Charcot-Marie-Tooth Disease and Other Genetic Polyneuropathies

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3,4 October 2017 5 disease and other ations have led to the re and clinically heterogeneous. recognize common presentations of harcot-Marie-Tooth Around the sameSottas described time, a hypertrophic Dejerine intersti- tial and neuritisinfantile associated form of with CMT. a severe the primary hereditaryneuropathies, motor known sensory Charcot-Marie-Tooth collectively disease as the (CMT); hereditary sensoryneuropathies; and and the autonomic polyneuropathies associated with genetichave systemic neurologic disorders manifestations. that PRIMARY HEREDITARY MOTOR SENSORY NEUROPATHIES The primary hereditary motorneuropathies sensory areas known Charcot-Marie-Tooth collectively diseaseafter (CMT) the threescribed investigators a whoperoneal familial de- muscular slowly atrophy progressive in 1886. ionale for current diagnostic testing and al features, neurologic and electrodiagnostic . Clinical trials are currently under way for t of targeted therapies and validation of nternational collabor This s an algorithm for genetic testing. 1,2 netic polyneuropathies. Genetic polyneuropathies are ra In the past 10 years, many of the mutations causing genetic Readers are provided a framework to Sindhu Ramchandren, MD, MS some genetic polyneuropathies. Summary: outcome measures for future clinical trials development of consortiumscorrelations that to facilitate are the undertaking developmen careful genotype-phenotype various genetic polyneuropathies and a rat management strategies in ge ABSTRACT genetic polyneuropathies as wellRecent a Findings: polyneuropathies have been identified. I This article provides an overviewfindings, of the clinic and management strategies for C Continuum (Minneap Minn) 2017;23(5):1360–1377. Purpose of Review: INTRODUCTION Chronic polyneuropathies have adifferential, broad ranging fromcommon the causes, such relatively astus, diabetes melli- to rareWhile at genetic times strong evidence polyneuropathies. an exists for underlying genetic(eg, clinical polyneuropathy presentation initive youth, family pos- history,course), slowly genetic progressive polyneuropathiesoccur can from declinically heterogeneous, and novo canother mutations, mimic disorders. are Givenpossible the etiologies and long the list limitedment treat- of options,diagnostic defining workup and the extent oftesting genetic specific can be challenging. Charcot-Marie-Tooth Disease and Other Genetic Polyneuropathies article presents a perspectiveevaluation, on testing, clinical and managementgenetic of polyneuropathies, focusing on Review Article Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Copyright © American Academy of Neurology. Unauthorized reproduction of this article is . ContinuumJournal.com

2017 American Academy Address correspondence to Dr Sindhu Ramchandren, University of Michigan, Department of Neurology, 2301 Commonwealth Blvd #1023, Ann Arbor, [email protected] 48105, Relationship Disclosure: Dr Ramchandren has served on advisory boards for Biogen and Sarepta Therapeutics, Inc, and has received research/grant support from the Muscular Dystrophy Association (Foundation Clinic Grant) and the National Institutes of Health (K23 NS072279). Unlabeled Use of Products/Investigational Use Disclosure: Dr Ramchandren reports no disclosure. * of Neurology. 1360

Downloaded from https://journals.lww.com/continuum by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== on 04/25/2018 Downloaded from https://journals.lww.com/continuum by mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== on 04/25/2018 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

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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 NEFL motor nerve conduction CMT2F HSPB1 velocity 938 meters per second; onset: CMT2G 12q12-q13 variable CMT2H/2K GDAP1 CMT2I/2J MPZ CMT2L HSPB8 CMT2M SYNM CMT2N AARS CMT2O DYNC1H1 CMT2P LRSAM1 CMT2S IGHMBP2 CMT2T DNAJB2 CMT2U MARS Intermediate Myelinopathy and axonal; Autosomal Less than 4 DI-CMTA Unknown form Motor nerve conduction dominant DI-CMTB DNM2 velocity 925 meters per DI-CMTC YARS second and G38 meters per second DI-CMTD MPZ DI-CMTF GNB4 Continued on page 1363

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Percentage of Charcot-Marie- Gene/ Type Pathology/Phenotype Inheritance Tooth Cases Subtype Chromosome CMT4 Demyelinating; recessive; Autosomal Rare CMT4A GDAP1 variable presentations/ recessive CMT4B1 MTMR2 phenotypes CMT4B2 SBF2 CMT4B3 SBF1 CMT4C SH3TC2 CMT4D NDRG1 CMT4E EGR2 CMT4F PRX CMT4G HK1 CMT4H FGD4 CMT4J FIG4 CMT2B1 LMNA CMT2B2 MED25 CMTX Axonal degeneration with X-linked 10Y15 CMTX1 GJB1 myelin abnormalities CMTX2 Xp22.2 CMTX3 Unknown CMTX4 AIFM1 CMTX5 PRPS1 CMTX6 PDK3 CMT = Charcot-Marie-Tooth disease; DI = dominant intermediate. a Modified with permission from McCorquodale D, et al, J Multidiscip Healthc.10 B 2016 The Authors. dovepress.com/management-of-charcotndashmariendashtooth-disease-improving-long-term–peer-reviewed-fulltext-article-JMDH.

The gene is expressed in myelinating progressing to footdrop and hand Schwann cells and the mutation is weakness (Case 7-1). On examination, thought to cause a loss of func- besides the distal weakness and sen- tion.15,16 CMT2A accounts for 20% to sory loss, reflexes are often globally 30% of all causes of CMT2 due to suppressed or absent. At most, these mutations in the MFN2 gene.17,18 patients require ankle-foot orthoses for ambulation.8,9,21 A second presentation Clinical Presentation is characterized by an earlier onset of CMT is the most common genetic symptoms with delayed walking (after neuromuscular disorder, with a preva- age 15 months or more), toe walking, lence between 1 in 1213 to 1 in or clumsiness in childhood. Patients 2500.19,20 Historically, patients have with this phenotype progress to one of three clinical patterns. The above-the-knee bracing, walkers, or typical phenotype is characterized by wheelchairs for ambulation.22Y25 Athird normal motor milestones but slowly presentation is characterized by adult progressive symmetric distal leg weak- onset (around 40 years) with variable ness with sensory loss, usually begin- subsequent progression. The same ning in the first to third decade and CMT gene mutation can present in any

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KEY POINT h Pes cavus and hammer Case 7-1 toes, while an important A 16-year-old boy with no family history of neuropathy was brought physical feature of to the clinic by his parents for evaluation of clumsy gait, tripping, Charcot-Marie-Tooth and falling. The patient denied any problems but had pes cavus and disease, are not specific bilateral footdrop and walked with a steppage gait; he had mild hand to the disease and may intrinsic muscle atrophy and was areflexic. His nerve conduction studies occur in isolation or in showed a conduction velocity of 22 meters per second along the conjunction with other ulnar and median motor nerves without conduction block or temporal disorders of the central dispersion. Because of his youth and the lack of family history, his nervous system. pediatrician had tried monthly IV immunoglobulin (IVIg) for 6 months in the hope that this was chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), without benefit. Genetic testing confirmed a diagnosis of Charcot-Marie-Tooth disease type 1A (PMP22 duplication). Comment. De novo mutations, as in this case, are not uncommon in Charcot-Marie-Tooth disease. In young patients, when the differential diagnosis includes a potentially treatable disorder, genetic testing becomes more valuable and is less costly and safer than a treatment trial of IVIg.

of these three ways, demonstrating Electrophysiology the marked phenotypic variability of a Electrodiagnostic studies, especially single genotype. nerve conduction studies, are important Foot deformities, such as pes cavus tools to establish the presence of andhammertoes,arecommoninCMT polyneuropathy, extent of damage, and and are often the reason providers first demyelinating versus axonal physiology. consider the diagnosis. Foot deformi- Demyelinating forms of CMT are diag- ties may progress to contracture with nosed based on uniformly slowed 26 marked osseous changes (Figure 7-1). conduction velocities of 38 meters per However, these deformities are not second or less in the upper extremities, always associated with neuropathies without evidence of conduction block and may occur in isolation or in con- or temporal dispersion (the latter two junction with central nervous system or are features associated with acquired 27,28 developmental disorders. demyelinating neuropathies). Diagnosis CMT in children and adults is associ- of axonal forms is based on relatively ated with psychological stress, reduced normal velocities but prominently re- health-related quality of life, and other duced sensory nerve action potential 29Y31 comorbidities. Although historically (SNAP) amplitudes, reduced CMAP am- characterized as painless, a significant plitudes, or both.6Y9 proportion of children and adults with CMT report pain that may be neuro- An Approach to Diagnosis and genic, musculoskeletal, or both.32Y34 Genetic Testing MaleswithCMT1Xmayrarelypresent Obtaining a detailed family pedigree, with strokelike symptoms, including dys- ideally of three generations or more, arthria, ataxia, weakness, and transient is one of the most important steps white matter hyperintensities on MRI in establishing a possible diagnosis (Figure 7-2 and Case 7-2).35 Hearing in CMT. Patients should specifically loss, hip dysplasia, and sleep apnea are be asked about early deaths in the also reported findings with CMT.36,37 extended family, consanguinity, and

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 7-1 Classification of Charcot-Marie-Tooth disease foot deformity. A, First stage: flexible cavus foot, reducible. B, Second stage: equinus and pronation of first ray (the column of bones and joints forming the medial border of the forefoot), possible reducible clawing of great toe. C, Third stage: equinus of whole forefoot, varus of the heel, irreducible clawing of great toe, no osseous structural abnormalities. D, Fourth stage: structural osseous changes, irreducible clawing of toes, possible tarsal movements. EYG, Fifth stage: firmly fixed deformity, pronounced osseous changes, irreducible clawing of toes with subluxation or luxation of metatarsophalangeal joints.

Reprinted with permission from Faldini C, et al, J Bone Joint Surg Am.26 B 2015 The Journal of Bone and Joint Surgery, Incorporated. journals.lww.com/jbjsjournal/Abstract/2015/03180/ Surgical_Treatment_of_Cavus_Foot_in.13.aspx. family members with walking prob- without a specific rationale is often lems without a clear diagnosis. The not in the patient’s best interest. More likelihood of genetic neuropathy is specific diagnosis provides the patient high in the patient with symmetric with the most accurate inheritance distal weakness and sensory loss and risk information, which is impor- starting in youth, pes cavus foot tant in making reproductive decisions. deformity with hammer toes, slowed Different mutations progress at different conduction velocities on nerve con- rates and are associated with different duction studies, and a strong family comorbidities that physicians should history. The diagnosis is not obvious look for in individuals who are at risk. when the family history is unknown or Motor nerve conduction velocities the mutation is de novo, the neurop- in the upper extremities can be used athy is axonal, or symptom onset is in diagnostic algorithms (Figure 7-3, later in life. Concluding that a patient Figure 7-4, Figure 7-5,andFigure 7-6).12 may have a genetic polyneuropathy The conduction velocity convention

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FIGURE 7-2 Imaging from a boy who presented at age 12 with three episodes of transient right face, arm, and leg motor and sensory symptoms over a 3-day period, lasting 4 to 10 hours. MRI on the third day showed abnormal increased T2 signal and reduced diffusion in the posterior portion of the centrum semiovale bilaterally (A, B), as well as in the splenium of the corpus callosum (C, D). He was noted to have hyporeflexia at the ankles and minimal weakness in ankle dorsiflexion; a family history of Charcot-Marie-Tooth disease (CMT) and subsequent genetic testing confirmed X-linked CMT. At age 15, he developed 2 days of mild right arm weakness and worsening handwriting, followed by 8 hours of severe hemiparesis of the left face and arm, dysarthria, and dysphagia, which lasted about 8 hours, with complete resolution. MRI performed 2 days later again showed symmetric abnormally increased T2 signal and diffusion reduction in the posterior frontal and parietal white matter bilaterally (E, F). Repeat brain MRI 11 weeks later showed a return to normal diffusion and improvement in the abnormal T2 signal, with some mild areas of persistently increased T2 signal in the white matter (G, H).

Reprinted with permission from Taylor RA, et al, Neurology.35 B 2003 American Academy of Neurology. neurology.org/content/61/11/1475.full.

Case 7-2 The 9-year-old son of a woman with mild Charcot-Marie-Tooth disease presented to the emergency department with 3 hours of sudden-onset slurred speech and left-sided clumsiness. Examination showed mild ataxia of the left arm and leg, slightly high-arched feet, and weakness of bilateral ankle dorsiflexion. MRI of the brain showed acute white matter changes in the posterior fossa. The patient’s symptoms slowly improved over the next 24 hours as he was kept in observation and completely resolved over the next 10 days. Comment. This is a typical case of Charcot-Marie-Tooth disease type 1X with transient strokelike symptoms. The gap junction protein connexin 32 is not only expressed in Schwann cells but also in the central nervous system oligodendrocytes. Symptom resolution may take weeks, and, while rare, repeated attacks may occur.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. used in this classification system defines Diagnostic algorithms work most normal as greater than 45 meters per effectively when used with patients second, intermediate as 35 meters per suspected to be at risk for CMT. The second to 45 meters per second, slow percent of positive gene tests for CMT as 15 meters per second to 35 meters was 18% in one large study of a diverse per second, and very slow as less than population of patients with neuro- 15 meters per second. pathy,38 compared with 60% in a

FIGURE 7-3 Axonal Charcot-Marie-Tooth disease with normal motor nerve conduction velocity. Algorithm for genetically diagnosing Charcot-Marie-Tooth disease in patients with normal motor nerve conduction velocities and evidence of axonal loss. In most cases, motor nerve conduction velocities in upper extremities are greater than 45 meters per second. However, in severe cases, these potentials may be absent. In those cases, it is important to test proximal nerves to ensure that the patient does not have a severe demyelinating neuropathy that can mimic axonal Charcot-Marie-Tooth disease. This algorithm is designed to be a general guide and is not intended to encompass every potential clinical scenario or all possible genetic etiologies.

CMT = Charcot-Marie-Tooth disease. Reprinted with permission from Saporta AS, et al, Ann Neurol.12 B 2011 American Neurological Association. onlinelibrary.wiley.com/doi/ 10.1002/ana.22166/abstract.

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FIGURE 7-4 Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocity. Algorithm for genetically diagnosing Charcot-Marie-Tooth disease in patients with intermediate upper extremity motor nerve conduction velocities. This algorithm is designed to be a general guide and is not intended to encompass every potential clinical scenario or all possible genetic etiologies.

CMT = Charcot-Marie-Tooth disease. Reprinted with permission from Saporta AS, et al, Ann Neurol.12 B 2011 American Neurological Association. onlinelibrary.wiley.com/doi/10.1002/ana.22166/abstract.

confirmed CMT population,39 empha- sequence database, such as the Na- sizing the need to select the right tional Heart, Lung, and Blood Institute patient for the right test. Exome Sequencing Project Exome Next-generation gene sequencing Variant Server (evs.gs.washington.edu/ can search for mutations in panels of EVS/), can help distinguish common genes, including cost-effective core polymorphisms from pathologic vari- panels that look for mutations in ants. Genetic counseling also serves an PMP22, MPZ, GJB1,andMFN2,com- important role before testing to deter- prising the etiology of 90% of muta- mine the appropriateness of the test and tions in CMT patients.12 Bulk gene the most cost-effective testing strategy. surveys also increase the probability of After testing, genetic counseling can aid identifying variants that may or may in the interpretation of results and not be pathologic. Using a reference direct future testing if needed.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 7-5 Charcot-Marie-Tooth disease with slow motor nerve conduction velocity. Algorithm for genetically diagnosing Charcot-Marie-Tooth disease in patients with slow upper extremity motor nerve conduction velocities. This algorithm is designed to be a general guide and is not intended to encompass every potential clinical scenario or all possible genetic etiologies. CMT = Charcot-Marie-Tooth disease. Reprinted with permission from Saporta AS, et al, Ann Neurol.12 B 2011 American Neurological Association. onlinelibrary.wiley.com/doi/10.1002/ ana.22166/abstract.

Management PXT3003, a combination of naltrexone, Currently no disease-modifying treat- baclofen, and sorbitol, in 300 patients ment exists for CMT. Several large with CMT1A (NCT02579759).46 multicenter trials showed no effect Current patient management can be of varying doses of ascorbic acid to optimized with a multidisciplinary treat CMT1A40Y42 but laid the ground- approach to care. An annual evaluation work for an international collaboration by a neurologist, physiatrist, or both studying the natural history of CMT39 can assess the patient’s function and and validating new outcome measures continuing needs. Additional ancillary for future clinical trials.43Y45 Currently, services are important to retain func- an international trial is under way tional independence. Physical therapy evaluating the safety and efficacy of plays a major role in gait retraining,

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FIGURE 7-6 Charcot-Marie-Tooth disease with very slow motor nerve conduction velocity. This algorithm is designed to be a general guide and is not intended to encompass every potential clinical scenario or all possible genetic etiologies.

CMT = Charcot-Marie-Tooth disease. Reprinted with permission from Saporta AS, et al, Ann Neurol.12 B 2011 American Neurological Association. onlinelibrary.wiley.com/doi/10.1002/ana.22166/abstract.

maintaining core muscle strength, en- using eating utensils.51 An orthotist ergy conservation, and use of serial may provide ankle-foot orthoses to casting and night splinting to improve improve gait and energy conservation, range of motion.47Y50 Occupational prevent falls, and reduce long-term therapy can improve hand range of damage to knee and hip joints.52,53 motion and provide tools to improve Orthopedic interventions, such as activities of daily living, such as but- tendon lengthening and tendon toning clothing, opening bottles, and transfer, can help maintain long-term

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 26,54 KEY POINTS function, and guidelines are cur- sphingolipids. Mutations in SPTCL1 re- h A multidisciplinary rently being developed to direct proper sult in neurotoxic sphingolipid metabo- approach to the care 57 timing of interventions to optimize out- lite accumulation. HSAN II is caused of patients with comes. Pain management for genetic by mutations in the WNK lysine defi- Charcot-Marie-Tooth neuropathies follows the same princi- cient protein kinase 1 gene (WNK1). disease helps patients ples as for other chronic neuropathies, HSAN III is caused by mutations in the retain functional including encouragement of movement inhibitor of kappa light polypeptide gene independence. and activity, maintenance of a healthy enhancer in B-cells, kinase complex- h While sensory body mass index, and avoidance of associated protein gene (IKBKAP)and symptoms narcotics for long-term pain control.55 is limited to children of Ashkenazi predominate, many Jewish descent. HSAN IV and HSAN V patients with HEREDITARY SENSORY AND are caused by mutations in neuro- hereditary sensory AUTONOMIC NEUROPATHIES trophic receptor tyrosine kinase 1 gene and autonomic neuropathies also The primary hereditary sensory and (NTRK1) and the nerve growth factor gene (NGF ).56 have motor autonomic neuropathies (HSANs) pre- abnormalities. dominantly affect myelinated and un- Clinical Presentation myelinated sensory nerves but also have motor nerve involvement. The typical presentation of patients with HSAN I includes sensory loss and neuropathic pain, sometimes with Classification of Hereditary foot ulceration. While mean age of Sensory and Autonomic presentation is in the mid-twenties, Neuropathies patients have presented in their teens The disorders are broadly classified into and in the late seventies to eighties. five types: HSAN I with autosomal Autonomic and motor involvement dominant inheritance (the most com- can be variable. Some patients also mon form, but genetically heteroge- have sensorineural deafness and neous), HSAN II (autosomal recessive dementia. Pes cavus and absent re- inheritance, early onset), HSAN III flexes can be seen on examination.58 (familial dysautonomia, also known as HSAN II, involving both large and Riley-Day syndrome, with autosomal small nerve fibers, presents with loss recessive inheritance), and HSAN IV of pain, temperature, pressure, and and HSAN V (congenital insensitivity to touch sensation. It is associated with pain with anhidrosis; autosomal reces- self-mutilation of fingers and toes sive inheritance). HSAN IV is also 56 and can come to initial medical atten- associated with developmental delay. tion because of recurrent infections.59 HSAN III presents with sympathetic Genetics of Hereditary Sensory autonomic dysfunction, including or- and Autonomic Neuropathies thostatic hypotension, excessive sali- HSAN I is clinically heterogeneous, vation, gastrointestinal dysmotility, resulting from mutations in the serine bladder dysfunction, decreased or palmitoyltransferase long chain base absent tearing, absent fungiform subunit 1 (SPTLC1), serine palmitoyl- tongue papillae, pupillary dilatation, transferase long chain base subunit 2 hypohidrosis, and episodic hyper- (SPTLC2), atlastin GTPase 1 (ATL1), hidrosis. Episodes of dysautonomic DNA methyltransferase 1 (DNMT1), crises can be triggered by physical and atlastin GTPase 3 (ATL3) genes. and emotional stress.60 Patients with The SPTCL1 gene encodes for serine HSAN IV present in infancy with palmitoyltransferase, which synthesizes mild to moderate developmental

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delay; profound insensitivity to pain; patients with a motor and sensory and self-mutilation of digits, face, and neuropathy, even in the presence of mouth regions. HSAN IV differs from demyelinating features, particularly if HSAN III by preservation of tearing and the patient has marked sensory involve- tongue papillae. Almost 20% of patients ment and a family history (Case 7-3). with HSAN die from hyperpyrexia be- Intrauterine diagnosis of HSAN III can fore the age of 3.61 HSAN V presents as now be made with about 98% percent a milder phenotype of HSAN IV; devel- accuracy using linked genetic markers opmental delay, if present, is mild.62 in affected families,65 and prenatal screening for this disease has contrib- Electrophysiology uted to its marked decline in the 66 Nerve conduction studies in HSAN are United States. highly variable, reflecting the genetic Experimental studies have attempted heterogeneity. HSAN I mostly pre- to reduce the level of toxic sphingolipid sents with an axonal sensory more metabolites to ameliorate HSAN I. Die- than motor neuropathy; however, mo- tary supplementation with oral L-serine tor nerve conduction slowing into the in SPTLC1-mutant mice reduced the demyelinating range can be seen.63 sphingolipid metabolites and improved HSAN II mainly shows an axonal motor and sensory performance. Four- neuropathy with absent sensory re- teen patients with HSAN I who received sponses. HSAN III, similar to HSAN I, L-serine supplementation for 10 weeks is associated with sensory more than also showed reduced sphingolipid 67 motor involvement.64 HSAN IV and metabolites. However, despite these HSAN V, which predominantly affect promising studies, no specific treatment small myelinated and unmyelinated exists for HSAN. Chronic sores and nerve fibers, typically show normal infections can lead to osteomyelitis 68 nerve conduction studies. and eventual amputation. Manage- ment requires protection of the extrem- Diagnosis and Management ities, shoes that fit properly, orthotics Prominent sensory and autonomic for footdrop, treatment of callus for- manifestations should raise concern mation, proper dressing of wounds to for the diagnosis of HSAN. The diagno- promote healing, and avoidance of sis of HSAN I secondary to SPTLC1 trauma to the hands and feet.69 Simi- mutations should be considered in larly, supportive care and symptomatic

Case 7-3 A 12-year-old girl had been repeatedly seen in urgent care over several months for symptoms of pain in the feet. Examination showed no visible foot deformities, limited strength examination because of pain, and allodynia to all sensory modalities at the feet with reduced perception to pin and vibration in the distal legs. Nerve conduction studies showed a demyelinating motor-sensory polyneuropathy. Genetic testing for PMP22 deletion, duplication, and sequencing were negative. The girl’s father had a long-term history of disabling pain in the feet. Testing for the SPTLC1 mutation was positive. Comment. The diagnosis of HSAN I secondary to SPTLC1 mutations should be considered in patients with a motor and sensory neuropathy, even in the presence of demyelinating features, particularly if the patient has marked sensory involvement and a family history.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS therapies are the mainstay of HSAN III port, causes Tangier disease. Choles- h Genetic disorders with management. terol esters deposit in the tonsils systemic neurologic (orange tonsils), gastrointestinal tract, manifestations POLYNEUROPATHIES bone marrow, and Schwann cells. Chil- occasionally have ASSOCIATED WITH GENETIC dren present with neuropathy charac- coexisting neuropathy. DISORDERS THAT HAVE terized by fluctuating numbness and The presence of central SYSTEMIC NEUROLOGIC sensory loss with distal muscle weak- nervous system or MANIFESTATIONS ness. Initiation of a low-fat diet may upper motor neuron Many systemic disorders caused by improve the neuropathy symptoms.72 signs should trigger genetic mutations have a coexisting the search for these neuropathy. Often the neuropathy is Abetalipoproteinemia rare disorders, some of which have overshadowed by the systemic manifes- Mutations in the microsomal triglyceride specific treatments. tations of the disease. An overview of transfer protein cause this disease, h selected disorders having CMT-like fea- resulting in failure to absorb and trans- Hereditary ataxias, tures and specific treatment options are port vitamin E, which causes a sensori- including spinocerebellar ataxia, described in the following sections. motorneuropathyaswellassignsof can present with distal myelopathy, vision impairment with axonal neuropathy Spinocerebellar Ataxias retinitis pigmentosa, and fat malabsorp- with loss of reflexes. Spinocerebellar ataxias are a hetero- tion with steatorrhea. Typical clinical Pyramidal and cerebellar geneous group of genetic disorders features, along with laboratory findings signs suggest the associated with cerebellar and brain- of acanthocytosis, very low triglyceride hereditary ataxias as stem dysfunction. Some spinocerebellar and total cholesterol levels, and absent the underlying process. $ ataxia subtypes have an associated -lipoproteins, aid in the diagnosis. h Complicated hereditary axonal peripheral neuropathy, with re- Treatment with vitamin E (150 mg/kg/d) spastic paraplegia has duced muscle stretch reflexes and vibra- and other fat-soluble vitamins can pre- associated neurologic tion sense. The presence of pyramidal vent and partially reverse the neurologic features, including and cerebellar signs points in the direc- manifestations.73 ataxia, seizures, memory tion of spinocerebellar ataxia.70 problems, or axonal Refsum Disease peripheral neuropathy. Hereditary Spastic Paraplegia Refsum disease, which is due to defi- In patients presenting Hereditary spastic paraplegia is a het- cient activity of the peroxisomal enzyme with distal axonal neuropathy, lower limb erogeneous group of genetic disorders phytanoyl-coenzyme A hydroxylase spasticity and characterized by very slowly progressive caused by mutations in the pytanoyl- hyperreflexia should symmetric lower extremity spasticity CoA 2-hydroxylase (PHYH) gene, results raise the possibility of 71 and weakness. They are classified as in accumulation of phytanic acid, a hereditary spastic ‘‘uncomplicated’’ if other neurologic branched-chain fatty acid typically pres- paraplegia. signs are not present and ‘‘complicated’’ ent in dairy products and the meat of h Tangier disease is a rare if they are accompanied by ataxia, ungulates. Patients present in late teens but treatable cause of seizures, memory problems, or axonal to young adulthood with peripheral neuropathy. Consider peripheral neuropathy. Bilateral lower polyneuropathy, cerebellar ataxia, retini- this possibility in extremity spasticity and hyperreflexia tis pigmentosa, and albuminocytologic children presenting with with extensor plantar responses on dissociation. Strict reduction in dietary orange tonsils, examination raises concern for heredi- phytanic acid, or plasma exchange, can fluctuating numbness, tary spastic paraplegia. improve clinical manifestations.74 and sensory loss with distal muscle weakness. Tangier Disease Lysosomal Storage Diseases A low-fat diet may Mutations in ATP binding cassette This is a group of heterogeneous neuro- improve the neuropathy. subfamily A member 1 (ABCA1), which degenerative disorders character- regulates intracellular cholesterol trans- ized by accumulation of unmetabolized

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KEY POINTS h In patients presenting macromolecules within lysosomes. have an adult onset of symptoms and with sensorimotor Fabry disease, Krabbe disease, and present either with psychiatric manifes- neuropathy and metachromatic leukodystrophy are tations or spastic paraparesis. The pe- myelopathy; retinitis three of these disorders that exhibit ripheral neuropathy associated with pigmentosa and peripheral neuropathy. metachromatic leukodystrophy is a uni- steatorrhea; and Fabry disease. Fabry disease is an X- form or nonuniform demyelinating laboratory findings of linked glycolipid storage disease caused polyneuropathy.77 acanthocytosis, low by mutations in the "-galactosidase A triglycerides, and gene, resulting in systemic accumula- CONCLUSION total cholesterol tion of glycosphingolipids in lysosomes The genetic polyneuropathies are a levels, consider of blood vessels, nerves, and organs heterogeneous group of rare disorders abetalipoproteinemia. and leading to progressive renal failure, with the common feature of disrupted Treatment with vitamin E and cardiac disease, strokes, skin lesions, peripheral nerve function. The discovery fat-soluble vitamins and a painful small fiber neuropathy. of the underlying genetic mutations can help prevent and Enzyme replacement therapy (agalsi- responsible for CMT and other gene- partly reverse the dase) can improve all outcomes in tic neuropathies has helped identify neurologic manifestations. Fabry disease, with greater benefits seen the molecules needed for normal pe- 75 h Enzyme replacement with earlier initiation of treatment. ripheral nerve function, leading to ef- therapy (agalsidase) Krabbe disease. Krabbe disease is forts to expand diagnostic and treatment can improve the various an autosomal recessive disorder caused options for these disorders. organ damage seen in by deficiency of the enzyme galacto- Fabry disease, with cerebrosidase, which causes toxic accu- REFERENCES greater benefits seen mulation of galactosylsphingosine in the 1. Dyck PJ, Dyck JB, Grant A, Fealey RD. Ten with earlier initiation steps in characterizing and diagnosing white matter of the central nervous sys- patients with peripheral neuropathy. of treatment. tem and peripheral nerves. While the Neurology 1996;47(1):10Y17. doi:10.1212/ majority of patients show infantile onset WNL.47.1.10. of symptoms (irritability, spasticity, and 2. McLeod JG. Investigation of peripheral developmental delay, progressing to neuropathy. J Neurol Neurosurg Psychiatry 1995;58(3):274Y283. doi:10.1136/jnnp.58.3.274. death by age 2), 10% to 15% have a later onset with slower progression, pre- 3. Charcot JM, Marie P. Sur une forme particulie` re d’atrophie musculaire senting with spastic paraparesis. The progressive souvent familiale de´ butant par peripheral neuropathy associated with les pieds et les jambes et atteignant plus Krabbe disease is a uniformly demyelin- tard les mains. Rev Me´ d Paris 1886;6:97Y138. ating polyneuropathy.76 4. Tooth HH. The peroneal type of progressive Metachromatic leukodystrophy. muscular atrophy. London, UK: HK Lewis, 1886. Metachromatic leukodystrophy is an 5. Dejerine J, Sottas J. Sur la ne´vrite autosomal recessive lysosomal storage interstitielle, hypertrophique et progressive de l’enfant. C R Soc Biol 1893;45:63Y96. disease caused by mutations in the 6. Dyck PJ, Lambert EH. Lower motor and arylsulfatase A gene (ARSA), resulting primary sensory neuron diseases with in accumulation of sulfatides in cells peroneal muscular atrophy. I. Neurologic, that produce myelin in the central and genetic, and electrophysiologic findings in peripheral nervous systems. The most hereditary polyneuropathies. Arch Neurol 1968;18(6):603Y618. doi:10.1001/ common presentation is in late infancy, archneur.1968.00470360025002. with patients losing speech, becoming 7. Dyck PJ, Lambert EH. Lower motor and weak, developing gait disturbances, and primary sensory neuron diseases with gradually becoming hypertonic to the peroneal muscular atrophy. II. Neurologic, point of rigidity until they succumb in genetic, and electrophysiologic findings in various neuronal degenerations. Arch childhood. Of individuals with meta- Neurol 1968;18(6):619Y625. doi:10.1001/ chromatic leukodystrophy, 10% to 15% archneur.1968.00470360041003.

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