title: Intermediate Charcot-Marie-Tooth disease: an electrophysiological reappraisal and systematic review.
abstract: Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited neuropathy with great variety of phenotypes, inheritance patterns, and causative genes. According to median motor nerve conduction velocity (MNCV), CMT is divided into demyelinating (CMT1) with MNCV below 38 m/s, axonal (CMT2) with MNCV above 38 m/s, and intermediate CMT with MNCV between 25 and 45 m/s. In each category, transmission may be autosomal dominant, autosomal recessive, or X-linked. The nosology of intermediate CMT is controversial because of concerns about electrophysiological delimitation. A systematic computer-based literature search was conducted on PubMed, using the following MeSH: (1) intermediate Charcot-Marie-Tooth; (2) X-linked intermediate Charcot-Marie-Tooth; and (3) X-linked Charcot-Marie-Tooth and electrophysiology. We retrieved 225 articles reporting X-linked CMT or intermediate CMT with electrophysiological information. After eligibility, 156 papers were used for this review. In assessing median MNCV, compound muscle action potential (CMAP) amplitudes were taken into account. In cases with attenuated CMAP and wherever possible, proximal median MNCV was used for accurate definition of conduction slowing in the intermediate range. In the vast majority of males with X-linked CMT associated with GJB1 mutation (CMTX1), median MNCV was intermediate. CMT associated with DRP2 mutation is another well-documented X-linked intermediate disorder. Autosomal dominant intermediate CMT (DI-CMT) encompasses 11 different types; six of them with assigned phenotype MIM number and the remaining five being unnumbered. Based on available electrophysiological information, we wonder if DI-CMTA should be reclassified within CMT2. Autosomal recessive intermediate CMT (RI-CMT) covers four numbered MIM phenotypes though, in accordance with reported electrophysiology, two of them (RI-CMTB and RI-CMTD) should probably be reclassified within AR-CMT2. We conclude that intermediate CMT is a complex inherited syndrome, whose characterization requires a specific electrophysiological protocol comprising evaluation of upper limb proximal nerve trunks when distal CMAP amplitudes are reduced, and that an updated version of MIM phenotype numbering is needed.
authors.affiliation: Service of Neurology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria (UC), and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain. jaberciano@humv.es.|Professor Emeritus, Department of Medicine and Psychiatry, "Edificio Escuela Universitaria de Enfermería (cuarta planta)", Avda. de Valdecilla s/n, University of Cantabria, 39008, Santander, Spain. jaberciano@humv.es.
authors.forename: José
authors.initials: J
authors.lastname: Berciano
authors.affiliation: Service of Clinical Neurophysiology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria (UC), and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: García
authors.affiliation: Service of Radiology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria (UC), and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Gallardo
authors.affiliation: VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
authors.forename: Kristien
authors.initials: K
authors.lastname: Peeters
authors.affiliation: Service of Neurology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria (UC), and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Pelayo-Negro
authors.affiliation: Service of Clinical Neurophysiology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria (UC), and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Álvarez-Paradelo
authors.affiliation: Service of Neurology, Hospital Universitario Miguel Servet, Saragossa, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Gazulla
authors.affiliation: Universidad de Cantabria (UC), Santander, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Martínez-Tames
authors.affiliation: Service of Neurology, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Universidad de Cantabria (UC), and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
authors.forename: Jon
authors.initials: J
authors.lastname: Infante
authors.affiliation: VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008475:Median Nerve / Q000503:physiopathology; D009431:Neural Conduction
keywords: Autosomal dominant inheritance; Autosomal recessive inheritance; Axonal degeneration; Charcot–Marie–Tooth disease; Compound muscle action potential; Demyelination; Electrophysiology; Intermediate Charcot–Marie–Tooth disease; Motor conduction velocity; Nerve biopsy; OMIM; PRISMA statement; Proximal motor nerve conduction velocity; Systematic review; X-linked inheritance