Review Article 04/25/2018 on mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== by https://journals.lww.com/continuum from Downloaded Downloaded Address correspondence to Dr Sindhu Ramchandren, University of Michigan, from Charcot-Marie-Tooth Department of Neurology, https://journals.lww.com/continuum 2301 Commonwealth Blvd #1023, Ann Arbor, MI 48105, Disease and [email protected]. Relationship Disclosure: Dr Ramchandren has served Other Genetic on advisory boards for Biogen and Sarepta Therapeutics, by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== Inc, and has received research/grant support from Polyneuropathies the Muscular Dystrophy Association (Foundation Sindhu Ramchandren, MD, MS Clinic Grant) and the National Institutes of Health (K23 NS072279). Unlabeled Use of ABSTRACT Products/Investigational Purpose of Review: Genetic polyneuropathies are rare and clinically heterogeneous. Use Disclosure: This article provides an overview of the clinical features, neurologic and electrodiagnostic Dr Ramchandren reports no disclosure. findings, and management strategies for Charcot-Marie-Tooth disease and other * 2017 American Academy genetic polyneuropathies as well as an algorithm for genetic testing. of Neurology. Recent Findings: In the past 10 years, many of the mutations causing genetic polyneuropathies have been identified. International collaborations have led to the development of consortiums that are undertaking careful genotype-phenotype correlations to facilitate the development of targeted therapies and validation of outcome measures for future clinical trials. Clinical trials are currently under way for some genetic polyneuropathies. Summary: Readers are provided a framework to recognize common presentations of various genetic polyneuropathies and a rationale for current diagnostic testing and management strategies in genetic polyneuropathies. Continuum (Minneap Minn) 2017;23(5):1360–1377. INTRODUCTION the primary hereditary motor sensory Chronic polyneuropathies have a broad neuropathies, known collectively as differential, ranging from the relatively Charcot-Marie-Tooth disease (CMT); common causes, such as diabetes melli- the hereditary sensory and autonomic tus, to rare genetic polyneuropathies. neuropathies; and the polyneuropathies While at times strong evidence exists for associated with genetic disorders that an underlying genetic polyneuropathy have systemic neurologic manifestations. (eg, clinical presentation in youth, pos- itive family history, slowly progressive PRIMARY HEREDITARY MOTOR course), genetic polyneuropathies can SENSORY NEUROPATHIES occur from de novo mutations, are The primary hereditary motor sensory clinically heterogeneous, and can mimic neuropathies are known collectively other disorders. Given the long list of as Charcot-Marie-Tooth disease (CMT) possible etiologies and the limited treat- after the three investigators who de- ment options, defining the specific scribed a familial slowly progressive diagnostic workup and extent of genetic peroneal muscular atrophy in 1886.3,4 testing can be challenging.1,2 This Around the same time, Dejerine and on article presents a perspective on clinical Sottas described a hypertrophic intersti- 04/25/2018 evaluation, testing, and management of tial neuritis associated with a severe genetic polyneuropathies, focusing on infantile form of CMT.5 1360 ContinuumJournal.com October 2017 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Classification of Charcot-Marie- KEY POINTS the number of known mutations in h Charcot-Marie-Tooth Tooth Disease genes has grown, a new system that disease is not a single Early classification schemes divided emphasizes genetic classification is entity but rather a 11 CMT into three types: CMT1, a predom- now under consideration. spectrum of inantly demyelinating polyneuropathy neuropathic disorders based on uniformly slow conduction Genetics of Charcot-Marie-Tooth that result from velocities of 38 meters per second or Disease genetic mutations. less in the upper extremities; CMT2, a Over 90% of patients with CMT harbor a Charcot-Marie-Tooth predominantly axonal polyneuropathy mutation in the PMP22, MFN2,myelin disease can be classified with relatively normal velocities but proteinzero(MPZ), or gap junction into type 1 (CMT1, prominently reduced sensory nerve or protein beta 1 (GJB1)gene.12 For the demyelinating), type 2 (CMT2, axonal), compound muscle action potential remaining 10%, inheritance patterns and Dejerine-Sottas disease (CMAP) amplitudes, indicating axonal associated comorbidities can help de- 10 (severe infantile-onset loss; and CMT3, speculated to include fine the genetic etiology (Table 7-1). Charcot-Marie-Tooth recessive disorders with a severe Most cases of CMT are inherited in an disease), type 4 (CMT4, 6Y9 phenotype. autosomal dominant manner. An auto- autosomal recessive), The spectrum of neuropathic disor- somal dominant mutation can also and type 1X (CMT1X, ders in the CMT category has broad- occurdenovoinapatient.Childrenof X-linked inheritance). ened, but several aspects of the original a parent with an autosomal dominant h Over 90% of patients classification scheme have been re- neuropathy have a 50% chance of with Charcot-Marie-Tooth tained. CMT remains broadly classified inheriting the disease, although variable disease have a mutation into CMT1 (demyelinating) and CMT2 expression often results in a milder or in the PMP22, MFN2, (axonal). Dejerine-Sottas disease is now more severe disease than the parent. If MPZ,orGJB1 gene. preferred over CMT3 to describe the the autosomal dominant mutation oc- h An autosomal dominant group of severely affected infants curred de novo, children of the affected mutation can occur de with CMT regardless of inheritance parent will also have a 50% chance of novo in a patient. pattern or genetic mutation. CMT4 having the disorder. Some cases of CMT h Each child of a parent refers to autosomal recessive CMT. are X-linked dominant; only one mutant with an autosomal With the discovery of the causal genetic gene copy is needed for the disease to dominant neuropathy mutations, letters have been added to be present. An affected mother with has a 50% chance of indicate the gene. For example, dupli- CMT1X has a 50% chance of passing it inheriting the disease. cation of the peripheral myelin protein on to her sons or to her daughters. An h A father who has 22 gene (PMP22)causesCMT1A,and affected father with CMT1X will never Charcot-Marie-Tooth mutations in the mitofusin 2 gene transmit the mutation to his sons, but disease type 1X will (MFN2) cause CMT2A. has a 100% chance of transmitting it to always transmit the The current CMT classification his daughters. Finally, some CMT cases disease to his daughters system is shown in Table 7-1.10 This are inherited in an autosomal recessive but never to his sons. system does not fully accommodate manner; persons with one normal copy the full genotypic and phenotypic and one mutant copy are carriers and variability of CMT. For example, are unaffected. The children of two CMT1X does not fit into this scheme carriers have a 25% chance of inheriting as it has intermediately slowed con- both copies and having the disease. All duction velocities and X-linked in- children of an affected parent with auto- heritance, so it is grouped separately. somal recessive disease will have one Some dominantly inherited forms copy of the mutant gene; assuming the of CMT have intermediate-range other parent is not also a carrier, none slowing of conduction velocities in of the children will have the disease. the arms and are grouped separately Approximately 80% to 90% of cases as a dominant-intermediate form. As of autosomal dominant CMT1 are Continuum (Minneap Minn) 2017;23(5):1360–1377 ContinuumJournal.com 1361 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Charcot-Marie-Tooth Disease CMT1A, which is due to a 1.4-Mb recurrent pressure palsies. Of the auto- duplication of the PMP22 gene on somal dominant CMT1 cases, 10% are chromosome 17p11.2, expressed in due to CMT1B, caused by mutations in Schwann cells that produce myelin the MPZ gene, which results in delete- sheaths for peripheral nerves. One rious overexpression of the major mye- percent to nine percent are due to a lin structural protein.12Y14 PMP22 deletion, which causes heredi- CMT1X is caused by a mutation on tary neuropathy with liability to pres- the X chromosome in the GJB1 gene, sure palsies (HNPP), presenting with also known as the connexin 32 gene. a TABLE 7-1 Classification Scheme of Charcot-Marie-Tooth Disease Percentage of Charcot-Marie- Gene/ Type Pathology/Phenotype Inheritance Tooth Cases Subtype Chromosome CMT1 Myelin abnormalities; Autosomal 50Y80 CMT1A PMP22 distal weakness, atrophy, dominant CMT1B MPZ and sensory loss; onset: CMT1C LITAF È5 to 20 years; motor nerve conduction velocity CMT1D EGR2 G38 meters per second CMT1E PMP22 CMT1F/2E NEFL CMT2 Axonal degeneration; Autosomal 10Y15 CMT2A MFN2 distal weakness and dominant CMT2B RAB7A atrophy, variable CMT2C TRPV4 sensory involvement; complicated and CMT2D GARS severe cases described; CMT2E/1F