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Semin Neurol 2008; 28(2): 185-194

Year DOI: 10.1055/s-2008-1062264
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2008
© Thieme Medical Publishers
Issue Charcot-Marie-Tooth Neuropathies: Diagnosis and Management
05: Neurological C onsultatio
Agnes Jani-Acsadi1 , Karen Krajewski1 , Michael E. Shy1
04: Neuroimaging Essentials

03: Epilepsy 1
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Table of Contents
Table of Contents ABSTRACT
HISTORICAL NOTES
Current Issue
RECLASSIFICATION OF CHARCOT-MARIE-TOOTH DISEASE: THE MOLECULAR ERA
Sample Issue (01/2019) EPIDEMIOLOGY
CLINICAL FEATURES OF INHERITED NEUROPATHY
PATHOGENESIS: GENOTYPE-PHENOTYPE CORRELATIONS
DOES THE ELECTROPHYSIOLOGY REFLECT THE PATHOPHYSIOLOGY?
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APPROACH TO DIAGNOSIS AND MANAGEMENT
MANAGEMENT
THERAPY: NEW CLINICAL APPROACHES
CONCLUSIONS
ADDENDUM: RESOURCES FOR PATIENTS AND FAMILIES
Patient Support Organizations
Online Resources
REFERENCES
#

ABSTRACT

Charcot-Marie-Tooth (CMT) disease is caused by mutations in several genes expressed in myelinating

Schwann cells and the axons they ensheathe. Typical patients present with distally accentuated motor
weakness, muscle wasting, and sensory loss leading to significant and progressive clinical morbidity and
impaired quality of life. The wealth of recent information regarding genotype-phenotype correlations,
recognition of disease heterogeneity, and newly characterized animal models provide exciting insights into
the molecular disease-related pathogenetic and pathophysiologic mechanisms. These advances at the
same time also represent a challenge for the diagnosis and management of these patients, with no
presently available specific curative or disease modifying treatments. A better understanding of the
pathogenesis of peripheral neuropathies is an invaluable tool in developing future supportive and curative
Related Journals therapies for patients with CMT disease that will improve their quality of life. In this review, we provide
practical insights on current diagnostic and therapeutic modalities and suggest future diagnostic and
Neuropediatrics therapeutic directions. #

Journal of Pediatric
Neurology
KEYWORDS
Journal of Brachial Plexus
Charcot-Marie-Tooth disease - heterogeneity - diagnosis - treatment
and Peripheral Nerve
Injury
Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited, nonmetabolic neuropathies
Journal of Neurological afflicting ~1 in 2500 people worldwide.[1] [2] [3] This disease was first referred to as peroneal muscular
Surgery Part A: Central atrophy by Charcot, Marie,[4] and Tooth[5] in 1886 and was considered until recently as one specific
European Neurosurgery disease entity. Advances in the field of clinical and molecular diagnosis and in genetic and
Journal of Neurological electrophysiological testing have enhanced our understanding of the syndrome of Charcot, Marie, and
Surgery Part B: Skull Tooth, and have led to the development of new diagnostic and treatment possibilities. #
Base
Journal of Neurological HISTORICAL NOTES
Surgery Reports
Journal of Pediatric The term CMT disease is broadly interchangeable with hereditary motor-sensory neuropathies (HMSNs). The
Epilepsy typical clinical presentation of these patients is well recognized: progressive, distally accentuated
weakness and atrophy of muscles innervated by the peroneal nerve followed by weakness and atrophy of
Indian Journal of hands, sensory loss, and characteristic foot abnormalities. The disease is most often passed from one
Neurosurgery generation to the other. The clinical heterogeneity of this peripheral nerve disease was recognized at the
Indian Journal of turn of the century when Dejerine and Sottas (1893) described cases that were more severe and had an
Neurotrauma onset in infancy,[6] and later when Roussy and Levy[7] (1926) described cases associated with tremor,
ataxia, areflexia, and pes cavus. First attempts at classification were based on clinicopathological and
International Journal of
inheritance patterns,[8] [9] but the real breakthrough came with the introduction of nerve conduction
Epilepsy
testing in the 1960s. Early electrodiagnostic studies suggested that most patients with CMT could be
Journal of divided into two groups, one with slow nerve conduction velocities and pathological evidence of a
Neuroanaesthesiology hypertrophic demyelinating neuropathy (CMT type 1 [CMT1]), and another with relatively preserved nerve
and Critical Care conduction velocities with pathological evidence of axonal loss (CMT type 2 [CMT2]).[10] [11] [12] [13]
Journal of Neurosciences Patients with CMT1 were found to have median motor nerve conduction velocities below 38 m/s, whereas
in Rural Practice median motor nerve conduction velocities were greater than 38 m/s in patients with CMT2. Approximately
75% of the patients belonging to the first group, similar to the ones described by Charcot, Marie, and
Tooth, were found to have an autosomal-dominant pattern of inheritance, weakness, and sensory loss
predominantly in the distal legs, and muscle wasting in the distribution of weakened muscles. Most patients
Related Books
presented within the first two decades of life. However, sporadic occurrence observed in 25% of patients
suggested a different inheritance pattern, such as autosomal-recessive or potentially new dominant
Neurology mutations. #

RECLASSIFICATION OF CHARCOT-MARIE-TOOTH DISEASE: THE

MOLECULAR ERA

The electrophysiological dichotomy of demyelinating and axonal CMT neuropathies (as reflected in the
original classification by Dyck and Lambert [Table [1]]) was supported by early experimental data from
transgenic animal models,[14] [15] which linked the demyelinating and axonal forms of CMT to primary
defects in Schwann cell and axonal function. This concept had to be revised, however, when it was
recognized that despite obvious similarities among patients with CMT1, the group is genetically
heterogeneous. The most common form of CMT1, CMT1A, was associated with a 1.4 Mb duplication at
chromosome 17p11.2.[16] [17] Reports of other genetic defects associated with hereditary neuropathies
soon followed. CMT1B, linked to chromosome 1, is caused by mutations in the gene of myelin protein zero
(MPZ) glycoprotein; X-linked neuropathy, CMTX1, is due to mutations in the gap junction (GJB1) on the X
chromosome encoding the gap junction protein, connexin 32. Deletion of the identical 1.4-Mb region
responsible for CMT1A is associated with hereditary neuropathy with susceptibility to pressure palsies
(HNPPs). Dejerine-Sottas disease (DSD), a severe infantile neuropathy, is associated with mutations or
deletions in peripheral myelin protein 22 (PMP22), MPZ, early growth response gene 2 (EGR2), and several
other dominantly and recessively inherited genes. To date, at least 40 different forms of CMT have been
described (http://www.molgen.ua.ac.be/CMTMutations). This diversity also reflects a challenge in diagnosis
and therapy, and has consequently led to the need to modify the traditional classification system.
Genotype-phenotype studies have been an invaluable aid in describing the clinical variability associated
with identical pathogenic mutations, such as is seen in the different phenotypes associated with
pathogenic mutations in major peripheral myelin genes like MPZ or PMP22. For example, most patients with
MPZ mutations fall into two major groups, one with a severe early onset neuropathy with extremely slow
nerve conduction velocity (NCV) (less than 10 m/s) and a later onset, milder form that fits the typical CMT1
phenotype.[18] Many early onset cases present sporadically with no family history and would have
traditionally been diagnosed as HMSN-III or DSD. Different mutations in the same gene, such as MPZ, may
also lead to near normal velocities more characteristic of CMT2. Early on it was also recognized that there
was a group of neuropathies that had nerve conduction velocities falling in the intermediate range.[19]
[20] We know now that most of these neuropathies are related to mutations in the GJB1 gene causing X-
linked CMT.[21] [22] More recently, both dominant and recessive forms have been identified. These
neuropathies do not fit easily into the original Dyck and Lambert classification scheme because of their X-
linked inheritance and intermediately slow NCV. Classification schemes modified to accommodate the
genetic causes of the neuropathy and inheritance pattern have been published.[2] CMT4 is used to classify
the recessive forms of CMT, regardless of whether they are demyelinating or axonal. Another reason the
classification schemes remain a challenge is that pathogenic mutations in the same genes are associated
with different inheritance patterns, such as is seen in mutations in the PMP22 gene. A change from
threonine to methionine at position 118 (Thr118Met) may appear to cause recessively inherited
neuropathies, when in fact it is a dominantly inherited neuropathy where the mutation leads to partial gain
of function of the affected gene.[23] Clinical variability related to mutations involving identical genes and
phenotypical similarities noted in mutations associated with different genes invariably lead to challenges
not only in classification, but also, consequently, in diagnosis and patient management. Table [1] presents
some of the useful parameters that have been applied to classify CMT neuropathy.

Table 1 Frequently Applied Classification Parameters of Charcot-Marie-Tooth Disease

EPIDEMIOLOGY

Early data on epidemiology of CMT were obtained before the era of molecular testing. Estimated prevalence
of CMT neuropathies has been reported as 23 to 46 per 100,000 people in Northern Europe,[1] with
comparable numbers reported by Dyck and colleagues in southeastern Minnesota.[13] [24] Harding and
Thomas's cohort of 227 patients with CMT was comprised of 76% (173) CMT1 and 24% CMT2.[13] This
correlates well with data reported by Dyck and Lambert in 1968.[10] [11] Increasing availability of
commercial genetic testing allowed for new data about mutational frequencies worldwide. Databases from
both North America and Europe previously have put the frequency of the most common form of CMT1,
CMT1A, at ~60 to 70%; CMTX accounts for ~10 to 20%, and CMT1B for up to 5%.[22] [25] [26] HNPP is
caused in ~80% of cases by chromosome 17p11.2 deletion,[22] with most remaining cases likely to be
related to point mutations in the PMP22 gene.[27] [28] More recent reports showed comparable mutation
frequency in Chinese patients.[3] CMT2 accounts for ~22% of dominantly inherited neuropathies in the
series of Inonasescu et al.[29] Distribution of CMT mutations in the database at the CMT Clinic at Wayne
State University is shown in Table [2]. These data are similar to mutational frequencies reported by other
groups cited previously.

Table 2 Frequency of Charcot-Marie-Tooth Disease[*]

Type of CMT Percentage of Patients with Type (%) (n = 224)

CMT1A 45

CMT1B 4

CMTX 9

CMT2 18

Unknown 15

CMT, Charcot-Marie-Tooth disease (followed by type designations).

1 Based on genetic classification in the first 224 patients seen at the Wayne State University CMT Clinic. #

CLINICAL FEATURES OF INHERITED NEUROPATHY

Clinical classification of patients with CMT is based on establishing identifying features of an inherited
peripheral neuropathy based on typical presentation, family history, and supporting electrophysiological
and genetic testing. Making a clinical diagnosis in typical cases is no challenge for the experienced
neurologist. Phenotypic variability of CMT neuropathies and scarce availability of natural history data are
increasingly recognized, however. Taken together with newly presenting mutations, variable penetrance
and progression rates between and within the same generations may lead to diagnostic challenges and
ultimately the need for referral of these patients to special tertiary neurological centers for diagnosis and
management. Clinical features of the different CMT phenotypes are presented in Table [3].

Table 3 Features of Charcot-Marie-Tooth Disease Neuropathy

PATHOGENESIS: GENOTYPE-PHENOTYPE CORRELATIONS

Many recent studies have investigated the molecular pathways underlying various forms of CMT.
Understanding how different genetic defects lead to the development of disease phenotypes is a
challenging,[30] [31] [32] but potentially very rewarding task because effective novel therapies may
someday be developed based on these new discoveries.

Normal myelination implies the well-coordinated interaction of Schwann cells and axons.[33] [34] [35]
Traditional classifications of CMT have emphasized the primarily demyelinating or axonal features of CMT
based on the changes noted in nerve conduction velocities. In a very simplistic approach, this means that
markedly reduced forearm motor nerve conduction velocities (below 38 m/s) are indicative of demyelination
or a dysmyelination process, whereas normal motor nerve conduction velocities with markedly reduced
nerve action potential amplitudes signal axonal pathology. However, recent data highlight the dynamic
interaction between Schwann cell and axon during development; MPZ mutations may lead to a typical
“axonal” CMT,[18] and primary disturbance of axonal signaling pathways may lead to
hypomyelinated/dysmyelinated nerve fibers with slow nerve conductions, such as has been shown in the
transgenic NRG1 mice.[36] [37] Axonal CMT and axon-glia interactions in various CMTs have been reviewed
in detail elsewhere.[31] Table [4] lists the different mechanisms that are currently implicated in the
pathogenesis of demyelinating and axonal CMT. Recognizing molecular mechanisms, how mutated proteins
contribute to the clinical phenotypes, and in particular distinguishing the exact contribution of individual
Schwann cell and neuronal genes to clinical disability may provide a means to further treatments.

Table 4 Potential Pathogenic Mechanisms of Known Charcot-Marie-Tooth Disease

DOES THE ELECTROPHYSIOLOGY REFLECT THE PATHOPHYSIOLOGY?

Introduction of nerve conduction studies (NCS) into neurological diagnosis has revolutionized the diagnosis
of neuropathies. The obtained nerve conduction parameters provide valuable clues as to whether
neuropathies are primarily demyelinating or axonal processes. Nerve conduction studies remain the primary
test used to classify CMT because they are easily performed and minimally invasive. The principle that
inherited and acquired demyelinating neuropathies could be distinguished in most cases by their nerve
conduction velocities was introduced by Lewis and Sumner[31] with their recognition that inherited
demyelinating neuropathies have uniformly slow nerve conduction velocities, whereas acquired
demyelinating neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy, have
asymmetric or nonuniform slowing. Recent studies have pointed to some exemptions to this principle; even
though most patients with CMT1, particularly those with CMT1A, have uniformly slow motor nerve
conduction velocities of ~20 m/s, values as high as 42 m/s have been reported (Fig. [1]), and are
sometimes used as a cut-off value. Also, HNPP has been recognized for an asymmetric electrophysiological
pattern. Asymmetric nerve conduction velocities may also be found in patients with missense mutations in
PMP22, MPZ, EGR2 and GJB1.[38]

Figure 1 Distribution of median nerve conduction velocity (NCV) of

Charcot-Marie-Tooth (CMT) patients at the Wayne State University CMT
Clinic in 2004.

The usefulness of electrophysiology to guide the clinician in obtaining an accurate diagnosis is increasingly
being reevaluated. Fig. [2] presents a possible guide for the clinician in making a diagnosis. Early on it was
recognized that there is a group of CMT that is frequently referred to as “intermediate” CMT.[19] [39] [40]
This term is being used without consensus in research publications and Medline to identify the group of
patients with conduction velocities “between” CMT1 and CMT2 despite the obvious overlaps with CMT1 and
CMT2. At this point, however, no clear criteria or definitions are available to clarify this entity or delineate
the pathophysiology. CMTX patients constitute the majority of patients with intermediately slowed NCV.[21]
Patients with CMTX and CMT1B may present with NCVs in the intermediate range but also with
electrodiagnostic features misleadingly suggestive of a “primarily axonal” neuropathy (e.g., markedly
reduced sensory nerve action potential [SNAP] and compound muscle action potential [CMAP] amplitudes
[Fig. [1]]). In such cases, however, distal motor latencies and F-wave latencies are usually prolonged,
consistent with the underlying mutations in the Cx32 protein, a protein that is expressed in the myelinating
Schwann cell. Similar issues occur in some patients with mutations in the MPZ gene (Thr118Met).

Figure 2 NCV, nerve conduction velocity; PMP22, peripheral myelin

protein gene; MPZ, myelin protein zero gene; LITAF, lipopolysaccharide-
induced tumor necrosis factor-alpha factor gene; EGR2, early growth
response gene 2; NFL, neurofilament light chain gene; MFN2, mitofusin
2 gene; GDAP1, ganglioside-induced differentiation-associated protein 1
gene; GJB1, gap junction protein, beta-1 gene. *It is important that the
family history is taken in a careful manner and that all possibilities are
considered that fit a given pedigree. **NCV testing indicates velocity of
impulses; amplitudes not included.

Because all of these disorders may appear de novo, one has to be careful in applying NCV parameters
alone to separate acquired from inherited demyelinating neuropathies or to use them as a guide to
distinguish between inherited neuropathies.[38] Electrodiagnostic assessment of inherited neuropathies is
important, however, because CMAPs are considered a measure of axonal integrity, and it has been shown
in clinical studies[41] that axonal loss correlates better with the patient's actual disability. #

APPROACH TO DIAGNOSIS AND MANAGEMENT

Marked variations in phenotypic presentations represent a challenge in the diagnosis of CMT. It is well
documented in patients with CMT that they may present with variable age of onset and different speed of
symptom progression.[2] The diagnosis and management of the patient with CMT is best undertaken by a
multidisciplinary approach that involves a neurologist, and, when appropriate, a genetic counselor,
orthopedic surgeon, physiatrist, pulmonary specialist, physical therapist, occupational therapist, and/or
social worker to provide the maximum care for patients with chronic disability.

It seems obvious that severe, early onset nerve dysfunction, such as seen in DSD and some of the early
onset CMT1B patients,[18] puts a different type of burden on families and provides more challenges for
healthcare providers than a slower, progressive, adult-onset form of the disorder that nonetheless may
also lead to significant reductions in quality of life over time.[42] No clear estimates are currently available
that assess the financial burden of this chronic disease on families and the healthcare system. Early
diagnosis and, if possible, interventions impact the patient's day-to-day life in a positive way at multiple
levels.[43] [44] [45]

One of the most important issues is genetic testing and counseling.[46] Despite the increasing availability
of commercial and research testing, CMT remains principally a clinical diagnosis established by signs and
symptoms of examination, family history, and electrodiagnostic testing (Fig. [2]).[46] [47] Genetic testing
supports the clinical and electrophysiological diagnosis, and at the same time genetic counseling is
important for the patients and their families to help with disease prognosis. Decisions regarding genetic
testing should be made in consensus with the individual family members. Distinction should be made
regarding testing in affected or at-risk individuals. Appropriate indications for genetic testing may soon
change as more genes causing neuropathy are identified and more is learned about the phenotypic range
produced by mutations in these genes. For example, cases of CMT1B are now being reported with normal
NCV; these would have been missed if genetic testing had not been performed.

Predictive testing of individuals at risk for CMT should be approached with more circumspection. A patient,
along with a support person, should be seen by both a neurologist and genetic counselor and be
counseled about the possible implications of testing with respect to their family relationships, insurance,
and employability. Every effort should be made to obtain documentation of the disease in a relative. Testing
is not recommended for asymptomatic children who are at risk for CMT, in agreement with the Statement of
the Practice Committee Genetics Testing Task Force of the American Academy of Neurology (1996). When a
child is clearly showing symptoms of CMT, testing may be appropriate.

Other than establishing an individual's risk for the disease, genetic testing may also help delineate more
accurate genotype-phenotype interactions.[46] Online resources are available and provide comprehensive
information for both healthcare providers and patients (see Addendum). #

MANAGEMENT

Management of hereditary neuropathies is aimed at complex supportive and, when available, curative
treatment modalities. Table [5] provides a summary of current supportive treatment options, addressing
leading symptoms. Treating physicians need to also be aware of potential dangers associated with
iatrogenic complications associated with therapeutic interventions to be able to assess risk-benefit ratios
and provide appropriate counseling for their patients.

Table 5 Charcot-Marie-Tooth Disease Management: Supportive Therapy

There is currently no cure for CMT. Basic research into therapeutic strategies is being done using transgenic
animal models to develop new human applications. Gene therapy approaches for gene replacement are
only possible in monogenic disorders if the mutation leads to clear loss of function. The gene dosage-
dependent changes in CMT1A[48] or partial loss of function disease mechanism found in certain CMT1B
(Thr118Met) patients represent a challenge to overcome despite advances in the field.[49] [50] It has
been shown that clinical disability is related to axonal degeneration.[41] Therefore, the attempt to provide
trophic support by neurotrophic factors is a promising approach. It is likely that despite promising results in
animal models[51] more research needs to be done before this can be extrapolated to human applications.
Further studies need to be performed regarding potential immunomodulatory therapies in CMT despite
recent indications of improved myelination in immunodeficient transgenic mice.[52] #

THERAPY: NEW CLINICAL APPROACHES

Ascorbic acid treatment of the animal model of CMT1A has improved myelination and reduced PMP22 levels
in affected rats. A multicenter international clinical trial is already on the way that uses high-dose ascorbic
acid for treatment in patients with CMT1A.[53] Another exciting new approach is based on data obtained in
the animal model of CMT1A, which showed that a selective progesterone antagonist, onapristone, reduced
PMP22 overexpression in tissue culture and improved the CMT phenotype in CMT1A rats.[54] #

CONCLUSIONS

Inherited neuropathies are among the most prevalent genetic neurological diseases. They affect the quality
of life of the patients by leading to marked disability due to progressive weakness and social and
psychological burden. Treatment of this chronic disorder challenges families and healthcare workers.
Developing treatments for patients will directly affect thousands of individuals. In addition, the genes and
their proteins that cause inherited neuropathies serve as a source of molecules that are important for
peripheral nerve function. Identifying the molecular pathways involved in these disorders will also lead to a
better understanding of pathways involved in neurodegenerative disease in general. #

ADDENDUM: RESOURCES FOR PATIENTS AND FAMILIES

Multiple resources exist for people with CMT to learn more about their disease, genetic conditions in
general, where to find others in a similar situation, and keep abreast of new therapies and/or clinical trials.
This addendum provides the path to some of these resources. #

Patient Support Organizations

Charcot-Marie-Tooth Association (CMTA)

Address: Charcot-Marie-Tooth Association, 2700 Chestnut Street, Chester, PA 19013-4867

Toll-Free: 800-606-2682 (U.S. only)

Phone: 610-499-9264

Fax: 610-499-9267

E-mail: info@charcot-marie-tooth.org

Web site: http://www.charcot-marie-tooth.org

Muscular Dystrophy Association (MDA)

Address: Muscular Dystrophy Association - USA, National Headquarters, 3300 E. Sunrise Drive, Tucson, AZ
85718

Toll Free: 800-FIGHT-MD (344-4863)

E-mail: mda@mdausa.org

Web site: http://www.mdausa.org

The Charcot-Marie-Tooth Foundation

Address: The Charcot-Marie-Tooth Foundation, 142 Gazebo Park, Johnstown, PA 15901

Toll-free: 877-296-2341

Phone: 814-539-2341-JD Griffith

E-mail: jdgriffith@atlanticbb.net

Web site: http://www.cmtfoundation.org

Hereditary Neuropathy Foundation (HNF)

Address: Hereditary Neuropathy Foundation Inc., PO Box 287103, New York, NY 10128

Phone: 917-648-6971

E-mail: info@hnf-cure.org

Web site: http://www.hnf-cure.org

The Neuropathy Association

Address: The Neuropathy Association, Inc.®, PO Box 26226, New York, NY 10117-3422

Phone: 212-692-0662

E-mail: info@neuropathy.org

Web site: http://www.neuropathy.org

National Organization of Rare Disorders (NORD)

Address: National Organization for Rare Disorders, 55 Kenosia Avenue, PO Box 1968, Danbury, CT 06813-
1968

Toll free: 800-999-6673 (voicemail only)

Phone: 203-744-0100

Fax: 203-798-2291

E-mail: orphan@rarediseases.org

Web site: http://www.rarediseases.org #

Online Resources

Patients should be cautioned that information on the Internet is not always accurate or reliable and issues
regarding a person's management or treatment should always be discussed with the person's physician.

GeneTests (http://www.geneclinics.org)

This Web site offers detailed information about the availability of genetic testing, information about genetic
conditions, and contact information for genetics services providers such as laboratories performing
preimplantation genetic diagnosis.

Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM)

Thousands of entries on genetic disorders and genes can be found on this Web site. The information listed
here tends to be more technical and contains summaries of significant findings in the published literature.

PubMed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi)

This Web site allows the user to find citations in the biomedical literature.

National Coalition for Health Professional Education in Genetics(http://www.nchpeg.org)

This Web site provides information on genetics advances and genetics health information.

Genetic Alliance (http://www.geneticalliance.org)

The Genetic Alliance is an international coalition comprised of millions of individuals with genetic conditions
and more than 600 advocacy, research, and healthcare organizations that represent their interests. The
Web site provides access to links for support groups for many genetic conditions as well as to other
genetics-related informational sites.

Inherited Peripheral Neuropathies Mutation Database

(http://www.molgen.ua.ac.be/CMTMutations/default.cfm)

This database contains detailed information on all of the published mutations that cause inherited
peripheral neuropathies, including references.

HNPP Web site (www.hnpp.org)

This site is a place where people with HNPP, their physicians, and therapists can learn about the disease,
where to find help, and how to manage their symptoms.

Clinical Trials (http://www.clinicialtrials.gov)

This Web site, supported by the U.S. National Institutes of Health, contains regularly updated information
about federally and privately supported clinical research in human volunteers. #

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Agnes Jani-Acsadi, M.D.

Assistant Professor of Neurology, Department of Neurology, Wayne State University School of Medicine

8A UHC, 4201 St. Antoine, Detroit, MI 48201

Email: aacsadi@med.wayne.edu

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