Functional Electrical Stimulation: A Possible Strategy to Improve Muscle Function in Central Core Disease?

Pierpaolo Iodice,Lucia Galli,Helmut Kern,Massimo Caulo,Simona Boncompagni,Laura Pietrangelo,Vincenzo Sorrentino,Daniela Rossi,Enrico Pierantozzi,Feliciano Protasi,Aurora Fusella

doi:10.3389/fneur.2019.00479

Abstract

Central Core Disease (CCD) is a congenital myopathy characterized by presence of amorphous central areas (or cores) lacking glycolytic/oxidative enzymes and mitochondria in skeletal muscle fibers. Most CCD families are linked to mutations in ryanodine receptor type-1 (RYR1), the gene encoding for the sarcoplasmic reticulum (SR) Ca2+ release channel of skeletal muscle. As no treatments are available for CCD, currently management of patients is essentially based on a physiotherapic approaches. Functional electrical stimulation (FES) is a technique used to deliver low energy electrical impulses to artificially stimulate selected skeletal muscle groups. Here we tested the efficacy of FES in counteracting muscle loss and improve function in the lower extremities of a 55-year-old female patient which was diagnosed with CCD at the age of 44. Genetic screening of the RyR1 gene identified a missense mutation (c.7354C>T) in exon 46 resulting in an amino acid substitution (p.R2452W) and a duplication (c.12853_12864dup12) in exon 91. The patient was treated with FES for 26 months and subjected before, during, and after training to a series of functional and structural assessments: measurement of maximum isometric force of leg extensor muscles, magnetic resonance imaging, a complete set of functional tests to assess mobility in activities of daily living, and analysis of muscle biopsies by histology and electron microscopy. All results point to an improvement in muscle structure and function induced by FES suggesting that this approach could be considered as an additional supportive measure to maintain/improve muscle function (and possibly reduce muscle loss) in CCD patients.

Highlights

Central core disease (CCD), first described in 1956 [1], is one of the most common human congenital myopathies characterized by hypotonia and proximal muscle weakness [2]
Mutation screening by conventional Sanger sequencing on specific regions of the ryanodine receptor type-1 (RYR1) gene was performed in all family members for whom DNA was available (Figure 1)
The Short Physical Performance Battery (SPPB) used for this study evaluates the lower extremities function by using tests of gait speed, standing balance and the time needed to rise from a chair for five times as quickest as possible with the arms folded across their chest

Summary

Introduction

Central core disease (CCD), first described in 1956 [1], is one of the most common human congenital myopathies characterized by hypotonia and proximal muscle weakness [2]. Diagnosis of CCD is confirmed by examination of muscle biopsies showing amorphous central areas (or cores) lacking glycolytic/oxidative enzymes and mitochondria [6], and disorganization of contractile and sarcotubular systems [7]. About 90% of CCD cases are linked to mutations in the RYR1 gene [11,12,13], encoding for a tetrameric protein of about 2,200 KDa that forms the sarcoplasmic reticulum (SR) Ca2+ release channel of skeletal muscle, i.e., the ryanodine receptor type-1 (RyR1). Mutations in the RYR1 gene are responsible of malignant hyperthermia susceptibility (MHS), a hypermetabolic response to commonly used halogenated/volatile anesthetics [16]. Many patients with CCD test positive for MHS, and, should be considered at risk during general anesthesia

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