A presynaptic congenital myasthenic syndrome attributed to a homozygous sequence variant in LAMA5

Ricardo A Maselli, Juan Arredondo, Jessica Vázquez, Jessica X. Chong, Michael J. Bamshad, Deborah A. Nickerson, Marian Lara, Fiona Ng, Victoria Lee Lo, Peter Pytel, Craig M McDonald

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

We report a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin α5 subunit gene (LAMA5). The variant c.8046C > T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had normal cognitive function, but magnetic resonance brain imaging showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation at 2 Hz showed 50% decrement of compound muscle action potential amplitudes but 250% facilitation immediately after exercise, similar to that seen in Lambert-Eaton myasthenic syndrome. Endplate studies demonstrated a profound reduction of the endplate potential quantal content but normal amplitudes of miniature endplate potentials. Electron microscopy showed endplates with increased postsynaptic folding that were denuded or only partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin α5 to SV2A and impaired laminin-521 cell adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding α-laminins.

Original languageEnglish (US)
JournalAnnals of the New York Academy of Sciences
DOIs
StateAccepted/In press - Jan 1 2018

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Congenital Myasthenic Syndromes
Laminin
Lambert-Eaton Myasthenic Syndrome
Defects
Gene encoding
Cell adhesion
Magnetic resonance
Cell Adhesion
Neuroimaging
Cognition
Electron microscopy
Genes
Action Potentials
Muscle
Brain
Electron Microscopy
Magnetic Resonance Imaging
Exercise
Phenotype
Imaging techniques

Keywords

  • Congenital myasthenic syndrome (CMS)
  • LAMA5
  • Laminin α5
  • Presynaptic

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

A presynaptic congenital myasthenic syndrome attributed to a homozygous sequence variant in LAMA5. / Maselli, Ricardo A; Arredondo, Juan; Vázquez, Jessica; Chong, Jessica X.; Bamshad, Michael J.; Nickerson, Deborah A.; Lara, Marian; Ng, Fiona; Lo, Victoria Lee; Pytel, Peter; McDonald, Craig M.

In: Annals of the New York Academy of Sciences, 01.01.2018.

Research output: Contribution to journalArticle

Maselli, Ricardo A ; Arredondo, Juan ; Vázquez, Jessica ; Chong, Jessica X. ; Bamshad, Michael J. ; Nickerson, Deborah A. ; Lara, Marian ; Ng, Fiona ; Lo, Victoria Lee ; Pytel, Peter ; McDonald, Craig M. / A presynaptic congenital myasthenic syndrome attributed to a homozygous sequence variant in LAMA5. In: Annals of the New York Academy of Sciences. 2018.
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abstract = "We report a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin α5 subunit gene (LAMA5). The variant c.8046C > T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had normal cognitive function, but magnetic resonance brain imaging showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation at 2 Hz showed 50{\%} decrement of compound muscle action potential amplitudes but 250{\%} facilitation immediately after exercise, similar to that seen in Lambert-Eaton myasthenic syndrome. Endplate studies demonstrated a profound reduction of the endplate potential quantal content but normal amplitudes of miniature endplate potentials. Electron microscopy showed endplates with increased postsynaptic folding that were denuded or only partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin α5 to SV2A and impaired laminin-521 cell adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding α-laminins.",
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AU - Nickerson, Deborah A.

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