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NEFL E396K mutation is associated with a novel dominant intermediate Charcot–Marie–Tooth disease phenotype

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Abstract

The purpose of the study was to describe a pedigree with NEFL E396K mutation associated with a novel dominant intermediate Charcot–Marie–Tooth disease (DI-CMT) phenotype. The pedigree comprised four patients over two generations, aged between 35 and 59 years, who have been serially evaluated since 1993. Their clinical picture was characterized by pes cavus, sensorimotor neuropathy and spastic gait. Both older patients showed ascending leg weakness to involve pelvic musculature. CMT neuropathy score ranged from 14 to 26 (moderate to severe disease). Electrophysiology showed uniform nerve conduction slowing in the intermediate range, both in distal and proximal nerve segments. Multimodal evoked potential and blink reflex studies revealed abnormalities indicative of central sensorimotor pathway dysfunction. On imaging studies of lower-limb musculature, there was massive atrophy of intrinsic foot muscles and to a lesser degree of calves and thighs predominating in muscles innervated by tibial and sciatic nerves. In both patients exhibiting waddling gait, there was atrophy of pelvic muscles mainly involving gluteus medius, gluteus minimus and piriformis. We conclude that NEFL E396K mutation may manifest with a novel DI-CMT phenotype, characterized by simultaneous involvement of the peripheral and central nervous system.

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Acknowledgments

We thank our patients for their collaboration, without which this study would not have been possible. The study was supported by Research Institute of University Hospital “Marqués de Valdecilla” (IDIVAL) Grants BFR 05/10 and WLA 03/12. The Antwerp team was funded in part by the University of Antwerp (TOP BOF 29069); the Fund for Scientific Research-Flanders (FWO) and the Belgian Association against Neuromuscular Disorders (ABMM). KP is supported by a PhD fellowship from the Fund for Scientific Research-Flanders (FWO).

Conflicts of interest

We declare no conflicts of interest.

Ethical standard

Ethical approval was obtained and all patients and at-risk subjects, and control subjects gave informed consent for this study. This investigation was approved by the “Comité Ético de Investigación Clínica de Cantabria”.

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Authors and Affiliations

  1. Service of Neurology, University Hospital “Marqués de Valdecilla (IDIVAL)”, University of Cantabria (UC) and “Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)”, Santander, Spain

    José Berciano, Ana L. Pelayo-Negro & Jon Infante

  2. Service of Clinical Neurophysiology, University Hospital “Marqués de Valdecilla (IDIVAL)”, UC and CIBERNED, Santander, Spain

    Antonio García

  3. Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium

    Kristien Peeters, Els De Vriendt & Albena Jordanova

  4. Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

    Kristien Peeters, Els De Vriendt & Albena Jordanova

  5. Service of Radiology, University Hospital “Marqués de Valdecilla (IDIVAL)”, UC and CIBERNED, Santander, Spain

    Elena Gallardo

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  1. José Berciano
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  2. Antonio García
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  3. Kristien Peeters
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  4. Elena Gallardo
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Corresponding author

Correspondence to José Berciano.

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415_2015_7709_MOESM1_ESM.mpg

Supplementary material, video 1. This video illustrates serial clinical signs in patient III-1 (the proband). Segment 1: In 2004 (at age 29), there was lower-leg wasting slightly more marked on the left side. Note normal appearance of both thighs. Segment 2: Ten years later note progression of lower-leg amyotrophy. Segment 3: Gait in 2004 was stepping, waddling and spastic; tiptoe walking was difficult and heel walking almost impossible. Segment 4: Ten years later, there was marked progression of gait abnormalities. Segment 5: Mild hand amyotrophy with wasting of the first dorsal interossei and flattening of thenar eminences. Segment 6: Ten years later note evident progression of hand amyotrophy, now with incipient and bilateral clawing of the third to fifth fingers. Segment 7: In 2014, there was neither amyotrophy nor weakness of proximal upper-limb musculature. (MPG 13204 kb)

415_2015_7709_MOESM2_ESM.mpg

Supplementary material, video 2. This video illustrates serial clinical signs in patient II-4. Segment 1: In 2004 (at age 49), there was lower-leg wasting minimally more marked on the left side. Note normal appearance of both thighs. Segment 2: Ten years later stance is possible only with support; lower-limb amyotrophy is now masked by weight gain. Segment 3: Gait in 2004 was stepping, waddling and spastic; tiptoe walking was difficult and heel walking impossible. Segment 4: Ten years later, there was marked progression of gait abnormalities, the patient requiring support for walking. Segment 5: In 2004 note evident wasting of the first dorsal interossei and flattening of thenar eminences. Segment 6: Ten years later note evident progression of hand amyotrophy. Segment 7: Plantar reflexes were always extensor; this segment illustrates the left plantar reflex. (MPG 13524 kb)

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Berciano, J., García, A., Peeters, K. et al. NEFL E396K mutation is associated with a novel dominant intermediate Charcot–Marie–Tooth disease phenotype. J Neurol 262, 1289–1300 (2015). https://doi.org/10.1007/s00415-015-7709-4

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