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Inherited Neuropathies 407 Inherited Neuropathies Vera Fridman, MD1 M. M. Reilly, MD, FRCP, FRCPI2 1 Department of Neurology, Neuromuscular Diagnostic Center, Address for correspondence Vera Fridman, MD, Neuromuscular Massachusetts General Hospital, Boston, Massachusetts Diagnostic Center, Massachusetts General Hospital, Boston, 2 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology Massachusetts, 165 Cambridge St. Boston, MA 02114 and The National Hospital for Neurology and Neurosurgery, Queen (e-mail: [email protected]). Square, London, United Kingdom Semin Neurol 2015;35:407–423. Abstract Hereditary neuropathies (HNs) are among the most common inherited neurologic Keywords disorders and are diverse both clinically and genetically. Recent genetic advances have ► hereditary contributed to a rapid expansion of identifiable causes of HN and have broadened the neuropathy phenotypic spectrum associated with many of the causative mutations. The underlying ► Charcot-Marie-Tooth molecular pathways of disease have also been better delineated, leading to the promise disease for potential treatments. This chapter reviews the clinical and biological aspects of the ► hereditary sensory common causes of HN and addresses the challenges of approaching the diagnostic and motor workup of these conditions in a rapidly evolving genetic landscape. neuropathy ► hereditary sensory and autonomic neuropathy Hereditary neuropathies (HN) are among the most common Select forms of HN also involve cranial nerves and respiratory inherited neurologic diseases, with a prevalence of 1 in 2,500 function. Nevertheless, in the majority of patients with HN individuals.1,2 They encompass a clinically heterogeneous set there is no shortening of life expectancy. of disorders and vary greatly in severity, spanning a spectrum Historically, hereditary neuropathies have been classified from mildly symptomatic forms to those resulting in severe based on the primary site of nerve pathology (myelin vs. disability. The most common form of HN, Charcot-Marie- axon) and the inheritance pattern (autosomal dominant, Tooth disease (CMT; also called hereditary motor and sensory recessive, or X-linked). The distinction between demyelinat- neuropathy [HMSN]), manifests with slowly progressive ing and axonal forms is defined by motor nerve conduction muscle weakness and sensory loss—with symptoms emerg- velocities (CV) in the upper extremities. Demyelinating forms ing in a length-dependent fashion. There are also motor and of HN are those with median motor nerve CVs below 38 m/s, Downloaded by: University of Pennsylvania Libraries. Copyrighted material. sensory predominant forms of HN, referred to as hereditary whereas in axonal forms CVs are greater than 38 m/s.3 In motor neuropathy (HMN) and hereditary sensory neuropa- recent years, it has become increasingly recognized that thy (HSN), respectively. These diseases can be viewed along a certain mutations are associated with CV slowing to an spectrum of motor and sensory involvement, from purely intermediate range (25–45 m/s); hence, “intermediate motor and motor predominant (HMN) neuropathies, through CMT” was designated as a separate category.4,5 Incorporating motor and sensory (CMT) neuropathies, to sensory predomi- both primary pathology and mode of inheritance, the sub- nant and pure sensory (HSN) neuropathies; for simplicity, we types of CMT can be divided as follows: autosomal dominant designate all diseases along the spectrum as “CMT and related demyelinating CMT (AD CMT1), autosomal dominant axonal disorders.” In addition to the sensory or motor or both CMT (AD CMT2), autosomal recessive demyelinating CMT symptoms, patients with HN often develop foot deformities (CMT4), autosomal recessive axonal CMT (AR CMT2), X-linked including pes cavus and pes planus, as well as other muscu- CMT, dominant intermediate CMT (DI CMT), recessive inter- loskeletal complications such as scoliosis and hip dysplasia. mediate CMT (RI CMT), hereditary neuropathy with liability Issue Theme Neuromuscular Disorders; Copyright © 2015 by Thieme Medical DOI http://dx.doi.org/ Guest Editors: William S. David, MD, PhD, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0035-1558981. FAAN,andDavidA.Chad,MD,FAAN New York, NY 10001, USA. ISSN 0271-8235. Tel: +1(212) 584-4662. 408 Inherited Neuropathies Fridman, Reilly to pressure palsies (HNPP), hereditary motor neuropathy Clinical Diagnosis of Hereditary Neuropathy (HMN), and hereditary sensory neuropathy (HSN). A letter designation follows the subtype representing the specific The History gene abnormality; for example, CMT1A refers to autosomal Making a diagnosis of HN is straightforward in a patient who dominant CMT1 due to a duplication of the PMP22 gene presents with a slowly progressive polyneuropathy and a (►Table 1). The classification is complex and constantly known family history of the disease. However, many patients evolving and not everyone agrees with the classification present as adults without a known family history. This can be above, especially with regards to CMT4, where some prefer due to unrecognized cases in the family, de novo mutations or to use CMT4 for all autosomal recessive forms of CMT autosomal recessive cases. In the United States and north (demyelinating and axonal). European populations, de novo mutations are a well-de- Since the discovery of the first CMT gene (PMP-22)over scribed cause of so-called sporadic cases in both CMT1 (e.g., two decades ago, the fieldofHNhaswitnessedanexplosion some mutations in PMP22 and MPZ) and in CMT2 (e.g., of gene discovery that has been facilitated by the develop- CMT2A due to some MFN2 mutations), whereas in countries ment of advanced diagnostic techniques including next- or ethnic groups with a high rate of consanguinity, such cases generation sequencing. At this time, over 80 causative may be due to autosomal recessive inheritance. The clinical genes have been identified.6 Despitethis,largestudies history in patients with suspected HN should include detailed from neuromuscular centers have shown that a genetic questions regarding the first two decades of life, including diagnosis is being achieved in only 54% to 67% of pa- timing of early milestones, ability to keep up with other tients.5,7,8 Among the known forms of hereditary neurop- children in races, history of ankle sprains or surgeries, and athy, demyelinating forms are more common, with axonal the need for special shoes or orthotics. Patients often recall forms comprising only 25% to 30% of all HN.5,9 More having instability of the ankles and difficulty fitting shoes causative genes have also been identified for demyelinating long before symptoms of muscle weakness or gait abnormal- HNs,andthediagnosticyieldisthereforehigherinthese ity emerge. These early symptoms, while extremely common, patients.5,7,8 are not universal, as some forms of HN (especially some The increasing ease of genetic testing and the growing axonal forms) remain asymptomatic until the sixth decade. number of identified mutations has improved the accuracy of In contrast to acquired peripheral neuropathies, HN is diagnosis of patients with HN, but has also expanded the generally associated with few “positive” sensory symptoms complexity of the diagnostic process. It has become apparent such as burning or paresthesias. Pain is common, but is that there is marked heterogeneity in the clinical phenotypes usually related to musculoskeletal complications. Certain associated with individual genes, even within single families. forms of HN, particularly those related to SPTLC1, GJB1, and Mutations in the myelin protein zero gene, for example, can MPZ genes, can be associated with significant neuropathic result in a severe, childhood-onset, demyelinating neuropa- pain, and these symptoms should not dissuade one from thy or a mild adult-onset axonal neuropathy.10 Mutations in a considering a genetic etiology. single gene can also result in either dominantly or recessively A careful family history, including at least three genera- inherited disease, as exemplified by the GDAP1 mutation.11 tions, should be obtained and the possibility of consanguinity Newly discovered genes have also shed light on the extensive assessed. It is also important to consider ethnicity and overlap of disease categories previously thought to be dis- geography, as AD and de novo mutations are known to be tinct, particularly with regard to CMT and hereditary spastic more common in the United States and in northern Europe, paraparesis (HSP). Mutations in the KIF5A gene, for example, whereas in regions with a high rate of consanguinity, AR 12 15,16 can manifest as CMT2 or HSP. disease accounts for up to 50% of HN. The presence of Downloaded by: University of Pennsylvania Libraries. Copyrighted material. Mutated proteins in HN appear to be involved in common male-to-male transmission excludes the possibility of molecular pathways including maintenance of Schwann cell X-linked disease, and pure maternal inheritance may point cytoskeleton, myelin assembly, axonal transport, transcrip- to one of the rare mitochondrial-encoded genes associated tion and mRNA processing, maintenance of channel func- with HN.17 tions, mitochondrial function, and protein translation (►Fig. 1).13,14 One way to classify HN in the future may be The Examination through the lens of specific pathophysiologic mechanisms Gait is almost always abnormal in CMT, and is most com- that underlie the pathology of the Schwann cell or axon or monly the high stepping gait that results from bilateral foot both.14
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