Carr, AS

Laura, M

Pelayo-Negro, AL

Reilly, MM

Skorupinska, M

English

UCL Discovery

LETTERAn observational studyof asymmetry in CMT1ACharcot-Marie-Tooth (CMT) disease is aclinically and genetically heterogeneousgroup of inherited neuropathies that wasﬁrst described in 1886. CMT1A is thecommonest form of CMT and accountsfor 70% of demyelinating CMT(CMT1).1 It is an autosomal dominantneuropathy due to a 1.4 Mb duplicationor rarely a triplication on chromosome17p11.2 that contains the peripheralmyelin protein 22 (PMP22) gene.Potential pathogenic mechanisms includealterations in protein homoeostasis, chol-esterol dysregulation, increased calciuminﬂux via P2X7 upregulation resulting indysmyelination and/or disruption of axon-glia interactions contributing to axonalloss.2 The characteristic phenotype deli-neated by Harding and Thomas is ofchildhood-onset distal wasting, weaknessand sensory loss, which progresses slowlyover decades in a length-dependent, sym-metrical manner.3 One study of paediatricCMT reported asymmetry of foot align-ment and ankle ﬂexibility in 3–5% ofpatients and found that asymmetry wasassociated with greater overall neuropathyseverity according to CMTNS scale butthere was no breakdown according to spe-ciﬁc CMT genotypes.4 Careful clinicaldescriptions from many large CMT1Acohorts have not reported signiﬁcantasymmetry in muscle strength or sensorydeﬁcits.56However, rare cases of superimposedinﬂammatory neuropathy or radiculopa-thy, either secondary to degenerativespinal disease or as a complication ofenlarged nerve roots, have been reportedin CMT1A. There has been one reportedcase of marked asymmetry with unilateralfootdrop without an alternative explan-ation despite extensive assessment in a19-year-old male patient.7 Interestingly,this patient was one of a pair of monozy-gotic twins with CMT1A who had similarelectrophysiological markers of thedisease but signiﬁcant differences insemeiology. In practice, it is important toknow how much asymmetry is allowed inthis condition so as not to assume thatasymmetry always suggests a differentialor coincidental diagnosis. No study todate has systematically examined thisissue.We performed a retrospective caseseries review in a cohort of patients withclinically and genetically conﬁrmedCMT1A followed up at least annually atthe inherited neuropathy clinic in theNational Hospital for Neurology andNeurosurgery. Routine practice involvesannual clinical assessment using the CMTExamination Score (CMTES), whichincludes Medical Research Council(MRC) scoring of muscle strength andvalidated scales for quantiﬁcation of pin-prick (PP) and vibration sensation (VS)deﬁcit .We recorded presence of asym-metry in strength in the commonlyaffected ﬁrst dorsal interosseous (FDIO)and abductor pollicis brevis (APB) musclesin the upper limbs (UL) and ankle dorsi-ﬂexion and plantarﬂexion in the lowerlimbs (LL). Asymmetry was deﬁned as adifference of greater than 1 MRC gradein contralateral muscles (without differen-tiation between grade 4−, 4 and 4+) andasymmetry of sensation as a difference of1 point on the CMTES PP and vibrationscales. We excluded patients with electro-physiological evidence of superimposedcompressive neuropathy and those withexamination ﬁndings suggesting signiﬁcantfoot, ankle and hip problems or spinaldeformities, which are commonly asso-ciated orthopaedic complications in inher-ited neuropathy that can contribute tonon-neuropathic motor deﬁcits.One hundred and eighty patients wereincluded in this review, 40.1% male, mean(SD) age at examination was 41.7 (14.8)years. Asymmetry of strength was seen in38 patients (21.1%), of whom 24 (13.3%)had asymmetrical UL and 17 (9.4%) asym-metrical LL strength. The distribution ofasymmetry in UL was as follows: FDIO(range: 1–2 points on MRC scale) in 13patients (7.2%) and APB (range: 1–3points) in 14 patients (7.8%). In the LL:ankle dorsiﬂexion (range: 1–2 points) in17 (9.4%) and ankle plantarﬂexion (range:2–3 points) in two patients (1.1%; table1). In three patients asymmetry was notedin both upper and LL; weaker left FDIOand right ankle dorsiﬂexion in one patient,weaker right APB and right dorsiﬂexion ina second, and right FDIO and right ankledorsiﬂexion in the third. Patients withmotor asymmetry were older (mean (SD)=49.2 (12.9) years with asymmetry; 39.35(14.48) years without asymmetry;(p<0.005) and had a more severe neur-opathy (mean (S.D.) CMTES=13.4 (4.7)with asymmetry, 9.7 (4.5) without asym-metry; (p=0.000). There was no correl-ation between weaker side and handedness(r=0.11, p=0.52). The proportion ofaffected relative to probands were similarin both groups; 32.3% probands in sym-metrical and 36.8% in asymmetricalpatients (p=0.49).In terms of sensation, asymmetry wasnoted in 23 patients (12.8%); PP asym-metry (range: 1–3 points on CMTES scale)in nine patients (5%) and VS (range 2–4)in 10 (5.6%; table 1). Asymmetry insensory deﬁcit was more common in theLL 20/23 than in the UL (3/23). In patientswith asymmetry, alternative pathologieswere ruled out through careful clinicalreview by an experienced consultant neur-ologist (MMR), and directed electrophysi-ology and neuroimaging (MRI of thebrain, spinal cord, nerve roots±plexii). Alldifferences reported were attributed toCMT1A. The evolution of these signs andparaclinical evidence suggests this ﬁndingas compatible with the natural history ofthe condition, a phenomenon which hasnot been previously reported. It may bethat dynometry and/or routine electro-physiological examination of all four limbsmay increase sensitivity for subtle asym-metry in CMT1A but was beyond thescope of this observational clinical study.In conclusion, we observed motor andsensory asymmetry in a signiﬁcant minor-ity of patients in this well phenotypedCMT1A cohort. The presence of asym-metry alone in CMT1A does not necessar-ily suggest that an alternative explanationneeds to be sought.Ana L Pelayo-Negro,1,2 Aisling S Carr,1Matilde Laura,1 Mariola Skorupinska,1Mary M Reilly11MRC Centre for Neuromuscular Diseases, UCL Instituteof Neurology, London, UK2Service of Neurology, University Hospital “Marqués deValdecilla (IDIVAL)”, University of Cantabria (UC) and“Centro de Investigación Biomédica en Red deEnfermedades Neurodegenerativas (CIBERNED)”,Santander, SpainCorrespondence to Professor Mary M Reilly, MRCCentre for Neuromuscular Diseases, UCL Institute ofTable 1 Number of patients with motorand/or sensory asymmetry according todifferences in MRC and CMTES sensoryscoring systemsDifference 1 2 3 4MRC scoreFDIO 10 3 1 0APB 10 3 0 0ADF 11 6 0 0APF 0 1 1 0CMTES sensory scoreP P 5110V S 0261ADF, ankle dorsiflexion; APB, abductor pollicis brevis;APF, ankle plantar flexion; CMTES,Charcot-Marie-Tooth Examination Score; FDIO, firstdorsal interosseous; MRC, Medical Research Council;PP, pinprick; VS, vibration sense.J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0 1PostScript  JNNP Online First, published on October 13, 2014 as 10.1136/jnnp-2014-309096Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence. group.bmj.com  on March 9, 2015 - Published by  http://jnnp.bmj.com/ Downloaded from Neurology, National Hospital for Neurology andNeurosurgery and UCL Institute of Neurology, Box 108,Queen Square, London WC1N 3BG, UK; m.reilly@ucl.ac.ukAcknowledgements MMR is grateful to the MedicalResearch Council (MRC), MRC Centre grant(G0601943), and MMR and ML are grateful to theNational Institutes of Neurological Diseases and Strokeand Ofﬁce of Rare Diseases (U54NS065712) for theirsupport. This work was undertaken at UniversityCollege London Hospitals/University College London,which received a proportion of funding from theDepartment of Health’s National Institute for HealthResearch Biomedical Research Centres funding scheme.Contributors MS is responsible for consent, datainput and upkeep of the CMT Natural History Studydatabase. ALP-N collected and analysed the data andwrote the ﬁrst draft of the paper. ASC helped withdrafting and revision of the paper. MMR conceived thestudy and contributed to revision of the ﬁnal paper.Competing interests None.Provenance and peer review Not commissioned;externally peer reviewed.Data sharing statement The collection of clinicaldata under the Charcot-Marie-Tooth and relateddisorders: A Natural History Study is ongoing. Furtherdetails may be available on discussion from theprincipal investigator and corresponding author of thispaper: MMR.Open Access This is an Open Access articledistributed in accordance with the terms of the CreativeCommons Attribution (CC BY 4.0) license, whichpermits others to distribute, remix, adapt and buildupon this work, for commercial use, provided theoriginal work is properly cited. See: http://creativecommons.org/licenses/by/4.0/To cite Pelayo-Negro AL, Carr AS, Laura M, et al. JNeurol Neurosurg Psychiatry Published Online First:[please include Day Month Year] doi:10.1136/jnnp-2014-309096Received 26 July 2014Revised 10 September 2014Accepted 19 September 2014J Neurol Neurosurg Psychiatry 2014;0:1–2.doi:10.1136/jnnp-2014-309096REFERENCES1 Murphy SM, Laura M, Fawcett K, et al. Charcot-Marie-Tooth disease: frequency of genetic subtypesand guidelines for genetic testing. J Neurol NeurosurgPsychiatry 2012;83:706–10.2 Li J, Parker B, Martyn C, et al. The PMP22 gene andits related diseases. Mol Neurobiol 2013;47:673–98.3 Harding AE, Thomas PK. The clinical features ofhereditary motor and sensory neuropathy types I andII. Brain 1980;103:259–80.4 Burns J, Ouvrier R, Estilow OT, et al. Symmetry of footalignment and ankle ﬂexibility in paediatricCharcot-Marie-Tooth disease. Clin Biomech (Bristol,Avon) 2012;27:744–7.5 Birouk N, Gouider R, Le Guern E, et al.Charcot-Marie-Tooth disease type 1A with 17p11.2duplication. Clinical and electrophysiologicalphenotype study and factors inﬂuencing diseaseseverity in 119 cases. Brain 1997;120:813–23.6 Marques W Jr, Freitas MR, Nascimento OJ, et al. 17pduplicated Charcot-Marie-Tooth 1A. Characteristics ofa new population. J Neurol 2005;252:972–9.7 García CA, Malamut RE, England JD, et al. Clinicalvariability in two pairs of identical twins with theCharcot-Marie-Tooth disease type 1A duplication.Neurology 1995;45:2090–3.2 J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0PostScriptgroup.bmj.com  on March 9, 2015 - Published by  http://jnnp.bmj.com/ Downloaded from CMT1AAn observational study of asymmetry inand Mary M ReillyAna L Pelayo-Negro, Aisling S Carr, Matilde Laura, Mariola Skorupinska published online October 13, 2014 J Neurol Neurosurg Psychiatry   http://jnnp.bmj.com/content/early/2014/10/13/jnnp-2014-309096Updated information and services can be found at: These include:References  #BIBL http://jnnp.bmj.com/content/early/2014/10/13/jnnp-2014-309096This article cites 7 articles, 3 of which you can access for free at: Open Accesshttp://creativecommons.org/licenses/by/4.0/use, provided the original work is properly cited. See: others to distribute, remix, adapt and build upon this work, for commercialthe Creative Commons Attribution (CC BY 4.0) license, which permits This is an Open Access article distributed in accordance with the terms ofserviceEmail alertingbox at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in theCollectionsTopic Articles on similar topics can be found in the following collections  (157) Open accessNoteshttp://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:http://journals.bmj.com/cgi/reprintformTo order reprints go to:http://group.bmj.com/subscribe/To subscribe to BMJ go to:group.bmj.com  on March 9, 2015 - Published by  http://jnnp.bmj.com/ Downloaded from 

An observational study of asymmetry in CMT1A

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