The genetics of Charcot–Marie–Tooth disease: current trends and future implications for diagnosis and management

The Application of Clinical Genetics Dovepress open access to scientific and medical research Review The Application of Clinical Genetics downloaded from https://www.dovepress.com/ by 54.37.117.73 on 12-Jul-2018 For personal use only. Open Access Full Text Article The genetics of Charcot–Marie–Tooth disease: current trends and future implications for diagnosis and management This article was published in the following Dove Press journal: The Application of Clinical Genetics 19 October 2015 Number of times this article has been viewed J Chad Hoyle 1 Michael C Isfort 1 Jennifer Roggenbuck 1,2 W David Arnold 1,3,4 Department of Neurology, Division of Neuromuscular Disorders, 2 Department of Internal Medicine, Division of Human Genetics, 3 Department of Physical Medicine and Rehabilitation, 4Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA 1 Abstract: Charcot–Marie–Tooth (CMT) disease is the most common hereditary polyneuropathy and is classically associated with an insidious onset of distal predominant motor and sensory loss, muscle wasting, and pes cavus. Other forms of hereditary neuropathy, including sensory predominant or motor predominant forms, are sometimes included in the general classification of CMT, but for the purpose of this review, we will focus primarily on the forms associated with both sensory and motor deficits. CMT has a great deal of genetic heterogeneity, leading to diagnostic considerations that are still rapidly evolving for this disorder. Clinical features, inheritance pattern, gene mutation frequencies, and electrodiagnostic features all are helpful in formulating targeted testing algorithms in practical clinical settings, but these still have shortcomings. Next-generation sequencing (NGS), combined with multigene testing panels, is increasing the sensitivity and efficiency of genetic testing and is quickly overtaking targeted testing strategies. Currently, multigene panel testing and NGS can be considered first-line in many circumstances, although obtaining initial targeted testing for the PMP22 duplication in CMT patients with demyelinating conduction velocities is still a reasonable strategy. As technology improves and cost continues to fall, targeted testing will be completely replaced by multigene NGS panels that can detect the full spectrum of CMT mutations. Nevertheless, clinical acumen is still necessary given the variants of uncertain significance encountered with NGS. Despite the current limitations, the genetic diagnosis of CMT is critical for accurate prognostication, genetic counseling, and in the future, specific targeted therapies. Although whole exome and whole genome sequencing strategies have the power to further elucidate the genetics of CMT, continued technological advances are needed. Keywords: Charcot–Marie–Tooth disease, next-generation sequencing, neurogenetic testing, nerve conduction studies, neuropathy Overview and clinical background Correspondence: J Chad Hoyle Department of Neurology, Division of Neuromuscular Disorders, The Ohio State University Wexner Medical Center, 7th Floor, 395 West 12th Avenue, Columbus, OH 43210, USA Phone +1 614 293 4969 Fax +1 614 293 6111 Email 235 submit your manuscript | www.dovepress.com The Application of Clinical Genetics 2015:8 235–243 Dovepress © 2015 Hoyle et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/TACG.S69969 Powered by TCPDF (www.tcpdf.org) Charcot–Marie–Tooth (CMT) disease is a genetically and phenotypically heterogeneous group of disorders. Classically, CMT includes hereditary disorders associated with sensory and motor deficits of the peripheral nervous system, sometimes also referred to as hereditary motor and sensory neuropathy. Other variants, including hereditary sensory neuropathy (or hereditary sensory and autonomic neuropathy) and distal hereditary motor neuropathy (or distal spinal muscular atrophy), are also sometimes grouped under the general classification of CMT. These disorders are usually phenotypically distinct. Hereditary sensory neuropathy is usually sensory predominant and may be associated with autonomic dysfunction and skin ulcerations due to insensate skin.1,2 Conversely, distal hereditary motor neuropathy usually lacks or has minimal Dovepress The Application of Clinical Genetics downloaded from https://www.dovepress.com/ by 54.37.117.73 on 12-Jul-2018 For personal use only. Hoyle et al sensory involvement.3 In this review, our focus will be to provide an overview of the clinical presentation, laboratory workup, diagnosis, and management of the classic CMT phenotype of sensory and motor deficits. The majority of patients with CMT have onset of symptoms in the first to second decade, although there is significant variability ranging from severe deficits in early childhood to only mild features in very late life.4 For instance, patients with the most common form, CMT1A, rarely require use of a wheelchair during their lifetime, but the most common axonal variant of CMT (CMT2A) has greater severity with most patients becoming nonambulatory at a young age, with 23 of 27 patients becoming nonambulatory before the age of 20 in one review of CMT2A.5–7 The symptoms and exam findings of CMT typically present insidiously and include distal predominant features of slowly progressive muscle weakness and wasting, most evident in the anterior leg and foot muscles, decreased reflexes, and vibratory sensory loss.4 Pes cavus (or high arched feet) and hammer toes are common, seen in approximately 70% of CMT patients.4 Scoliosis is less common but may occur in one-third to half of cases, usually with kyphoscoliosis.4,8–10 Hip dysplasia is another orthopedic complication that may occur.11 Although neuropathic pain is not a classic feature of CMT, moderate pain is noted by the majority of patients, and small nerve fiber function is frequently impaired in CMT1A patients.12–15 Soft tissue and joint-related pain are also significant sources of pain in patients with CMT.16 Sleep disturbances, including restless legs syndrome in 28% of patients, and muscle cramping may also be seen.17–19 Clinical presentation and examination As is the case with hereditary neuromuscular conditions in general, the insidious onset and progression often make deficits less obvious to a patient subjectively compared with the examiner’s findings. For instance, overt vibratory (...truncated)