - JOUR
T1 - GFPT1-myasthenia
T2 - Clinical, structural, and electrophysiologic heterogeneity
AU - Selcen, Duygu
AU - Shen, Xin Ming
AU - Milone, Margherita
AU - Brengman, Joan
AU - Ohno, Kinji
AU - Deymeer, Feza
AU - Finkel, Richard
AU - Rowin, Julie
AU - Engel, Andrew G.
PY - 2013/7/23
Y1 - 2013/7/23
N2 - 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 musclespecific isoformdetermines the phenotype, this has devastating clinical, pathologic, and biochemical consequences.
AB - 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 musclespecific isoformdetermines the phenotype, this has devastating clinical, pathologic, and biochemical consequences.
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U2 - 10.1212/WNL.0b013e31829c5e9c
DO - 10.1212/WNL.0b013e31829c5e9c
M3 - Article
C2 - 23794683
AN - SCOPUS:84881282393
SN - 0028-3878
VL - 81
SP - 370
EP - 378
JO - Neurology
JF - Neurology
IS - 4
ER -