Publications about genetic testing for neurological disorders
  1. Charcot–Marie–Tooth (CMT) Neuropathy Gene Panel

Charcot–Marie–Tooth (CMT) Neuropathy Gene Panel

June 08, 2018

Disease summary:

Charcot-Marie-Tooth (CMT) disease is a group of hereditary neuropathies, and represents one of the most common neurological conditions, characterized by a chronic motor and sensory polyneuropathy.

CMT is divided into the primary demyelinating neuropathies (CMT1, CMT3, and CMT4) and the primary axonal neuropathies (CMT2), with significant clinical overlap. All CMT subtypes are hereditary and >100 genes have been associated with CMT (Table 1) 1, 2.                   

The most common cause of CMT (70–80% of the cases) is the duplication of a large region on the short arm of chromosome 17 that includes gene PMP223, 4

Autosomal recessive, X-linked recessive, rarely autosomal dominant

Major clinical symptoms 1, 2:

  • Slowly progressive distal muscle weakness in the feet and/or hands
  • Variable age of onset
  • Difficulties walking, frequent tripping, falls
  • High-arched feet, weak ankle dorsiflexion, foot drop, pes cavus
  • Poor hand control, difficulties writing
  • Depressed tendon reflexes
  • Distal sensory loss
  • Presence of the specific clinical features (distal muscle weakness, sensory loss)
  • Positive family history of disease
  • Characteristic findings on electro-myographic (EMG) tests
  • Specific findings on nerve biopsy
  • Identification of pathogenic variant in one of the associated genes (Table 1)

There is no cure for Charcot-Marie-Tooth disease and other hereditary neuropathies but numerous symptomatic treatments exist, including the following 1, 4:

  • Management by a multidisciplinary team of neurologists, orthopedic surgeons, physical and occupational therapists
  • Special shoes and ankle/foot orthoses
  • Orthopedic surgery as needed for severe pes cavus
  • Pain-relief medication, carbamazepine or gabapentin for neuropathic pain.
  • Hereditary neuropathy with liability to pressure palsies (HNPP) caused by deletions in PMP22
  • CMT syndrome with spasticity caused by pathogenic variants in BSCL2, SPART or other genes
  • Familial brachial plexus neuropathy caused by pathogenic variants in SEPT9
  • Amyloid neuropathies caused by pathogenic variants in TTR and other genes
  • Refsum disease caused by pathogenic variants in PEX7 or PHYH
  • Metachromatic leukodystrophy caused by pathogenic variants in ARSA
  • Krabbe disease caused by pathogenic variants in GALC
  • Friedreich ataxia caused by pathogenic variants in FXN
  • X-linked disorders with neuropathy (Pelizaeus-Merzbacher disease, Adrenomyeloneuropathy)
  • Diabetes mellitus
  • Thyroid disease
  • Alcoholism
  • Vitamin B12 deficiency

To confirm/establish the diagnosis of CMT, CENTOGENE offers the following tests:

  • PMP22 gene deletion/duplication analysis
  • CMT neuropathy panel NGS Panel + CNV: sequencing and additionally detection of large deletions and duplications from the NGS data
  • Individuals with a positive family history of CMT disease
  • Individuals with most common symptoms of CMT disease (regardless of family history)

Confirmation of a clinical diagnosis through genetic testing of CMT disorder can allow for genetic counseling and may direct medical management.

Table 1: Overview of genes included in Charcot–Marie–Tooth (CMT) neuropathy panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
AARS 601065 type 2N Charcot-Marie-Tooth disease; early infantile epileptic encephalopathy 29 AD, AR 6
AIFM1 300169 Deafness, X-linked 5; Combined oxidative phosphorylation deficiency 6; Cowchock syndrome XLR 6
ARHGEF10 608136 slowed nerve conduction velocity AD 88
ATL1 606439 spastic paraplegia 3A AD 37
ATP7A 300011 X-linked distal spinal muscular atrophy type 3; Occipital horn syndrome; Menkes disease XLR 19
BSCL2 606158 Lipodystrophy, congenital generalized, type 2; spastic paraplegia 17; Neuropathy, distal hereditary motor, type V; Encephalopathy, progressive, with or without lipodystrophy AD, AR 16
COX6A1 602072 intermediate type D Charcot-Marie-Tooth AR 1
DHTKD1 614984 2-aminoadipic 2-oxoadipic aciduria; type 2Q Charcot-Marie-Tooth disease AD, AR 6
DNAJB2 604139 autosomal recessive distal spinal muscular atrophy type 5 AR 1
DNM2 602378 Myopathy, centronuclear 1; CHARCOT-MARIE-TOOTH, DOMINANT INTERMEDIATE TYPE B; Lethal congenital contracture syndrome 5 AD, AR 12
DNMT1 126375 cerebellar ataxia, deafness and narcolepsy; Neuropathy, hereditary sensory, type IE AD 48
DYNC1H1 600112 lower extremity-predominant spinal muscular atrophy type 1; type 2O Charcot-Marie-Tooth disease; mental retardation-13 AD 56
EGR2 129010 Dejerine-Sottas syndrom; congenital hypomyelinating neuropathy; type 1D Charcot-Marie-Tooth disease AD, AR 10
ELP1 603722 hereditary sensory and autonomic neuropathy type III AR 10
FBLN5 604580 Cutis laxa, autosomal recessive, type IA; hereditary neuropathy with or without age-related macular degeneration AD, AR 1
FGD4 611104 type 4H Charcot-Marie-Tooth disease AR 22
FIG4 609390 Yunis-Varon syndrome; type 4J Charcot-Marie-Tooth disease; amyotrophic lateral sclerosis 11; Polymicrogyria, bilateral temporooccipital AD, AR 34
GAN 605379 giant axonal neuropathy AR 13
GARS 600287 Neuropathy, distal hereditary motor, type V; type 2D Charcot-Marie-Tooth disease AD 23
GDAP1 606598 type 4A Charcot-Marie-Tooth disease; type 2K Charcot-Marie-Tooth disease AD, AR 21
GJB1 304040 Charcot-Marie-Tooth disease type 1 XLD 11
GNB4 610863 intermediate type F Charcot-Marie-Tooth AD 1
HINT1 601314 Neuromyotonia and axonal neuropathy, autosomal recessive AR 1
HK1 142600 Hemolytic anemia due to hexokinase deficiency; Neuropathy, hereditary motor and sensory, Russe type; Retinitis pigmentosa 79 AD, AR 1
HOXD10 142984 AD 0
HSPB1 602195 type 2F Charcot-Marie-Tooth disease; Neuropathy, distal hereditary motor, type IIB AD 10
HSPB8 608014 Neuropathy, distal hereditary motor, type IIA; type 2L Charcot-Marie-Tooth disease AD 2
IGHMBP2 600502 spinal muscular atrophy with respiratory distress type 1; type 2S Charcot-Marie-Tooth disease AR 12
INF2 610982 Focal Segmental Glomerulosclerosis 5; intermediate type E Charcot-Marie-Tooth AD 13
KARS 601421 CHARCOT-MARIE-TOOTH, RECESSIVE INTERMEDIATE TYPE B; Deafness, autosomal recessive 89 AR 0
KIF1A 601255 spastic paraplegia 30; Neuropathy, hereditary sensory, type IIC; MENTAL RETARDATION, AUTOSOMAL DOMINANT 9 AD, AR 62
KIF1B 605995 type 2A1 Charcot-Marie-Tooth disease; pheochromocytoma AD 62
KIF5A 602821 spastic paraplegia 10 AD 34
LITAF 603795 type 1C Charcot-Marie-Tooth disease AD 24
LMNA 150330 dilated cardiomyopathy-1A; Lipodystrophy, familial partial, 2; Hutchinson-Gilford progeria; Emery-Dreifuss muscular dystrophy 2; Malouf syndrome; Mandibuloacral dysplasia; Restrictive dermopathy, lethal; type 2B1 Charcot-Marie-Tooth disease; Heart-hand syndrome, Slovenian type; Muscular dystrophy, congenital; Emery-Dreifuss muscular dystrophy 3, AR AD, AR 22
LRSAM1 610933 type 2P Charcot-Marie-Tooth disease AD, AR 3
MARS 156560 Interstitial lung and liver disease; type 2U Charcot-Marie-Tooth disease AD, AR 4
MED25 610197 type 2B2 Charcot-Marie-Tooth disease; Basel-Vanagait-Smirin-Yosef syndrome AR 31
MFN2 608507 axonal Charcot-Marie-Tooth disease type 2A2A; axonal Charcot-Marie-Tooth disease type 2A2B AD, AR 23
MPZ 159440 type 1B Charcot-Marie-Tooth disease; Dejerine-Sottas syndrom; type 2I Charcot-Marie-Tooth disease; type 2J Charcot-Marie-Tooth disease AD, AR 9
MTMR2 603557 type 4B1 Charcot-Marie-Tooth disease AR 13
NDRG1 605262 type 4D Charcot-Marie-Tooth disease AR 18
NEFL 162280 type 2E Charcot-Marie-Tooth disease; type 1F Charcot-Marie-Tooth disease AD, AR 12
NTRK1 191315 familial medullary thyroid carcinoma; hereditary sensory and autonomic neuropathy type 4 AD, AR 9
PDK3 300906 type X6 Charcot-Marie-Tooth XLD 0
PLEKHG5 611101 autosomal recessive distal spinal muscular atrophy type 4; recessive intermediate Charcot-Marie-Tooth disease type C AR 13
PMP22 601097 type 1A Charcot-Marie-Tooth disease; Dejerine-Sottas syndrom; Neuropathy, recurrent, with pressure palsies ?AD, AD, AR 11
PRPS1 311850 Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; deafness type 1; type X5 Charcot-Marie-Tooth XL, XLR 5
PRX 605725 Dejerine-Sottas syndrom; type 4F Charcot-Marie-Tooth disease AD, AR 22
RAB7A 602298 type 2B Charcot-Marie-Tooth disease AD 3
REEP1 609139 spastic paraplegia 31; Neuronopathy, distal hereditary motor, type VB AD 27
RETREG1 613114 Neuropathy, hereditary sensory and autonomic, type IIB AR 4
SBF1 603560 type 4B3 Charcot-Marie-Tooth disease AR 12
SBF2 607697 type 4B2 Charcot-Marie-Tooth disease AR 42
SH3TC2 608206 type 4C Charcot-Marie-Tooth disease; Mononeuropathy of the median nerve, mild AD, AR 13
SLC12A6 604878 Agenesis of the corpus callosum with peripheral neuropathy AR 26
SLC25A46 610826 Neuropathy, hereditary motor and sensory, type VIB AR 1
SPG11 610844 Amyotrophic lateral sclerosis 5, juvenile; spastic paraplegia type 11; Charcot-Marie-Tooth disease, axonal, type 2X AR 71
SPTLC1 605712 Neuropathy, hereditary sensory and autonomic, type IA AD 1
SPTLC2 605713 Neuropathy, hereditary sensory and autonomic, type ic AD 1
TFG 602498 Hereditary motor and sensory neuropathy, Okinawa type; spastic paraplegia 57 AD, AR 2
TRIM2 614141 type 2R Charcot-Marie-Tooth disease AR 1
TRPV4 605427 Brachyolmia type 3; Metatropic dysplasia; Spondylometaphyseal dysplasia, Kozlowski type; Hereditary motor and sensory neuropathy, type IIc AD 11
VCP 601023 inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1; amyotrophic lateral sclerosis 14; Charcot-Marie-Tooth disease type 2Y AD 15
WNK1 605232 Neuropathy, hereditary sensory and autonomic, type II; Pseudohypoaldosteronism, type IIC AD, AR 14
YARS 603623 intermediate type C Charcot-Marie-Tooth AD 10