Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome

Ricardo A Maselli, J. J. Ng, J. A. Anderson, O. Cagney, J. Arredondo, C. Williams, H. B. Wessel, H. Abdel-Hamid, R. L. Wollmann

Research output: Contribution to journalArticle

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Abstract

Background: We describe a severe form of congenital myasthenic syndrome (CMS) associated with congenital nephrosis and ocular malformations caused by two truncating mutations in the gene encoding the laminin β2 subunit (LAMB2). Methods and results: Mutational analysis in the affected patient, who has a history of a serious untoward reaction to treatment with acetylcholinesterase inhibition, revealed two frame-shifting heteroallelic mutations, a maternally inherited 1478delG and a paternally inherited 4804delC. An anconeus muscle biopsy demonstrated a profound distortion of the architecture and function of the neuromuscular junction, which was strikingly similar to that seen in mice lacking laminin β2 subunit. The findings included: pronounced reduction of the axon terminal size with encasement of the nerve endings by Schwann cells, severe widening of the primary synaptic cleft and invasion of the synaptic space by the processes of Schwann cells, and moderate simplification of postsynaptic folds and intact expression of the endplate acetylcholinesterase. The endplate potential quantal content was notably reduced, while the frequencies and amplitudes of miniature endplate potentials were only moderately diminished and the decay phases of miniature endplate potentials were normal. Western blot analysis of muscle and kidney tissue and immunohistochemistry of kidney tissue showed no laminin β2 expression. Conclusion: This case, which represents a new type of synaptic CMS, exemplifies the wide variability of phenotypes associated with LAMB2 mutations and underscores the fundamental role that laminin β2 plays in the development of the human neuromuscular junction.

Original languageEnglish (US)
Pages (from-to)203-208
Number of pages6
JournalJournal of Medical Genetics
Volume46
Issue number3
DOIs
StatePublished - Mar 2009

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Congenital Myasthenic Syndromes
Laminin
Mutation
Neuromuscular Junction
Schwann Cells
Acetylcholinesterase
Kidney
Muscles
Nerve Endings
Presynaptic Terminals
Human Development
Western Blotting
Immunohistochemistry
Phenotype
Biopsy
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Maselli, R. A., Ng, J. J., Anderson, J. A., Cagney, O., Arredondo, J., Williams, C., ... Wollmann, R. L. (2009). Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. Journal of Medical Genetics, 46(3), 203-208. https://doi.org/10.1136/jmg.2008.063693

Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. / Maselli, Ricardo A; Ng, J. J.; Anderson, J. A.; Cagney, O.; Arredondo, J.; Williams, C.; Wessel, H. B.; Abdel-Hamid, H.; Wollmann, R. L.

In: Journal of Medical Genetics, Vol. 46, No. 3, 03.2009, p. 203-208.

Research output: Contribution to journalArticle

Maselli, RA, Ng, JJ, Anderson, JA, Cagney, O, Arredondo, J, Williams, C, Wessel, HB, Abdel-Hamid, H & Wollmann, RL 2009, 'Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome', Journal of Medical Genetics, vol. 46, no. 3, pp. 203-208. https://doi.org/10.1136/jmg.2008.063693
Maselli, Ricardo A ; Ng, J. J. ; Anderson, J. A. ; Cagney, O. ; Arredondo, J. ; Williams, C. ; Wessel, H. B. ; Abdel-Hamid, H. ; Wollmann, R. L. / Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. In: Journal of Medical Genetics. 2009 ; Vol. 46, No. 3. pp. 203-208.
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