FeedbackMultiplex Ligation-dependent Probe Amplification/Massively Parallel Sequencing
- 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.
Multiplex Ligation-dependent Probe Amplification
- 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.
Massively Parallel Sequencing
- 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.
Polymerase Chain Reaction/Sequencing
- 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
- 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
-
GeneReviews - Charcot-Marie-Tooth Hereditary Neuropathy Overview
Bird TD. Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Revision: Jan 2020; Accessed: Feb 2020]
-
GeneReviews - Charcot-Marie-Tooth Neuropathy X Type 1
Bird TD. Charcot-Marie-Tooth Neuropathy X Type 1. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Sep 2016; Accessed: Feb 2020]
-
GeneReviews - Hereditary Neuropathy with Liability to Pressure Palsies
Bird TD. Hereditary Neuropathy with Liability to Pressure Palsies. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Sep 2014; Accessed: Feb 2020]
-
GeneReviews - Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum
Dupré N, Howard HC, Rouleau GA. Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Jun 2014; Accessed: Feb 2020]
-
GeneReviews - Giant Axonal Neuropathy
Kuhlenbäumer G, Timmerman V, Bomont P. Giant Axonal Neuropathy. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Oct 2014; Accessed: Feb 2020]
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Auer-Grumbach M, Weger M, Fink-Puches R, et al. Fibulin-5 mutations link inherited neuropathies, age-related macular degeneration and hyperelastic skin. Brain. 2011;134(Pt 6):1839-1852.
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Claeys KG, Züchner S, Kennerson M, et al. Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy. Brain. 2009;132(Pt 7):1741-1752.
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Dierick I, Baets J, Irobi J, et al. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. Brain. 2008;131(Pt 5):1217-1227.
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Rossor AM, Polke JM, Houlden H, et al. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol. 2013;9(10):562-571.