Charcot-Marie-Tooth Disease and Related Hereditary Neuropathies

  • Recommended test for suspected autosomal dominant or sporadic demyelinating CMT, CMT1 or CMT1A.
  • Deletion/duplication of PMP22 gene is performed first. If no large deletions or duplications are detected and/or results do not explain the clinical scenario, sequencing of hereditary neuropathy genes is performed (see Genes Tested table for gene list).
  • Deletion/duplication and sequencing components are also orderable separately, see below.
  • Recommended test for suspected HNPP, appropriate first-tier test for suspected autosomal dominant or sporadic demyelinating CMT, CMT1 or CMT1A; does not detect sequence variants.
  • Recommended test if there is a known familial PMP22 deletion or duplication previously identified in a family member. A copy of the family member’s test result documenting the known familial variant is required.
  • Recommended test for hereditary neuropathies or CMT subtype other than CMT1/CMT1A (see Genes Tested table for gene list).
  • Appropriate second-tier test for suspected CMT1 after result of PMP22 deletion/duplication analysis is negative.
  • Recommended test for a known familial sequence variant previously identified in a family member.
  • A copy of the family member’s test result documenting the known familial variant is required.

Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy with many types and subtypes, including types 1 (CMT1), 1A (CMT1A), 2 (CMT2), and 4 (CMT4), among others. Disorders with similar clinical findings include hereditary motor neuropathy (HMN), hereditary motor and sensory neuropathy (HMSN), hereditary sensory neuropathies (HSN), hereditary sensory and autonomic neuropathies (HSAN), and hereditary neuropathy with liability to pressure palsies (HNPP). Diagnostic testing for these conditions can be performed to confirm the diagnosis in symptomatic individuals or to identify family members at risk for developing the condition; genetic etiology generally determines the CMT type and subtype.

Disease Overview

Prevalence of CMT hereditary neuropathy – 1/3,300

Age of onset – first through third decade

Diagnosis of Hereditary Neuropathy

Based on combination of:

  • Physical examination
  • Personal history
  • Family history
  • Electromyography
  • Nerve conduction velocity (NCV)
  • Nerve biopsy
  • Genetic testing
  • Exclusion of acquired neuropathies

Symptoms

  • CMT
    • Progressive distal motor and sensory neuropathy
    • Muscle weakness/atrophy
    • Pes cavus foot deformity, foot drop
  • HSN/HSAN
    • Predominant sensory neuropathy with motor involvement in advanced disease
  • HMN
    • Distal motor neuropathy without sensory loss
  • HNPP
    • Transient/recurring focal pressure neuropathies (eg, carpal tunnel syndrome)
    • Mild to moderate peripheral neuropathy

Types of Peripheral Neuropathies

  • Demyelinating
    • Upper-limb motor NCV <38 meters/second (m/s)
    • Pathological evidence of myelin abnormalities
  • Axonal/nondemyelinating
    • Upper-limb motor NCV >38 m/s
    • Pathological evidence of axonal degeneration and regeneration
  • Intermediate
    • Upper-limb motor NCV 25-45 m/s

Types of CMT

  • CMT disease is comprised of multiple types defined by phenotype and/or inheritance pattern.
    • CMT1 – demyelinating neuropathy, autosomal dominant
    • CMT2 – axonal motor and sensory neuropathy, autosomal dominant and recessive
    • CMT4 – demyelinating neuropathy, autosomal recessive
    • CMTX – variable neuropathy, X-linked
    • DI-CMT – dominant intermediate neuropathy
    • RI-CMT – recessive intermediate neuropathy
  • CMT subtypes are further divided based on specific causative gene.
    • CMT1A, for example, is caused by variants in PMP22, and CMT1B is caused by variants in MPZ
    • Symptoms are often indistinguishable among CMT subtypes
    • Genetic testing to determine subtype can be performed
      • Sequentially, based on phenotype and inheritance pattern OR
      • With large panels that test multiple genes simultaneously

Test Description

See Genes Tested table for genes included in the panel.

Sensitivity/Specificity

  • PMP22 deletion/duplication analysis
    • Clinical sensitivity    ,    
      • 70-80% for CMT1
      • 80% for HNPP
    • Analytical sensitivity/specificity – 99%
  • Sequencing panel
    • Clinical sensitivity is disorder dependent.

Limitations

  • A negative result does not exclude a heritable form of neuropathy.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications in PMP22
    • Large deletions/duplications in genes other than PMP22
    • Noncoding transcripts
  • The following exons are not sequenced due to technical limitations of the assay:
    • SPTLC1 (NM_006415) 3
    • DNMT1 (NM_001130823) 5
    • SETX (NM_001351528) 26
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants

Analytical Sensitivity

  • For MLPA: 99%
  • For massively parallel sequencing:
  • Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

    SNVs

    99.2

    96.9-99.4

    Deletions 1-10 bp

    93.8

    84.3-98.2

    Deletions 11-44 bp

    100

    87.8-100

    Insertions 1-10 bp

    94.8

    86.8-98.5

    Insertions 11-23 bp

    100

    62.1-100

    aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

    bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene MIM Number Disorder and Subtype (Abbreviation) Inheritance

AARS

601065

CMT disease, axonal, type 2N (CMT 2N)

AD

AIFM1

300169

Cowchock syndrome (CMT X4)

XL

ATL1

606439

Spastic paraplegia 3A, autosomal dominant (SPG 3A)

Neuropathy, hereditary sensory, type ID (HSN 1D)

AD

ATP7A

300011

Menkes disease

Occipital horn syndrome

Spinal muscular atrophy, distal, X-linked 3

XL

BAG3

603883

Myopathy, Myofibrillar, 6

Giant axonal neuropathy

AD

BICD2

609797

Spinal muscular atrophy, lower extremity-predominant, 2

AD

BSCL2

606158

BSCL2-related neurologic disorders/seipinopathy

neuropathy, distal hereditary motor, type VA (dHMN/HMN 5A)

Silver spastic paraplegia syndrome

Charcot-Marie-Tood disease type 2 (CMT 2)

AD

CCT5

610150

Neuropathy, hereditary sensory, with spastic paraplegia (HSN with SPG)

AR

DCTN1

601143

Neuropathy, distal hereditary motor, type VIIB (dHMN 7B)

Perry syndrome

AD

DHTKD1

614984

CMT disease type 2Q (CMT 2Q)

AD

DNAJB2

604139

Spinal muscular atrophy, distal, autosomal recessive, 5

AR

DNM2

602378

CMT disease, axonal type 2M (CMT 2M)

CMT disease, dominant intermediate B (DI-CMT B)

Centronuclear myopathy 1

AD

DNMT1

126375

Neuropathy, hereditary sensory, type IE (HSAN 1E)

Cerebellar ataxia, deafness, and narcolepsy

AD

DYNC1H1

600112

CMT disease, axonal, type 2O (CMT 2O)

Spinal muscular atrophy, lower extremity-predominant 1

AD

EGR2

129010

CMT disease, type 1D (CMT 1D)

AD

Dejerine-Sottas disease

Neuropathy, congenital hypomyelinating, 1 (CMT 4E)

AD or AR

ELP1 (IKBKAP)

603722

Familial dysautonomia

Hereditary sensory and autonomic neuropathy type III (HSAN 3)

AR

FBLN5

604580

Neuropathy, hereditary, with or without age-related macular degeneration

AD

FGD4

611104

CMT disease, type 4H (CMT 4H)

AR

FIG4

609390

CMT disease, type 4J (CMT 4J)

AR

Amyotrophic lateral sclerosis 11

AD

GAN

605379

Giant axonal neuropathy-1

AR

GARS

600287

CMT disease, type 2D (CMT 2D)

Neuropathy, distal hereditary motor, type VA (dHMN 5A)

AD

GDAP1

606598

CMT disease, type 4A (CMT 4A)

CMT disease, axonal, with vocal cord paresis CMT disease, axonal, type 2K (CMT 2K)

CMT disease, recessive intermediate, A (RI-CMT A)

AR

GJB1

304040

CMT neuropathy, X-linked dominant, 1 (CMT X1)

XL

GNB4

610863

CMT disease, dominant intermediate F (DI-CMT 1F)

AD

HARS

142810

CMT disease, axonal, type 2W (CMT 2W)

AD

HEXA

606869

Tay-Sachs disease/ hexosaminidase A deficiency

AR

HINT1

601314

Neuromyotonia and axonal neuropathy

AR

HOXD10

142984

Isolated congenital vertical talus

AD

HSPB1

602195

CMT disease, axonal, type 2F (CMT 2F)

Neuropathy, distal hereditary motor, type IIB; (dHMN 2B)

AD

HSPB3

604624

Neuronopathy, distal hereditary motor, type IIC (dHMN 2C)

AD

HSPB8

608014

CMT disease, axonal, type 2L (CMT 2L)

Neuropathy, distal hereditary motor, type IIA (dHMN 2A)

AD

IGHMBP2

600502

Neuronopathy, distal hereditary motor, type VI (HMN 6)

Charcot-Marie-Tooth disease, axonal, type 2S (CMT 2S)

AR

INF2

610982

CMT disease, dominant intermediate E (DI-CMT E)

AD

KARS

601421

CMT disease, recessive intermediate, B (RI-CMT B)

AR

KIF1A

601255

Neuropathy, hereditary sensory, type IIC (HSAN 2C SPG 30)

AR

KIF1B

605995

CMT disease, type 2A1 (CMT 2A1)

AD

KIF5A

602821

SPG 10

AD

LAS1L

300964

Spinal muscular atrophy with respiratory distress (SMARD)

XL

LITAF

603795

CMT disease, type 1C (CMT 1C)

AD

LMNA

150330

CMT disease, type 2B1 (CMT 2B1)

AR

LRSAM1

610933

CMT disease, axonal, type 2P (CMT 2P)

AD or AR

MARS

156560

CMT disease, axonal, type 2U (CMT 2U)

AD

MED25

610197

CMT disease, type 2B2 (CMT 2B2)

AR

MFN2

608507

Hereditary motor and sensory neuropathy VIA (HMSN 6A)

CMT disease, axonal, type 2A2A (CMT 2A2A)

AD

CMT disease, axonal, type 2A2B (CMT 2A2B)

AR

MORC2

616661

CMT disease, axonal, type 2Z (CMT 2Z)

AD

MPZ

159440

CMT disease, dominant intermediate D (DI-CMT D)

CMT disease, type 1B (CMT 1B)

CMT disease, type 2I (CMT 2I)

CMT disease, type 2J (CMT 2J)

Roussy-Levy syndrome

AD

Neuropathy, congenital hypomyelinating (CMT 4)

Dejerine-Sottas disease

AD or AR

MTMR2

603557

CMT disease, type 4B1 (CMT 4B1)

AR

NDRG1

605262

CMT disease, type 4D (CMT 4D)

AR

NEFL

162280

CMT disease, type 2E (CMT 2E)

CMT disease, dominant intermediate G (DI-CMT G)

AD

CMT disease, type 1F (CMT 1F)

AD or AR

NGF

162030

Neuropathy, hereditary sensory and autonomic, type V (HSAN 5)

AR

NTRK1

191315

Insensitivity to pain, congenital, with anhidrosis (HSAN 4)

AR

PDK3

300906

CMT disease, X-linked dominant, 6 (CMT X6)

XL

PLEKHG5

611101

CMT disease, recessive intermediate C (RI-CMT C)

Spinal muscular atrophy, distal, autosomal recessive, 4

AR

PMP22

601097

CMT disease, type 1A (CMT 1A) (Gene duplication)

Neuropathy, recurrent, with pressure palsies (HNPP) (Gene deletion and sequence variants)

CMT disease, type 1E (CMT 1E) (Sequence variants)

AD

PRNP

176640

Hereditary prion diseases

AD

PRPS1

311850

CMT disease, X-linked recessive, 5 (CMT X5)

XL

PRX

605725

CMT disease, type 4F (CMT 4F)

AR

RAB7A

602298

CMT disease, type 2B (CMT 2B)

AD

REEP1

609139

Neuronopathy, distal hereditary motor, type VB (dHMN 5B)

Spastic paraplegia 31, autosomal dominant

AD

RETREG1 (FAM134B)

613114

Neuropathy, hereditary sensory and autonomic, type IIB (HSAN 2B)

AR

SBF1

603560

CMT disease, type 4B3 (CMT 4B3)

AR

SBF2

607697

CMT disease, type 4B2 (CMT 4B2)

AR

SCN9A

603415

Small fiber neuropathy

Paroxysmal extreme pain disorder 

AD

Hereditary sensory and autonomic neuropathy type IID (HSAN 2D)

Insensitivity to pain, congenital

AR

SETX

608465

Amyotrophic lateral sclerosis 4, juvenile

AD

Spinocerebellar ataxia, autosomal recessive 1

AR

SH3TC2

608206

Mononeuropathy of the median nerve, mild

AD

CMT disease, type 4C (CMT 4C)

AR

SLC12A6

604878

Agenesis of the corpus callosum with peripheral neuropathy

AR

SLC5A7

608761

Neuronopathy, distal hereditary motor, type VIIA (dHMN 7A)

AD

SPTLC1

605712

Neuropathy, hereditary sensory and autonomic, type IA (HSAN 1A)

AD

SPTLC2

605713

Neuropathy, hereditary sensory and autonomic, type IC (HSAN 1C)

AD

TDP1

607198

Spinocerebellar ataxia, autosomal recessive with axonal neuropathy

AR

TFG

602498

Hereditary motor and sensory neuropathy, Okinawa type

AD

TRIM2

614141

CMT disease, type 2R (CMT 2R)

AR

TRPV4

605427

Hereditary motor and sensory neuropathy, type IIC (HMSN 2C)

AD

TTR

176300

Amyloidosis, hereditary, transthyretin-related

Carpal tunnel syndrome, familial

AD

WNK1

605232

Neuropathy, hereditary sensory and autonomic, type II (HSAN 2A)

AR

YARS

603623

CMT disease, dominant intermediate C (DI-CMT C)

AD

AD, autosomal dominant; AR, autosomal recessive; dHMN/HMN, (distal) hereditary motor neuropathy; DI-CMT, dominant-intermediate CMT; HMSN, hereditary motor and sensory neuropathy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN, hereditary sensory and autonomic neuropathy; HSN, hereditary sensory neuropathy; RI-CMT, recessive-intermediate CMT; SPG, spastic paraplegia; XL, X-linked
    References