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Case Reports
. 2009 Mar;46(3):203-8.
doi: 10.1136/jmg.2008.063693.

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

R A Maselli  1 , J J Ng, J A Anderson, O Cagney, J Arredondo, C Williams, H B Wessel, H Abdel-Hamid, R L Wollmann
Affiliations
Case Reports

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

R A Maselli et al. J Med Genet. 2009 Mar.

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 beta2 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 beta2 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 beta2 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 beta2 plays in the development of the human neuromuscular junction.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1. Ultrastructural findings at the neuromuscular junction (NMJ). Control (A) and the patient (B–F). (A) Normal NMJ from a control demonstrating normal nerve terminal size and highly complex postsynaptic membrane folding with well formed secondary synaptic clefts. The arrow heads point to Schwann cell processes, which cap the nerve terminal (N), without extending into the synaptic cleft. The arrows point to the primary synaptic cleft (top) and at a secondary synaptic cleft (bottom). The asterisk in A–C is placed over the Schwann cell. (B) Small nerve terminal partially encased by a Schwann cell process, which intrudes into the synaptic space. (C) Small nerve terminal retracted from the synaptic space and completely engulfed by the Schwann cell. Note also pronounced simplification of the postsynaptic membrane (arrow). (D) Bifurcated nerve terminal with one nerve ending completely engulfed (top arrowhead) and the other ending partially encased (bottom arrowhead) by the Schwann cell. Note also pronounced widening of the primary synaptic cleft and reduction of the density of synaptic vesicles in the nerve terminal. (E) Nerve terminal divided in three small endings, which are encased by the Schwann cell and retracted from the postsynaptic membrane. (F) Pronounced reduction of the area of apposition between the nerve terminal and the postsynaptic membrane, widening of primary synaptic cleft and invasion of the synaptic space by Schwann cell processes (horizontal arrowheads). The vertical arrowheads point to two active zones, which in contrast to the control, are not apposing postsynaptic secondary clefts. (G) and (H) Quantification of the area of apposition between the nerve and muscle. (G) Bar graph representing the average length of apposition between nerve and muscle in 11 controls and 11 patient endplates. (H) Percentages of direct nerve–muscle apposition relative to the total length of the synaptic cleft in 24 controls and 11 patient endplates (mean (SEM)). Calibration marks (A–F) represent 1 μm.
Figure 2
Figure 2. Mutational analysis findings. (A) Schematic view of the 32 coding regions of human LAMB2 showing the positions of the identified mutations in exons 11 and 29. White regions correspond to untranslated portions of the gene. The 100 bp marker corresponds to exons and introns. (B) Pedigree of the family and the electropherograms displaying the heterozygous frameshifting 1478delG and 4804delC mutations in the patient, the heterozygous 1478delG mutations and a normal sequence or wild type (WT) in the non-affected mother, and the heterozygous 4804delC mutation and a WT sequence in the non-affected father and brother. The arrows point to the nucleotide deletions.
Figure 3
Figure 3. Western blot analysis. Results of a Western blot using a rabbit polyclonal antibody directed against an epitope corresponding to amino acids 1549–1798 of human laminin β2 (Santa Cruz Biotechnology, Santa Cruz, California, USA) and frozen tissue from renal and muscle biopsies of the patient. There is no laminin β2 expression in muscle and renal tissues from the patient.
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