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A novel mutation in LRSAM1 causes axonal Charcot-Marie-Tooth disease with dominant inheritance

Maik Engeholm12*, Julia Sekler12, David C Schöndorf123, Vineet Arora123, Jens Schittenhelm4, Saskia Biskup15, Caroline Schell1 and Thomas Gasser12

Author Affiliations

1 Department of Neurology and Hertie Institute for Clinical Brain Research, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany

2 German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 27, 72076 Tübingen, Germany

3 Graduate School of Cellular & Molecular Neuroscience, Österbegstr. 3, 72074 Tübingen, Germany

4 Division of Neuropathology, Calwerstr. 3, 72076 Tübingen, Germany

5 CeGaT GmbH, Paul-Ehrlich-Str. 17, 72076 Tübingen, Germany

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BMC Neurology 2014, 14:118  doi:10.1186/1471-2377-14-118

Published: 3 June 2014



Charcot-Marie-Tooth disease (CMT) refers to a heterogeneous group of genetic motor and sensory neuropathies. According to the primary site of damage, a distinction is made between demyelinating and axonal forms (CMT1 and 2, respectively, when inherited as an autosomal dominant trait). Leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) is a ubiquitin-protein ligase with a role in sorting internalised cell-surface receptor proteins. So far, mutations in the LRSAM1 gene have been shown to cause axonal CMT in three different families and can confer either dominant or recessive transmission of the disease.

Case presentation

We have identified a novel mutation in LRSAM1 in a small family with dominant axonal CMT. Electrophysiological studies show evidence of a sensory axonal neuropathy and are interesting in so far as giant motor unit action potentials (MUAPs) are present on needle electromyography (EMG), while motor nerve conduction studies including compound motor action potential (CMAP) amplitudes are completely normal. The underlying mutation c.2046+1G >T results in the loss of a splice donor site and the inclusion of 63 additional base pairs of intronic DNA into the aberrantly spliced transcript. This disrupts the catalytically active RING (Really Interesting New Gene) domain of LRSAM1.


Our findings suggest that, beyond the typical length-dependent degeneration of motor axons, damage of cell bodies in the anterior horn might play a role in LRSAM1-associated neuropathies. Moreover, in conjunction with other data in the literature, our results support a model, by which disruption of the C-terminal RING domain confers dominant negative properties to LRSAM1.

Axonal CMT; LRSAM1; Anterior horn cell disease; Splice site mutation; RING domain; Exome sequencing