GFPT1-myasthenia: Clinical, structural, and electrophysiologic heterogeneity
| Autor: | Kinji Ohno, Duygu Selcen, Joan M. Brengman, Xin Ming Shen, Richard S. Finkel, Andrew G. Engel, Feza Deymeer, Julie Rowin, Margherita Milone |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_specialty Adolescent Genotype Nonsense mutation DNA Mutational Analysis Neuromuscular transmission Neuromuscular Junction Action Potentials Biology In Vitro Techniques Neuromuscular junction Article chemistry.chemical_compound Young Adult Microscopy Electron Transmission Internal medicine Myasthenia Gravis medicine Humans Receptors Cholinergic Child Muscle Skeletal Acetylcholine receptor Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) Infant medicine.disease Acetylcholinesterase Myasthenia gravis Acetylcholine Sarcoplasmic Reticulum Endocrinology medicine.anatomical_structure chemistry Child Preschool Mutation Cholinergic Female Neurology (clinical) medicine.drug Pyridostigmine Bromide |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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