IGHMBP2 mutation associated with organ-specific autonomic dysfunction

Pedro J Tomaselli, Alejandro Horga, Alexander M Rossor, Zane Jaunmuktane, Andrea Cortese, Julian C Blake, Natalia Zarate-Lopez, Henry Houlden, Mary M Reilly, Pedro J Tomaselli, Alejandro Horga, Alexander M Rossor, Zane Jaunmuktane, Andrea Cortese, Julian C Blake, Natalia Zarate-Lopez, Henry Houlden, Mary M Reilly

Abstract

Biallelic mutations in the IGHMBP2 have been associated with two distinct phenotypes: spinal muscular atrophy with respiratory distress type 1 (SMARD1) and CMT2S. We describe a patient who developed progressive muscle weakness and wasting in her upper and lower limbs from infancy. She developed respiratory involvement at age 9, eventually requiring 24-h non-invasive ventilation, and severe autonomic dysfunction restricted to the gastrointestinal tract. Neurophysiological studies at age 27 years revealed absent sensory and motor responses and severe chronic denervation changes in proximal muscles of the upper limbs. Targeted multigene panel sequencing detected a novel homozygous missense variant in the IGHMBP2 gene (c.1325A > G; p.Tyr442Cys). This variant was validated by Sanger sequencing and co-segregation analysis confirmed that both parents were asymptomatic heterozygous carriers. This case report confirms that IGHMBP2 related disorders can result in a severe peripheral neuropathy with gastrointestinal autonomic dysfunction requiring parenteral nutrition.

Keywords: CMT; IGHMBP2 gene; Next generation sequencing; SMARD1; Target multigene panel.

Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Clinical images of the proband. Photographs of the patient's legs, arms and trunk show severe wasting distally and proximally in upper and lower limbs and severe kyphoscoliosis.
Fig. 2
Fig. 2
Sural nerve biopsy. Semi-thin resin sections from the patient's sural nerve (A) and age-matched control (B), stained with methylene blue azure basic fuchsin (MBA-BF). The nerve fascicles in the patient's biopsy in comparison with the control were of very small size. Image A shows reduced fibre density, small fibre size and complete absence of large normally myelinated fibres across the fascicles. There was no evidence of active axonal degeneration or signs of demyelinating and remyelinating process.There were occasional clusters of regeneration (A, arrow). Scale bar (A and B): 25 μm.

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Source: PubMed

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