title: Underestimated associated features in CMT neuropathies: clinical indicators for the causative gene?
abstract: Charcot-Marie-Tooth neuropathy (CMT) is a genetically heterogeneous group of peripheral neuropathies. In addition to the classical clinical phenotype, additional features can occur.
  
  
  
  We studied a wide range of additional features in a cohort of 49 genetically confirmed CMT patients and performed a systematic literature revision.
  
  
  
  Patients harbored a PMP22 gene alteration (n = 28) or a mutation in MPZ (n = 11), GJB1 (n = 4), LITAF (n = 2), MFN2 (n = 2), INF2 (n = 1), NEFL (n = 1). We identified four novel mutations (3 MPZ, 1 GJB1). A total of 88% presented at least one additional feature. In MPZ patients, we detected hypertrophic nerve roots in 3/4 cases that underwent spinal MRI, and pupillary abnormalities in 27%. In our cohort, restless legs syndrome (RLS) was present in 18%. We describe for the first time RLS associated with LITAF or MFN2 and predominant upper limb involvement with LITAF. Cold-induced hand cramps occurred in 10% (PMP22,MPZ,MFN2), and autonomous nervous system involvement in 18% (PMP22,MPZ, LITAF,MFN2). RLS and respiratory insufficiency were mostly associated with severe neuropathy, and pupillary abnormalities with mild to moderate neuropathy.
  
  
  
  In CMT patients, additional features occur frequently. Some of them might be helpful in orienting genetic diagnosis. Our data broaden the clinical spectrum and genotype-phenotype associations with CMT.
authors.affiliation: Department of Neurology University Hospital RWTH Aachen Aachen Germany; Institute of Neuropathology University Hospital RWTH Aachen Aachen Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Werheid
authors.affiliation: Institute of Neuropathology University Hospital RWTH Aachen Aachen Germany.
authors.forename: Hamid
authors.initials: H
authors.lastname: Azzedine
authors.affiliation: Department of Neurology University Hospital RWTH Aachen Aachen Germany; Institute of Neuropathology University Hospital RWTH Aachen Aachen Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Zwerenz
authors.affiliation: Department of Plastic and Reconstructive Surgery Hand Surgery-Burn Center University Hospital RWTH Aachen Aachen Germany; Department of Plastic & Aesthetic, Reconstructive & Hand Surgery Center for Reconstructive Microsurgery and Peripheral Nerve Surgery (ZEMPEN) Agaplesion Markus Hospital Frankfurt am Main Germany.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Bozkurt
authors.affiliation: Section Immunology and Nephrology Department of Internal Medicine University Hospital RWTH Aachen Aachen Germany.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Moeller
authors.affiliation: Department of Neurology University Hospital RWTH Aachen Aachen Germany; Institute of Neuropathology University Hospital RWTH Aachen Aachen Germany.
authors.forename: Lilian
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Neuroradiology University Hospital RWTH Aachen Aachen Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Mull
authors.affiliation: Division of Neuropediatrics and Social Pediatrics Department of Pediatrics University Hospital RWTH Aachen Aachen Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Häusler
authors.affiliation: Department of Neurology University Hospital RWTH Aachen Aachen Germany; JARA - Translational Brain Medicine Aachen Germany.
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.affiliation: Institute of Neuropathology University Hospital RWTH Aachen Aachen Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.affiliation: Department of Neurology University Hospital RWTH Aachen Aachen Germany; Institute of Neuropathology University Hospital RWTH Aachen Aachen Germany; Department of Neurology University Hospitals Leuven and University of Leuven (KU Leuven) Leuven Belgium.
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
mesh_terms: D000328:Adult; D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology*; D002648:Child; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D055815:Young Adult
keywords: Additional symptoms; HMSN; RLS; hereditary motor and sensory neuropathy; pupillary abnormalities