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Charcot-Marie-ToothDisease andOther GeneticPolyneuropathies

Sindhu Ramchandren, MD, MS

ABSTRACTPurpose of Review: Genetic polyneuropathies are rare and clinically heterogeneous.This article provides an overview of the clinical features, neurologic and electrodiagnosticfindings, and management strategies for Charcot-Marie-Tooth disease and othergenetic polyneuropathies as well as an algorithm for genetic testing.Recent Findings: In the past 10 years, many of the mutations causing geneticpolyneuropathies have been identified. International collaborations have led to thedevelopment of consortiums that are undertaking careful genotype-phenotypecorrelations to facilitate the development of targeted therapies and validation ofoutcome measures for future clinical trials. Clinical trials are currently under way forsome genetic polyneuropathies.Summary: Readers are provided a framework to recognize common presentations ofvarious genetic polyneuropathies and a rationale for current diagnostic testing andmanagement strategies in genetic polyneuropathies.

Continuum (Minneap Minn) 2017;23(5):1360–1377.

INTRODUCTIONChronic polyneuropathies have a broaddifferential, ranging from the relativelycommon causes, such as diabetes melli-tus, to rare genetic polyneuropathies.While at times strong evidence exists foran underlying genetic polyneuropathy(eg, clinical presentation in youth, pos-itive family history, slowly progressivecourse), genetic polyneuropathies canoccur from de novo mutations, areclinically heterogeneous, and can mimicother disorders. Given the long list ofpossible etiologies and the limited treat-ment options, defining the specificdiagnostic workup and extent of genetictesting can be challenging.1,2 Thisarticle presents a perspective on clinicalevaluation, testing, and management ofgenetic polyneuropathies, focusing on

Address correspondence toDr Sindhu Ramchandren,University of Michigan,Department of Neurology,2301 Commonwealth Blvd#1023, Ann Arbor, MI 48105,[email protected].

Relationship Disclosure:

Dr Ramchandren has servedon advisory boards for Biogenand Sarepta Therapeutics,Inc, and has receivedresearch/grant support fromthe Muscular DystrophyAssociation (FoundationClinic Grant) and theNational Institutes of Health(K23 NS072279).

Unlabeled Use ofProducts/Investigational

Use Disclosure:Dr Ramchandren reportsno disclosure.

* 2017 American Academyof Neurology.

the primary hereditary motor sensoryneuropathies, known collectively asCharcot-Marie-Tooth disease (CMT);the hereditary sensory and autonomicneuropathies; and the polyneuropathiesassociated with genetic disorders thathave systemic neurologic manifestations.

PRIMARY HEREDITARY MOTORSENSORY NEUROPATHIESThe primary hereditary motor sensoryneuropathies are known collectivelyas Charcot-Marie-Tooth disease (CMT)after the three investigators who de-scribed a familial slowly progressiveperoneal muscular atrophy in 1886.3,4

Around the same time, Dejerine andSottas described a hypertrophic intersti-tial neuritis associated with a severeinfantile form of CMT.5

1360 ContinuumJournal.com October 2017

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Classification of Charcot-Marie-Tooth DiseaseEarly classification schemes dividedCMT into three types: CMT1, a predom-inantly demyelinating polyneuropathybased on uniformly slow conductionvelocities of 38 meters per second orless in the upper extremities; CMT2, apredominantly axonal polyneuropathywith relatively normal velocities butprominently reduced sensory nerve orcompound muscle action potential(CMAP) amplitudes, indicating axonalloss; and CMT3, speculated to includerecessive disorders with a severephenotype.6Y9

The spectrum of neuropathic disor-ders in the CMT category has broad-ened, but several aspects of the originalclassification scheme have been re-tained. CMT remains broadly classifiedinto CMT1 (demyelinating) and CMT2(axonal). Dejerine-Sottas disease is nowpreferred over CMT3 to describe thegroup of severely affected infantswith CMT regardless of inheritancepattern or genetic mutation. CMT4refers to autosomal recessive CMT.With the discovery of the causal geneticmutations, letters have been added toindicate the gene. For example, dupli-cation of the peripheral myelin protein22 gene (PMP22) causes CMT1A, andmutations in the mitofusin 2 gene(MFN2) cause CMT2A.

The current CMT classificationsystem is shown in Table 7-1.10 Thissystem does not fully accommodatethe full genotypic and phenotypicvariability of CMT. For example,CMT1X does not fit into this schemeas it has intermediately slowed con-duction velocities and X-linked in-heritance, so it is grouped separately.Some dominantly inherited formsof CMT have intermediate-rangeslowing of conduction velocities inthe arms and are grouped separatelyas a dominant-intermediate form. As

the number of known mutations ingenes has grown, a new system thatemphasizes genetic classification isnow under consideration.11

Genetics of Charcot-Marie-ToothDiseaseOver 90% of patients with CMT harbor amutation in the PMP22, MFN2, myelinprotein zero (MPZ), or gap junctionprotein beta 1 (GJB1) gene.12 For theremaining 10%, inheritance patterns andassociated comorbidities can help de-fine the genetic etiology (Table 7-1).10

Most cases of CMT are inherited in anautosomal dominant manner. An auto-somal dominant mutation can alsooccur de novo in a patient. Children ofa parent with an autosomal dominantneuropathy have a 50% chance ofinheriting the disease, although variableexpression often results in a milder ormore severe disease than the parent. Ifthe autosomal dominant mutation oc-curred de novo, children of the affectedparent will also have a 50% chance ofhaving the disorder. Some cases of CMTare X-linked dominant; only one mutantgene copy is needed for the disease tobe present. An affected mother withCMT1X has a 50% chance of passing iton to her sons or to her daughters. Anaffected father with CMT1X will nevertransmit the mutation to his sons, buthas a 100% chance of transmitting it tohis daughters. Finally, some CMT casesare inherited in an autosomal recessivemanner; persons with one normal copyand one mutant copy are carriers andare unaffected. The children of twocarriers have a 25% chance of inheritingboth copies and having the disease. Allchildren of an affected parent with auto-somal recessive disease will have onecopy of the mutant gene; assuming theother parent is not also a carrier, noneof the children will have the disease.

Approximately 80% to 90% of casesof autosomal dominant CMT1 are

KEY POINTS

h Charcot-Marie-Toothdisease is not a singleentity but rather aspectrum ofneuropathic disordersthat result fromgenetic mutations.Charcot-Marie-Toothdisease can be classifiedinto type 1 (CMT1,demyelinating), type 2(CMT2, axonal),Dejerine-Sottas disease(severe infantile-onsetCharcot-Marie-Toothdisease), type 4 (CMT4,autosomal recessive),and type 1X (CMT1X,X-linked inheritance).

h Over 90% of patientswith Charcot-Marie-Toothdisease have a mutationin the PMP22, MFN2,MPZ, or GJB1 gene.

h An autosomal dominantmutation can occur denovo in a patient.

h Each child of a parentwith an autosomaldominant neuropathyhas a 50% chance ofinheriting the disease.

h A father who hasCharcot-Marie-Toothdisease type 1X willalways transmit thedisease to his daughtersbut never to his sons.

1361Continuum (Minneap Minn) 2017;23(5):1360–1377 ContinuumJournal.com



CMT1A, which is due to a 1.4-Mbduplication of the PMP22 gene onchromosome 17p11.2, expressed inSchwann cells that produce myelinsheaths for peripheral nerves. Onepercent to nine percent are due to aPMP22 deletion, which causes heredi-tary neuropathy with liability to pres-sure palsies (HNPP), presenting with

recurrent pressure palsies. Of the auto-somal dominant CMT1 cases, 10% aredue to CMT1B, caused by mutations inthe MPZ gene, which results in delete-rious overexpression of the major mye-lin structural protein.12Y14

CMT1X is caused by a mutation onthe X chromosome in the GJB1 gene,also known as the connexin 32 gene.

TABLE 7-1 Classification Scheme of Charcot-Marie-Tooth Diseasea

Type Pathology/Phenotype Inheritance

Percentage ofCharcot-Marie-Tooth Cases Subtype

Gene/Chromosome

CMT1 Myelin abnormalities;distal weakness, atrophy,and sensory loss; onset:È5 to 20 years; motornerve conduction velocityG38 meters per second

Autosomaldominant

50Y80 CMT1A PMP22

CMT1B MPZ

CMT1C LITAF

CMT1D EGR2

CMT1E PMP22

CMT1F/2E NEFL

CMT2 Axonal degeneration;distal weakness andatrophy, variablesensory involvement;complicated andsevere cases described;motor nerve conductionvelocity 938 metersper second; onset:variable

Autosomaldominant

10Y15 CMT2A MFN2

CMT2B RAB7A

CMT2C TRPV4

CMT2D GARS

CMT2E/1F NEFL

CMT2F HSPB1

CMT2G 12q12-q13

CMT2H/2K GDAP1

CMT2I/2J MPZ

CMT2L HSPB8

CMT2M SYNM

CMT2N AARS

CMT2O DYNC1H1

CMT2P LRSAM1

CMT2S IGHMBP2

CMT2T DNAJB2

CMT2U MARS

Intermediateform

Myelinopathy and axonal;Motor nerve conductionvelocity 925 meters persecond and G38 metersper second

Autosomaldominant

Less than 4 DI-CMTA Unknown

DI-CMTB DNM2

DI-CMTC YARS

DI-CMTD MPZ

DI-CMTF GNB4

Continued on page 1363


Charcot-Marie-Tooth Disease



The gene is expressed in myelinatingSchwann cells and the mutation isthought to cause a loss of func-tion.15,16 CMT2A accounts for 20% to30% of all causes of CMT2 due tomutations in the MFN2 gene.17,18

Clinical PresentationCMT is the most common geneticneuromuscular disorder, with a preva-lence between 1 in 1213 to 1 in2500.19,20 Historically, patients haveone of three clinical patterns. Thetypical phenotype is characterized bynormal motor milestones but slowlyprogressive symmetric distal leg weak-ness with sensory loss, usually begin-ning in the first to third decade and

progressing to footdrop and handweakness (Case 7-1). On examination,besides the distal weakness and sen-sory loss, reflexes are often globallysuppressed or absent. At most, thesepatients require ankle-foot orthoses forambulation.8,9,21 A second presentationis characterized by an earlier onset ofsymptoms with delayed walking (afterage 15 months or more), toe walking,or clumsiness in childhood. Patientswith this phenotype progress toabove-the-knee bracing, walkers, orwheelchairs for ambulation.22Y25 A thirdpresentation is characterized by adultonset (around 40 years) with variablesubsequent progression. The sameCMT gene mutation can present in any

TABLE 7-1 Classification Scheme of Charcot-Marie-Tooth Diseasea Continued from page 1362

Type Pathology/Phenotype Inheritance

Percentage ofCharcot-Marie-Tooth Cases Subtype

Gene/Chromosome

CMT4 Demyelinating; recessive;variable presentations/phenotypes

Autosomalrecessive

Rare CMT4A GDAP1

CMT4B1 MTMR2

CMT4B2 SBF2

CMT4B3 SBF1

CMT4C SH3TC2

CMT4D NDRG1

CMT4E EGR2

CMT4F PRX

CMT4G HK1

CMT4H FGD4

CMT4J FIG4CMT2B1 LMNA

CMT2B2 MED25

CMTX Axonal degeneration withmyelin abnormalities

X-linked 10Y15 CMTX1 GJB1

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.



http://dovepress.com/management-of-charcotndashmariendashtooth-disease-improving-long-term--peer-reviewed-fulltext-article-JMDH


of these three ways, demonstratingthe marked phenotypic variability of asingle genotype.

Foot deformities, such as pes cavusand hammer toes, are common in CMTand are often the reason providers firstconsider the diagnosis. Foot deformi-ties may progress to contracture withmarked osseous changes (Figure 7-1).26

However, these deformities are notalways associated with neuropathiesand may occur in isolation or in con-junction with central nervous system ordevelopmental disorders.27,28

CMT in children and adults is associ-ated with psychological stress, reducedhealth-related quality of life, and othercomorbidities.29Y31 Although historicallycharacterized as painless, a significantproportion of children and adults withCMT report pain that may be neuro-genic, musculoskeletal, or both.32Y34

Males with CMT1X may rarely presentwith strokelike symptoms, including dys-arthria, ataxia, weakness, and transientwhite matter hyperintensities on MRI(Figure 7-2 and Case 7-2).35 Hearingloss, hip dysplasia, and sleep apnea arealso reported findings with CMT.36,37

ElectrophysiologyElectrodiagnostic studies, especiallynerve conduction studies, are importanttools to establish the presence ofpolyneuropathy, extent of damage, anddemyelinating versus axonal physiology.Demyelinating forms of CMT are diag-nosed based on uniformly slowedconduction velocities of 38 meters persecond or less in the upper extremities,without evidence of conduction blockor temporal dispersion (the latter twoare features associated with acquireddemyelinating neuropathies). Diagnosisof axonal forms is based on relativelynormal velocities but prominently re-duced sensory nerve action potential(SNAP) amplitudes, reduced CMAP am-plitudes, or both.6Y9

An Approach to Diagnosis andGenetic TestingObtaining a detailed family pedigree,ideally of three generations or more,is one of the most important stepsin establishing a possible diagnosisin CMT. Patients should specificallybe asked about early deaths in theextended family, consanguinity, and

KEY POINT

h Pes cavus and hammertoes, while an importantphysical feature ofCharcot-Marie-Toothdisease, are not specificto the disease and mayoccur in isolation or inconjunction with otherdisorders of the centralnervous system.

Case 7-1A 16-year-old boy with no family history of neuropathy was broughtto the clinic by his parents for evaluation of clumsy gait, tripping,and falling. The patient denied any problems but had pes cavus andbilateral footdrop and walked with a steppage gait; he had mild handintrinsic muscle atrophy and was areflexic. His nerve conduction studiesshowed a conduction velocity of 22 meters per second along theulnar and median motor nerves without conduction block or temporaldispersion. Because of his youth and the lack of family history, hispediatrician had tried monthly IV immunoglobulin (IVIg) for 6 months inthe hope that this was chronic inflammatory demyelinatingpolyradiculoneuropathy (CIDP), without benefit. Genetic testingconfirmed a diagnosis of Charcot-Marie-Tooth disease type 1A(PMP22 duplication).

Comment. De novo mutations, as in this case, are not uncommonin Charcot-Marie-Tooth disease. In young patients, when the differentialdiagnosis includes a potentially treatable disorder, genetic testing becomesmore valuable and is less costly and safer than a treatment trial of IVIg.





family members with walking prob-lems without a clear diagnosis. Thelikelihood of genetic neuropathy ishigh in the patient with symmetricdistal weakness and sensory lossstarting in youth, pes cavus footdeformity with hammer toes, slowedconduction velocities on nerve con-duction studies, and a strong familyhistory. The diagnosis is not obviouswhen the family history is unknown orthe mutation is de novo, the neurop-athy is axonal, or symptom onset islater in life. Concluding that a patientmay have a genetic polyneuropathy

without a specific rationale is oftennot in the patient’s best interest. Morespecific diagnosis provides the patientwith the most accurate inheritanceand risk information, which is impor-tant in making reproductive decisions.Different mutations progress at differentrates and are associated with differentcomorbidities that physicians shouldlook for in individuals who are at risk.

Motor nerve conduction velocitiesin the upper extremities can be usedin diagnostic algorithms (Figure 7-3,Figure 7-4, Figure 7-5, and Figure 7-6).12

The conduction velocity convention

FIGURE 7-1 Classification of Charcot-Marie-Tooth diseasefoot deformity. A, First stage: flexible cavusfoot, reducible. B, Second stage: equinus and

pronation of first ray (the column of bones and jointsforming the medial border of the forefoot), possible reducibleclawing of great toe. C, Third stage: equinus of wholeforefoot, 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 fixeddeformity, pronounced osseous changes, irreducibleclawing of toes with subluxation or luxation ofmetatarsophalangeal 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.



http://journals.lww.com/jbjsjournal/Abstract/2015/03180/Surgical_Treatment_of_Cavus_Foot_in.13.aspx

http://journals.lww.com/jbjsjournal/Abstract/2015/03180/Surgical_Treatment_of_Cavus_Foot_in.13.aspx


Case 7-2The 9-year-old son of a woman with mild Charcot-Marie-Tooth diseasepresented to the emergency department with 3 hours of sudden-onsetslurred speech and left-sided clumsiness. Examination showed mild ataxiaof the left arm and leg, slightly high-arched feet, and weakness ofbilateral ankle dorsiflexion. MRI of the brain showed acute white matterchanges in the posterior fossa. The patient’s symptoms slowly improvedover the next 24 hours as he was kept in observation and completelyresolved over the next 10 days.

Comment. This is a typical case of Charcot-Marie-Tooth disease type 1Xwith transient strokelike symptoms. The gap junction protein connexin32 is not only expressed in Schwann cells but also in the central nervoussystem oligodendrocytes. Symptom resolution may take weeks, and,while rare, repeated attacks may occur.

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 thethird 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 wasnoted to have hyporeflexia at the ankles and minimal weakness in ankle dorsiflexion; a family history ofCharcot-Marie-Tooth disease (CMT) and subsequent genetic testing confirmed X-linked CMT. At age 15, hedeveloped 2 days of mild right arm weakness and worsening handwriting, followed by 8 hours of severehemiparesis of the left face and arm, dysarthria, and dysphagia, which lasted about 8 hours, with completeresolution. MRI performed 2 days later again showed symmetric abnormally increased T2 signal and diffusionreduction in the posterior frontal and parietal white matter bilaterally (E, F). Repeat brain MRI 11 weeks latershowed a return to normal diffusion and improvement in the abnormal T2 signal, with some mild areas ofpersistently 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.




http://neurology.org/content/61/11/1475.full


used in this classification system definesnormal as greater than 45 meters persecond, intermediate as 35 meters persecond to 45 meters per second, slowas 15 meters per second to 35 metersper second, and very slow as less than15 meters per second.

Diagnostic algorithms work mosteffectively when used with patientssuspected to be at risk for CMT. Thepercent of positive gene tests for CMTwas 18% in one large study of a diversepopulation of patients with neuro-pathy,38 compared with 60% in a

FIGURE 7-3 Axonal Charcot-Marie-Tooth disease with normal motornerve conduction velocity. Algorithm for geneticallydiagnosing Charcot-Marie-Tooth disease in patients with

normal motor nerve conduction velocities and evidence of axonal loss. Inmost cases, motor nerve conduction velocities in upper extremities aregreater than 45 meters per second. However, in severe cases, thesepotentials may be absent. In those cases, it is important to test proximalnerves to ensure that the patient does not have a severe demyelinatingneuropathy that can mimic axonal Charcot-Marie-Tooth disease. Thisalgorithm is designed to be a general guide and is not intended to encompassevery 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.



http://onlinelibrary.wiley.com/doi/10.1002/ana.22166/abstract



confirmed CMT population,39 empha-sizing the need to select the rightpatient for the right test.

Next-generation gene sequencingcan search for mutations in panels ofgenes, including cost-effective corepanels that look for mutations inPMP22, MPZ, GJB1, and MFN2, com-prising the etiology of 90% of muta-tions in CMT patients.12 Bulk genesurveys also increase the probability ofidentifying variants that may or maynot be pathologic. Using a reference

sequence database, such as the Na-tional Heart, Lung, and Blood InstituteExome Sequencing Project ExomeVariant Server (evs.gs.washington.edu/EVS/), can help distinguish commonpolymorphisms from pathologic vari-ants. Genetic counseling also serves animportant role before testing to deter-mine the appropriateness of the test andthe most cost-effective testing strategy.After testing, genetic counseling can aidin the interpretation of results anddirect future testing if needed.

FIGURE 7-4 Charcot-Marie-Tooth disease with intermediate motor nerveconduction velocity. Algorithm for genetically diagnosingCharcot-Marie-Tooth disease in patients with intermediate

upper extremity motor nerve conduction velocities. This algorithm is designed tobe a general guide and is not intended to encompass every potential clinicalscenario or all possible genetic etiologies.



B 2011 American Neurological Association. onlinelibrary.wiley.com/doi/10.1002/ana.22166/abstract.




http://evs.gs.washington.edu/EVS/

http://evs.gs.washington.edu/EVS/



ManagementCurrently no disease-modifying treat-ment exists for CMT. Several largemulticenter trials showed no effectof varying doses of ascorbic acid totreat CMT1A40Y42 but laid the ground-work for an international collaborationstudying the natural history of CMT39

and validating new outcome measuresfor future clinical trials.43Y45 Currently,an international trial is under wayevaluating the safety and efficacy of

PXT3003, a combination of naltrexone,baclofen, and sorbitol, in 300 patientswith CMT1A (NCT02579759).46

Current patient management can beoptimized with a multidisciplinaryapproach to care. An annual evaluationby a neurologist, physiatrist, or bothcan assess the patient’s function andcontinuing needs. Additional ancillaryservices are important to retain func-tional independence. Physical therapyplays a major role in gait retraining,

FIGURE 7-5 Charcot-Marie-Tooth disease with slow motor nerveconduction velocity. Algorithm for geneticallydiagnosing Charcot-Marie-Tooth disease in patients

with slow upper extremity motor nerve conduction velocities. Thisalgorithm is designed to be a general guide and is not intended toencompass every potential clinical scenario or all possible genetic etiologies.



B 2011 American Neurological Association. onlinelibrary.wiley.com/doi/10.1002/

ana.22166/abstract.






maintaining core muscle strength, en-ergy conservation, and use of serialcasting and night splinting to improverange of motion.47Y50 Occupationaltherapy can improve hand range ofmotion and provide tools to improveactivities of daily living, such as but-toning clothing, opening bottles, and

using eating utensils.51 An orthotistmay provide ankle-foot orthoses toimprove gait and energy conservation,prevent falls, and reduce long-termdamage to knee and hip joints.52,53

Orthopedic interventions, such astendon lengthening and tendontransfer, can help maintain long-term

FIGURE 7-6 Charcot-Marie-Tooth disease with very slow motor nerveconduction velocity. This algorithm is designed to be ageneral guide and is not intended to encompass everypotential clinical scenario or all possible genetic etiologies.



B 2011 American Neurological Association.

onlinelibrary.wiley.com/doi/10.1002/ana.22166/abstract.






function,26,54 and guidelines are cur-rently being developed to direct propertiming of interventions to optimize out-comes. Pain management for geneticneuropathies follows the same princi-ples as for other chronic neuropathies,including encouragement of movementand activity, maintenance of a healthybody mass index, and avoidance ofnarcotics for long-term pain control.55

HEREDITARY SENSORY ANDAUTONOMIC NEUROPATHIESThe primary hereditary sensory andautonomic neuropathies (HSANs) pre-dominantly affect myelinated and un-myelinated sensory nerves but alsohave motor nerve involvement.

Classification of HereditarySensory and AutonomicNeuropathiesThe disorders are broadly classified intofive types: HSAN I with autosomaldominant inheritance (the most com-mon form, but genetically heteroge-neous), HSAN II (autosomal recessiveinheritance, early onset), HSAN III(familial dysautonomia, also known asRiley-Day syndrome, with autosomalrecessive inheritance), and HSAN IVand HSAN V (congenital insensitivity topain with anhidrosis; autosomal reces-sive inheritance). HSAN IV is alsoassociated with developmental delay.56

Genetics of Hereditary Sensoryand Autonomic NeuropathiesHSAN I is clinically heterogeneous,resulting from mutations in the serinepalmitoyltransferase long chain basesubunit 1 (SPTLC1), serine palmitoyl-transferase long chain base subunit 2(SPTLC2), atlastin GTPase 1 (ATL1),DNA methyltransferase 1 (DNMT1),and atlastin GTPase 3 (ATL3) genes.The SPTCL1 gene encodes for serinepalmitoyltransferase, which synthesizes

sphingolipids. Mutations in SPTCL1 re-sult in neurotoxic sphingolipid metabo-lite accumulation.57 HSAN II is causedby mutations in the WNK lysine defi-cient protein kinase 1 gene (WNK1).HSAN III is caused by mutations in theinhibitor of kappa light polypeptide geneenhancer in B-cells, kinase complex-associated protein gene (IKBKAP) andis limited to children of AshkenaziJewish descent. HSAN IV and HSAN Vare caused by mutations in neuro-trophic receptor tyrosine kinase 1 gene(NTRK1) and the nerve growth factorgene (NGF).56

Clinical PresentationThe typical presentation of patientswith HSAN I includes sensory loss andneuropathic pain, sometimes withfoot ulceration. While mean age ofpresentation is in the mid-twenties,patients have presented in their teensand in the late seventies to eighties.Autonomic and motor involvementcan be variable. Some patients alsohave sensorineural deafness anddementia. Pes cavus and absent re-flexes can be seen on examination.58

HSAN II, involving both large andsmall nerve fibers, presents with lossof pain, temperature, pressure, andtouch sensation. It is associated withself-mutilation of fingers and toesand can come to initial medical atten-tion because of recurrent infections.59

HSAN III presents with sympatheticautonomic dysfunction, including or-thostatic hypotension, excessive sali-vation, gastrointestinal dysmotility,bladder dysfunction, decreased orabsent tearing, absent fungiformtongue papillae, pupillary dilatation,hypohidrosis, and episodic hyper-hidrosis. Episodes of dysautonomiccrises can be triggered by physicaland emotional stress.60 Patients withHSAN IV present in infancy withmild to moderate developmental

KEY POINTS

h A multidisciplinaryapproach to the careof patients withCharcot-Marie-Toothdisease helps patientsretain functionalindependence.

h While sensorysymptomspredominate, manypatients withhereditary sensoryand autonomicneuropathies alsohave motorabnormalities.




delay; profound insensitivity to pain;and self-mutilation of digits, face, andmouth regions. HSAN IV differs fromHSAN III by preservation of tearing andtongue papillae. Almost 20% of patientswith HSAN die from hyperpyrexia be-fore the age of 3.61 HSAN V presents asa milder phenotype of HSAN IV; devel-opmental delay, if present, is mild.62

ElectrophysiologyNerve conduction studies in HSAN arehighly variable, reflecting the geneticheterogeneity. HSAN I mostly pre-sents with an axonal sensory morethan motor neuropathy; however, mo-tor nerve conduction slowing into thedemyelinating range can be seen.63

HSAN II mainly shows an axonalneuropathy with absent sensory re-sponses. HSAN III, similar to HSAN I,is associated with sensory more thanmotor involvement.64 HSAN IV andHSAN V, which predominantly affectsmall myelinated and unmyelinatednerve fibers, typically show normalnerve conduction studies.

Diagnosis and ManagementProminent sensory and autonomicmanifestations should raise concernfor the diagnosis of HSAN. The diagno-sis of HSAN I secondary to SPTLC1mutations should be considered in

patients with a motor and sensoryneuropathy, even in the presence ofdemyelinating features, particularly ifthe patient has marked sensory involve-ment and a family history (Case 7-3).Intrauterine diagnosis of HSAN III cannow be made with about 98% percentaccuracy using linked genetic markersin affected families,65 and prenatalscreening for this disease has contrib-uted to its marked decline in theUnited States.66

Experimental studies have attemptedto reduce the level of toxic sphingolipidmetabolites to ameliorate HSAN I. Die-tary supplementation with oral L-serinein SPTLC1-mutant mice reduced thesphingolipid metabolites and improvedmotor and sensory performance. Four-teen patients with HSAN I who receivedL-serine supplementation for 10 weeksalso showed reduced sphingolipidmetabolites.67 However, despite thesepromising studies, no specific treatmentexists for HSAN. Chronic sores andinfections can lead to osteomyelitisand eventual amputation.68 Manage-ment requires protection of the extrem-ities, shoes that fit properly, orthoticsfor footdrop, treatment of callus for-mation, proper dressing of wounds topromote healing, and avoidance oftrauma to the hands and feet.69 Simi-larly, supportive care and symptomatic

Case 7-3A 12-year-old girl had been repeatedly seen in urgent care over several monthsfor symptoms of pain in the feet. Examination showed no visible footdeformities, limited strength examination because of pain, and allodynia to allsensory modalities at the feet with reduced perception to pin and vibration inthe distal legs. Nerve conduction studies showed a demyelinatingmotor-sensory polyneuropathy. Genetic testing for PMP22 deletion, duplica-tion, and sequencing were negative. The girl’s father had a long-term historyof disabling pain in the feet. Testing for the SPTLC1 mutation was positive.

Comment. The diagnosis of HSAN I secondary to SPTLC1 mutations shouldbe considered in patients with a motor and sensory neuropathy, even in thepresence of demyelinating features, particularly if the patient has markedsensory involvement and a family history.





therapies are the mainstay of HSAN IIImanagement.

POLYNEUROPATHIESASSOCIATED WITH GENETICDISORDERS THAT HAVESYSTEMIC NEUROLOGICMANIFESTATIONSMany systemic disorders caused bygenetic mutations have a coexistingneuropathy. Often the neuropathy isovershadowed by the systemic manifes-tations of the disease. An overview ofselected disorders having CMT-like fea-tures and specific treatment options aredescribed in the following sections.

Spinocerebellar AtaxiasSpinocerebellar ataxias are a hetero-geneous group of genetic disordersassociated with cerebellar and brain-stem dysfunction. Some spinocerebellarataxia subtypes have an associatedaxonal peripheral neuropathy, with re-duced muscle stretch reflexes and vibra-tion sense. The presence of pyramidaland cerebellar signs points in the direc-tion of spinocerebellar ataxia.70

Hereditary Spastic ParaplegiaHereditary spastic paraplegia is a het-erogeneous group of genetic disorderscharacterized by very slowly progressivesymmetric lower extremity spasticityand weakness.71 They are classified as‘‘uncomplicated’’ if other neurologicsigns are not present and ‘‘complicated’’if they are accompanied by ataxia,seizures, memory problems, or axonalperipheral neuropathy. Bilateral lowerextremity spasticity and hyperreflexiawith extensor plantar responses onexamination raises concern for heredi-tary spastic paraplegia.

Tangier DiseaseMutations in ATP binding cassettesubfamily A member 1 (ABCA1), whichregulates intracellular cholesterol trans-

port, causes Tangier disease. Choles-terol esters deposit in the tonsils(orange tonsils), gastrointestinal tract,bone marrow, and Schwann cells. Chil-dren present with neuropathy charac-terized by fluctuating numbness andsensory loss with distal muscle weak-ness. Initiation of a low-fat diet mayimprove the neuropathy symptoms.72

AbetalipoproteinemiaMutations in the microsomal triglyceridetransfer protein cause this disease,resulting in failure to absorb and trans-port vitamin E, which causes a sensori-motor neuropathy as well as signs ofmyelopathy, vision impairment withretinitis pigmentosa, and fat malabsorp-tion with steatorrhea. Typical clinicalfeatures, along with laboratory findingsof acanthocytosis, very low triglycerideand total cholesterol levels, and absent$-lipoproteins, aid in the diagnosis.Treatment with vitamin E (150 mg/kg/d)and other fat-soluble vitamins can pre-vent and partially reverse the neurologicmanifestations.73

Refsum DiseaseRefsum disease, which is due to defi-cient activity of the peroxisomal enzymephytanoyl-coenzyme A hydroxylasecaused by mutations in the pytanoyl-CoA 2-hydroxylase (PHYH) gene, resultsin accumulation of phytanic acid, abranched-chain fatty acid typically pres-ent in dairy products and the meat ofungulates. Patients present in late teensto young adulthood with peripheralpolyneuropathy, cerebellar ataxia, retini-tis pigmentosa, and albuminocytologicdissociation. Strict reduction in dietaryphytanic acid, or plasma exchange, canimprove clinical manifestations.74

Lysosomal Storage DiseasesThis is a group of heterogeneous neuro-degenerative disorders character-ized by accumulation of unmetabolized

KEY POINTS

h Genetic disorders withsystemic neurologicmanifestationsoccasionally havecoexisting neuropathy.The presence of centralnervous system orupper motor neuronsigns should triggerthe search for theserare disorders, someof which havespecific treatments.

h Hereditary ataxias,includingspinocerebellar ataxia,can present with distalaxonal neuropathywith loss of reflexes.Pyramidal and cerebellarsigns suggest thehereditary ataxias asthe underlying process.

h Complicated hereditaryspastic paraplegia hasassociated neurologicfeatures, includingataxia, seizures, memoryproblems, or axonalperipheral neuropathy.In patients presentingwith distal axonalneuropathy, lower limbspasticity andhyperreflexia shouldraise the possibility ofhereditary spasticparaplegia.

h Tangier disease is a rarebut treatable cause ofneuropathy. Considerthis possibility inchildren presenting withorange tonsils,fluctuating numbness,and sensory loss withdistal muscle weakness.A low-fat diet mayimprove the neuropathy.




macromolecules within lysosomes.Fabry disease, Krabbe disease, andmetachromatic leukodystrophy arethree of these disorders that exhibitperipheral neuropathy.

Fabry disease. Fabry disease is an X-linked glycolipid storage disease causedby mutations in the "-galactosidase Agene, resulting in systemic accumula-tion of glycosphingolipids in lysosomesof blood vessels, nerves, and organsand leading to progressive renal failure,cardiac disease, strokes, skin lesions,and a painful small fiber neuropathy.Enzyme replacement therapy (agalsi-dase) can improve all outcomes inFabry disease, with greater benefits seenwith earlier initiation of treatment.75

Krabbe disease. Krabbe disease isan autosomal recessive disorder causedby deficiency of the enzyme galacto-cerebrosidase, which causes toxic accu-mulation of galactosylsphingosine in thewhite matter of the central nervous sys-tem and peripheral nerves. While themajority of patients show infantile onsetof symptoms (irritability, spasticity, anddevelopmental delay, progressing todeath by age 2), 10% to 15% have alater onset with slower progression, pre-senting with spastic paraparesis. Theperipheral neuropathy associated withKrabbe disease is a uniformly demyelin-ating polyneuropathy.76

Metachromatic leukodystrophy.Metachromatic leukodystrophy is anautosomal recessive lysosomal storagedisease caused by mutations in thearylsulfatase A gene (ARSA), resultingin accumulation of sulfatides in cellsthat produce myelin in the central andperipheral nervous systems. The mostcommon presentation is in late infancy,with patients losing speech, becomingweak, developing gait disturbances, andgradually becoming hypertonic to thepoint of rigidity until they succumb inchildhood. Of individuals with meta-chromatic leukodystrophy, 10% to 15%

have an adult onset of symptoms andpresent either with psychiatric manifes-tations or spastic paraparesis. The pe-ripheral neuropathy associated withmetachromatic leukodystrophy is a uni-form or nonuniform demyelinatingpolyneuropathy.77

CONCLUSIONThe genetic polyneuropathies are aheterogeneous group of rare disorderswith the common feature of disruptedperipheral nerve function. The discoveryof the underlying genetic mutationsresponsible for CMT and other gene-tic neuropathies has helped identifythe molecules needed for normal pe-ripheral nerve function, leading to ef-forts to expand diagnostic and treatmentoptions for these disorders.

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h In patients presentingwith sensorimotorneuropathy andmyelopathy; retinitispigmentosa andsteatorrhea; andlaboratory findings ofacanthocytosis, lowtriglycerides, andtotal cholesterollevels, considerabetalipoproteinemia.Treatment withvitamin E andfat-soluble vitaminscan help prevent andpartly reverse theneurologic manifestations.

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