Molecular

Diagnosis of
Hereditary
Neuropathy

Guidance for Patients

with Hereditary
Neuropathy

Your Source for

Molecular Diagnosis of
Hereditary Neuropathy

Testing You Can Count On.

 Athena’s hereditary neuropathy profiles evaluate
multiple genes in the convenience of a single blood draw.

What is a Hereditary Neuropathy?

• Hereditary neuropathies are a heterogeneous group of disorders
that affect the peripheral nerves.1
• The most common cause of hereditary neuropathy is Charcot-
Marie-Tooth (CMT) syndrome, which has a prevalence of 1 in 2,500
people.1 Although CMT is the most common hereditary neuropathy,
remarkably 33% of all patients have no family history.2
• The clinical phenotype of CMT is characterized by:
– Wasting and weakness of distal limb muscles
– Distal sensory loss
– Skeletal deformities
– Decrease or absence of deep tendon reflexes3,4

Hereditary Neuropathies:
A Diagnostic Challenge
• The clinical variability and genetic heterogeneity in CMT often results in a diagnostic challenge.
• Contrary to popular understanding, hereditary neuropathies account for a significant number of chronic
peripheral neuropathies.2
• Disease severity is highly variable, even within the same family. Some individuals may show minimal symptoms
and are unaware of being affected, while others may have significant disabilities.3
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New Clinical Tests

CMT2 Gene Mutations5,6

Genes CMT2/HMSN II Benefit

GARS • CMT2 is primarily associated with
axonal degeneration
HSPB1/HSP27
• 30% of all CMT patients have CMT2
LMNA
• Clinical symptoms include slowly
progressive weakness of distal muscles,
RAB7
mild or no sensory loss, and atrophy of
feet and/or hands related to depressed
tendon reflexes
• Provides a more compehensive
diagnosis of CMT and CMT2
• Addition of the CMT2 genes
provides a differential diagnosis
between CMT2 and chronic
idiopathic axonal neuropathy
due to similar clinical symptoms
Genes Associated with Hereditary Neuropathy12, 13
Allelic Clinical Usual Inheritance Nerve Conduction
Gene Variants Features Onset Mode Velocity Test

Connexin32 (Cx32/GJB1) CMTX Distal weakness 2nd decade X-linked 25 to 40 m/s

Dominant
Early Growth CMT1D Distal weakness 2nd decade Autosomal 26 to 42 m/s
Response 2 (EGR2) Dominant
Congenital Severe weakness Birth Autosomal <10 m/s
Hypomyelination Recessive
Dejerine-Sottas Severe weakness 2 years Autosomal <10 m/s
Dominant or
Recessive
FIG4 CMT4J Early onset Early Autosomal 2 to 7 m/s14,15
Coordination disorder childhood14,15 Recessive14,15
Severe disability14,15
Ganglioside-Induced CMT2K Distal weakness Early Autosomal Intermediate
Differentiation-Associated Vocal cord paralysis4 childhood10 Recessive to slow4
Protein 1 (GDAP1)
CMT4A Distal weakness Childhood Slow
Glycyl-tRNA synthetase CMT2D Small hand 8 to 36 yrs Autosomal >38 m/s
(GARS) muscles atrophy Dominant
Heat Shock Protein CMT2F Distal weakness, 15 to 25 yrs Autosomal Reduced or absent
(HSPB1/HSP27) sensory loss Dominant compound action
potential (CMAP)
Lamin-A/C (LMNA) CMT2B1/CMT4C1 Distal weakness 6 to 27 yrs Autosomal >38 m/s
Recessive
Lipopolysaccharide- CMT1C Distal weakness 2nd decade Autosomal 16 to 25 m/s
Induced Tumor Necrosis Dominant
Factor-Alpha Factor
(LITAF/SIMPLE)
Mitofusin 2 (MFN2) CMT2A2 Distal weakness 10 yrs Autosomal >38 m/s
Dominant
Myelin Protein Zero (MPZ/P0) CMT1B Distal weakness 1st decade Autosomal <20 m/s
Dominant
CMT2I Distal weakness4 Late onset Autosomal >38 m/s4
(range 47 to 70 yrs)4 Dominant4
CMT2J Distal weakness Late onset Autosomal Varies from less
Hearing Loss (40 to 50 yrs)4 Dominant4 than 38 m/s to
Adie’s pupil4 normal values4
Dejerine-Sottas Severe weakness 2 years Autosomal <10 m/s
Dominant or
Recessive
Congenital Severe weakness Birth Autosomal <10 m/s
Hypomyelination Recessive
Neurofilament Protein, CMT2E Distal weakness 1 to 40 yrs Autosomal 13 to 38 m/s4
Light Chain (NFL/NEFL) Dominant
CMT1F Distal weakness 11
1 to 13 yrs 11
<38 m/s3
Periaxin (PRX) CMT4F Motor delay 1 to 3 yrs Autosomal Absent
Recessive
Dejerine-Sottas Severe weakness 2 years <10 m/s
Peripheral Myelin CMT1A Distal weakness 1st decade Autosomal 15 to 20 m/s
Protein 22 (PMP22) Dominant
Dejerine-Sottas Severe weakness 2 years Autosomal <10 m/s
Dominant or
Recessive
HNPP Focal episodic 3rd decade Autosomal Entrapments
weakness Dominant
RAS-associated GTP-binding CMT2B Distal weakness, 13 to 30 yrs Autosomal >38 m/s
Protein (RAB7) sensory loss Dominant
SH3 Domain and CMT4C Delayed walking 5 to 15 yrs Autosomal 14 to 32 m/s
Tetratricopeptide Repeat Recessive
Domain 2 (SH3TC2)
 Molecular Testing Based on Clinical Evaluation
Molecular testing is guided by the phenotype, inheritance pattern, and electrophysiological data.1

Primary Complaint: Weakness,

Numbness, Pain, Loss of Sensation

Sporadic

Presentation

Focal/
Symmetric Asymmetric
Multifocal

Age of Onset Age of Onset

Childhood Adult Childhood Adult

Nerve Conduction
Nerve Conduction Studies Nerve Conduction Studies Nerve Conduc
Studies

Demyelinating Axonal Demyelinating Axonal Conduction Conduction Demyelinating

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Block Block

Complete Complete Complete Complete Chronic Entrapment Partial CMT-

CMT #404 CMT #404 CMT #404 CMT #404 Demyelinative Neuropathy Dominant
PMP22 Dup./Del., PMP22 Dup./Del., PMP22 Dup./Del., PMP22 Dup./Del.,
Neuropathy #296 Only #414
PMP22, PMP22, PMP22, PMP22,
Profile #347 PMP22 Dup./Del., PMP22 Dup./Del.,
Connexin32 Connexin32 Connexin32 Connexin32
PMP22 Dup./Del., PMP22, TTR PMP22, Connexin32
(Sequencing and (Sequencing and (Sequencing and (Sequencing and
Deletion), FIG4, MPZ, Deletion), FIG4, MPZ, Deletion), FIG4, MPZ, Deletion), FIG4, MPZ, Connexin32 (Sequencing and
EGR2, NFL, PRX, EGR2, NFL, PRX, EGR2, NFL, PRX, EGR2, NFL, PRX, (Sequencing and Deletion), MPZ, EGR2,
GDAP1, LITAF/SIMPLE, GDAP1, LITAF/SIMPLE, GDAP1, LITAF/SIMPLE, GDAP1, LITAF/SIMPLE, Deletion), MAG NFL, LITAF/SIMPLE,
MFN2, SH3TC2, MFN2, SH3TC2, MFN2, SH3TC2, MFN2, SH3TC2, ‘Dual Antigen’® MFN2, RAB7,
LMNA, RAB7, LMNA, RAB7, LMNA, RAB7, LMNA, RAB7, GARS, HSPB1
GARS, HSPB1 GARS, HSPB1 GARS, HSPB1 GARS, HSPB1

Partial CMT Partial CMT Partial CMT Complete Complete

Demyelinating Demyelinating Axonal Only HNPP Dejerine-
Only #407 Only #407 #413 #243 Sottas
PMP22 Dup./Del., PMP22 Dup./Del., Connexin32 PMP22 Neuropathy
PMP22, Connexin32 PMP22, Connexin32 (Sequencing and Dup./Del., #286
(Sequencing and (Sequencing and Deletion), PMP22 PMP22,
Deletion), MPZ, EGR2, Deletion), MPZ, EGR2, MPZ, NFL, GDAP1, MPZ,
PRX, GDAP1, LITAF/ PRX, GDAP1, LITAF/ MFN2, LMNA, RAB7, EGR2,
SIMPLE, SH3TC2 SIMPLE, SH3TC2 GARS, HSPB1 PRX

Chronic Congenital
Demyelinative Hypomyelination
Neuropathy #245
Profile #347 MPZ,
PMP22 Dup./Del., EGR2
Connexin32
(Sequencing and
Deletion), MAG
‘Dual Antigen’®
 Athena Diagnostics offers a wide selection of CMT profiles to
aid in the diagnosis of hereditary neuropathy.

Evaluate Pattern of Weakness and

Atrophy, Reflexes, NCS/EMG

Family History Family DNA Sequence

Individual gene exon sequencing
for known mutations

Dominant Recessive

Presentation Presentation

Symmetric Asymmetric Focal/Multifocal Symmetric

Age of Onset Age of Onset Age of Onset

Amyloidosis #235
Childhood Adult Childhood Adult Childhood Adult
TTR

Nerve Conduction Nerve Conduction

ction Studies Nerve Conduction Studies Nerve Conduction Studies
Studies Studies

Axonal Demyelinating Axonal Conduction Demyelinating Axonal Demyelinating

Block

Partial CMT- Partial CMT- Partial CMT- Entrapment Partial CMT- Connexin32 Partial CMT-
Dominant Dominant Dominant Neuropathy Recessive #143 Recessive
Only #414 Only #414 Only #414 #296 Only #409 Connexin32 Only #409
PMP22 Dup./Del., PMP22 Dup./Del., PMP22 Dup./Del., PMP22 Dup./Del., EGR2, (Sequencing and EGR2,
PMP22, Connexin32 PMP22, Connexin32 PMP22, Connexin32 PMP22, TTR FIG4, Deletion) FIG4,
(Sequencing and (Sequencing and (Sequencing and GDAP1, GDAP1,
Deletion), MPZ, EGR2, Deletion), MPZ, EGR2, Deletion), MPZ, EGR2, PRX, PRX,
NFL, LITAF/SIMPLE, NFL, LITAF/SIMPLE, NFL, LITAF/SIMPLE, SH3TC2, SH3TC2,
MFN2, RAB7, MFN2, RAB7, MFN2, RAB7, LMNA LMNA
GARS, HSPB1 GARS, HSPB1 GARS, HSPB1

Connexin32 Complete Complete

#143 HNPP Dejerine-
Connexin32 #243 Sottas
(Sequencing and PMP22 Neuropathy
Deletion) Dup./Del., #286
PMP22 PMP22,
MPZ,
EGR2,
PRX

Congenital
Hypomyelination
#245
MPZ,
EGR2
 Athena’s hereditary neuropathy testing services
provide information for patients and their families.

• Confirm clinical findings

– Diagnosing hereditary neuropathies is challenging because of
overlapping symptoms with other disorders and the large variation
in clinical manifestations.
– Mendell et al. 2001 demonstrated that the cause of up to
50% of neuropathy cases was unknown even after a thorough
work-up.7
– Use Athena’s peripheral neuropathy testing services to
help make a definitive diagnosis.

• Clarify inheritance pattern

– A positive molecular genetic test provides specific information
about the inheritance pattern of CMT within a family, which is useful
in evaluating risk in family members.
– A negative result excludes the common forms of CMT and
will help narrow your search for the true cause.

• Determine treatment options

– Current therapies for CMT include physical therapy, assistive devices, pain management, and
surgical intervention.9
– Importantly, a positive genetic diagnosis can prevent the use of costly and ineffective treatments
for hereditary neuropathies such as Intravenous Immune Globulin (IVIG).
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• Avoid contra-indicated medications

– A positive molecular genetic test for any type of CMT can help guide patients away from
contra-indicated medications that may severely worsen symptoms.
– Patients that have a mutation but do not yet exhibit symptoms are at highest risk since their
physicians are not likely to screen them for CMT before prescribing these medications.

• Interpretive assistance
– Athena provides genetic counselors and laboratory directors for interpretative assistance.

Athena Diagnostics now evaluates fifteen genes

associated with CMT and helps diagnose more than
80% of patients with the disorder.
 33% of all patients have no family
history of Charcot-Marie-Tooth (CMT) syndrome,
the most common hereditary neuropathy.

A molecular diagnosis can help patients avoid contra-indicated medications.

• Weimer et al. 2006 compiled a list of contra-indicated medications segregated into probable relative
risk to CMT patients.8
• A definitive diagnosis using Athena’s hereditary neuropathy testing can help patients avoid
drug-induced exacerbation of CMT.

Contra-indicated Medications8

Definite high risk Nitrofurantoin Cyclosporin A Negligible or

(including asymptomatic Nitrous oxide (inhalation Ethambutol doubtful risk
CMT) abuse or vitamin B12 Etoposide (VP-16) Allopurinol
Vinca alkaloids (vincristine) deficiency) Gemcitabine Amitriptyline
Perhexiline* Griseofulvin Chloramphenicol
Moderate to
Pyridoxine (high dose) Hexamethylmelamine Chlorprothixene
significant risk
Stavudine (d4T) Hydralazine Cimetidine
Amiodarone
Suramin Ifosphamide Clioquinil
Bortezomib (velcade)
Tacrolimus (FK506, Infliximab Clofibrate
Cisplatin, carboplatin,
ProGraf) Isoniazid Enalapril
oxaliplatin
Taxoids (paclitaxel, Mefloquine Fluoroquinolones
Colchicine
docetaxel) Penicillamine Gabapentin
(extended use)
Thalidomide Penicillin – high IV doses Gluthethimide
Dapsone
Zalcitabine Phenytoin Lithium
Didanosine (ddI)
Podophyllin resin Phenelzine
Dichloroacetate Uncertain or
Sertraline (Zoloft) Propafenone
Disulfiram minor risk
Statins Sulfonamides
Gold salts 5-Fluoracil
Tumor necrosis factor-a Sulphasalzine
Leflunomide Adriamycin
Zimeldine*
Linezolid (extended use) Almitrine*
a-Interferon
Metronidazole/misonidazole Chloroquine
(extended use) Cytarabine (high dose)
*Not available in the United States.

A positive molecular genetic test result can help guide patients toward effective therapeutic strategies.

Therapeutic Strategies9

Physical Therapy Rehabilitation plays an important role in preserving the quality of life of CMT patients,
and Exercise and should focus on increasing strength of muscles, improving mobility, preventing
joint deformities, and ameliorate hand function.
Assistive Devices For example, an initial footdrop can benefit from a lateral wedge while a more pronounced
footdrop requires ankle-foot orthoses (AFOs).
Pharmacological Neuropathic pain can be treated with topical agents as well as oral medications.
Symptom
Management
Surgical Orthopedic surgery benefits patients with significant bone changes, such as high arches
Intervention and hammer toes.
 Athena’s Hereditary Neuropathy Testing Services
Athena offers the most comprehensive line of molecular genetic testing for CMT.

Testing Service Typical Presentation Genes/Antibodies Tested For

Complete CMT Individuals with a mild to severe neuropathy without PMP22 Dup./Del., PMP22, Connexin32
Evaluation #404 a clear family history and abnormal NCVs; age of (Sequencing and Deletion), MPZ, EGR2,
symptom onset is typically <50 years and the NFL, PRX, GDAP1, LITAF/SIMPLE, MFN2,
symptoms are symmetric and slowly progressive SH3TC2, FIG4, LMNA, RAB7, GARS, HSPB1
Partial CMT- Individuals with a severe demyelinating neuropathy; PMP22 Dup./Del., PMP22, Connexin32
Demyelinating Only #407 NCVs are typically <38 m/s (Sequencing and Deletion), MPZ, EGR2, GDAP1,
PRX, LITAF/SIMPLE, SH3TC2
Partial CMT- Individuals with a mild axonal neuropathy; NCVs are Connexin32 (Sequencing and Deletion), MPZ, NFL,
Axonal Only #413 typically >38 m/s with reduced action potentials GDAP1, MFN2, LMNA, RAB7, GARS, HSPB1
Partial CMT - Individuals with a clear dominantly inherited PMP22 Dup./Del., PMP22, Connexin32
Dominant Only #414 neuropathy in the family; symptoms can be from mild (Sequencing and Deletion), MPZ, EGR2,
to severe with variable NCVs; testing includes genes NFL, LITAF/SIMPLE, MFN2, RAB7, GARS,
that result in both autosomal and X-linked dominant HSPB1
inheritance patterns
Partial CMT- Individuals with a clear recessively inherited EGR2, GDAP1, PRX, SH3TC2, FIG4, LMNA
Recessive Only #409 neuropathy in the family; NCVs are typically <38 m/s
and age of onset is usually in childhood
Complete Dejerine-Sottas Children with a severe hereditary motor and sensory PMP22, MPZ, EGR2, PRX
Neuropathy neuropathy; NCVs are usually <38 m/s and the
Evaluation #286 symptoms are symmetric
Connexin32 CMT with a family history of Connexin32 mutations Connexin32 (Sequencing and Deletion)
Evaluation #143 identified in a proband
Entrapment Neuropathy Weakness and pain with motor or sensory PMP22 Dup./Del., PMP22,TTR
Evaluation #296 disturbances indicative of a focal or multifocal
compression neuropathy
Complete HNPP Individuals with transient focal or multifocal PMP22 Dup./Del., PMP22
Evaluation #243 compression neuropathy; may involve pain,
numbness and mild weakness
Chronic Demyelinative Chronic, progressive demyelinating neuropathy PMP22 Dup./Del., Connexin32 (Sequencing and
Neuropathy Profile #347 Deletion), MAG ‘Dual Antigen’®, GD1b
Congenital Floppy infants with severe neuropathy and absence MPZ, EGR2
Hypomyelination of peripheral nerve myelin
Evaluation #245
Amyloidosis Individuals may present with one or more of distal TTR
Evaluation (TTR) #235 limb sensory motor neuropathy, autonomic
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neuropathy, nephropathy, cardiopathy, arrhythmias,

gastrointestinal abnormalities and carpal tunnel
syndrome
Familial DNA Sequence Individual gene exon sequencing of known mutations Any individual gene listed above

Athena Diagnostics Customer Service Representatives

are available from 8:30 a.m. to 6:30 p.m. Eastern Time (US).
Customers in the US and Canada please call toll-free

866-AthenaDx Testing You Can Count On.

(866-284-3623)
Four Biotech Park, 377 Plantation Street
Non-US customers please call 508-756-2886 or fax 508-753-5601. Worcester, MA 01605 • www.AthenaDiagnostics.com

References: 1. Szigeti, K. et al. Molecular Diagnostics of Charcot-Marie-Tooth disease and related peripheral neuropathies. 2006. NeuroMolecular Medicine. 8:243-253. 2. Boerkoel,
C. et al. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol. 2002; (2):190-201. 3. D. Pareyson, V. Scaioli,
and M. Laurà. Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. 2006. NeuroMolecular Medicine. 8:3-22. 4. Zuchner, S. and Vance, J. Molecular genetics of
autosomal-dominant axonal Charcot-Marie-Tooth disease. 2006. NeuroMolecular Medicine. 8:63-74. 5. Züchner Stephan and Vance, Jeffrey M., Mechanisms of Disease: a molecular
genetic update of hereditary axonal neuropathies. Nat Clinical Practice Neurology, January 2006, Vol 2. No.1. 6. Barisic, N. et al., Charcot-Marie-Tooth Disease: A Clinico-genetic
Confrontation. Annals of Human Genetics (2008) 72, 416-441. 7. Mendell JR, Sahenik Z. Hereditary Motor and Sensory Neuropathies and Giant Axonal Neuropathy. In: Mendell JR,
Kissel JT, Cornplath DR, eds. Diagnosis and Management of Peripheral Nerve Disorders. New York, NY: Oxford University Press; 2001:429-59. 8. Weimer, L.H.; Podwall, D. Medication-
induced exacerbation of neuropathy in Charcot Marie Tooth Disease. Journal of the Neurological Sciences. 242 (2006) 47-54. 9. Shy, M. Therapeutic strategies for the inherited
neuropathies. 2006. NeuroMolecular Medicine. 8:255-278. 10. Birouk, N. et al. Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease
associated with the S194X mutation in the GDAP1 gene. Arch Neurol. 2003 Apr; 60(4):598-604. 11. Jordanova, A. et al. Mutations in the neurofilament light chain gene (NEFL) cause early
onset severe Charcot-Marie-Tooth disease. Brain. 126:590-7, 2003. 12. Kuhlenbaumer, G. et al. Clinical features and molecular genetics of hereditary peripheral neuropathies. J Neurol.
2002; 249:1629-1650. 13. Neuromuscular Disease Center. Washington University, St. Louis, MO. 12/15/2006. Available at: http://www.neuro.wustl.edu/neuromuscular/time/hmsn.html.
14. Chow, C. et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature. Vol 448. 5 July 2007. 15. Barisic, N. et al. Charcot-Marie-Tooth
Disease: A Clinico-genetic Confrontation. Annals of Human Genetics. Jan. 2008. 16. Human Gene Mutation Database. Available at: http://www.biobase international.com/hgmd/pro/start.php.

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