Novel MTMR2 mutation causing severe Charcot-Marie-Tooth type 4B1 disease: a case report
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Novel MTMR2 mutation causing severe Charcot-Marie-Tooth type 4B1 disease: a case report Daniel Halperin 1 & Aviad Sapir 1 & Ohad Wormser 1 & Max Drabkin 1 & Yuval Yogev 1 & Vadim Dolgin 1 & Hagit Flusser 2 & Ohad S. Birk 1,3 Received: 31 March 2020 / Accepted: 16 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Mutations in myotubularin-related protein 2 (MTMR2) were shown to underlie Charcot-Marie-Tooth type 4B1 (CMT4B1) disease, a rare autosomal recessive demyelinating neuropathy, characterized by severe early-onset motor and sensory neuropathy. We describe three siblings of consanguineous kindred presenting with hypotonia, reduced muscle tone, action tremor, dysmetria, areflexia, and skeletal deformities, consistent with a diagnosis of CMT. Whole-exome sequencing identified a novel homozygous c.336_337 insertion mutation in MTMR2, resulting in a frameshift and putative truncated protein. In this concise report, we discuss the clinical presentation of this rare disease and support the limited number of observations regarding the pathogenesis of MTMR2-related neuropathies. Keywords MTMR2 . Charcot-Marie-Tooth type 4B1 . Hereditary neuropathy
Introduction Charcot-Marie-Tooth (CMT) disease is one of the most common hereditary peripheral neuropathies characterized by progressive degeneration of muscles in the extremities, decreased motor and sensory function, and pes cavus [1]. It is a phenotypically and genetically heterogeneous group of disorders classically subdivided into axonal or demyelinating forms based on underlying molecular pathology and electrophysiological studies [2]. CMT4, a rare autosomal recessive type of CMT, encompasses a group of progressive sensory-motor axonal and demyelinating neuropathies distinguished from other forms of CMT, with patients presenting with slow nerve conduction velocities (NCVs), distal muscle atrophy, and sensory
loss. Several CMT4 subtypes have been described, including three forms associated with genes of the myotubularin-related protein (MTMR) family: CMT4B1 (MTMR2, OMIM *603557), CMT4B2 (MTMR13/SBF2, OMIM *607697), and CMT4B3 (MTMR5/SBF1, OMIM *603560) [3]. To date, only a limited number of families with MTMR2 mutations have been described. Through whole-exome sequencing (WES), we identified a novel homozygous insertion mutation in MTMR2, resulting in a frameshift and putative aberrant protein, culminating in severe CMT4B1 phenotype with unique findings. In this concise report, we discuss the clinical presentation of this rare disease and support the limited number of observations regarding the pathogenesis of MTMR2related neuropathies.
* Ohad S. Birk [email protected]
Materials and methods
1
The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
2
Zusman Child Development Center, Division of Pediatrics, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Isra
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