Dataset Information

GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity.

ABSTRACT:

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.

SUBMITTER: Selcen D

PROVIDER: S-EPMC3772836 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity.

Selcen Duygu D Shen Xin-Ming XM Milone Margherita M Brengman Joan J Ohno Kinji K Deymeer Feza F Finkel Richard R Rowin Julie J Engel Andrew G AG

Neurology 20130621 4

<h4>Objective</h4>To identify patients with GFPT1-related limb-girdle myasthenia and analyze phenotypic consequences of the mutations.<h4>Methods</h4>We performed genetic analysis, histochemical, immunoblot, and ultrastructural studies and in vitro electrophysiologic analysis of neuromuscular transmission.<h4>Results</h4>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 ...[more]

PMID: 23794683

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Dataset Information

GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity.

Objective

Methods

Results

Conclusions

Publications

GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity.

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