What causes Charcot-Marie-Tooth (CMT) disease?

Updated: Feb 19, 2019
  • Author: Francisco de Assis Aquino Gondim, MD, MSc, PhD, FAAN; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

Answer

The Table below provides a summary of the current classification of CMT disorders based on updated knowledge of molecular biology and genetics. For completeness, several conditions are included that are discussed in this article.

In 1991, 2 groups showed that CMT1A, the most common form of CMT1, was associated with a 1.5-Mb duplication within chromosome arm 17p11.2. Some 70% of CMT1 cases and 90% of CMT1A cases result from this duplication, while the deletion of the same DNA region causes HNPP and related disorders. Importantly, other cases of CMT1A and HNPP result from point mutations in the PMP22 gene. [22] HNA is linked to chromosome arm 17q25.

CMT1B, which was linked to chromosome 1, was found to be associated with mutations in the myelin protein zero glycoprotein.

Usually, CMTX1 results from mutations in coding sequences of the gap junction protein beta 1/connexin 32 on chromosome arm Xq13.1, but some mutations occur in regulatory sequences such as the promotor or in introns. X-linked Charcot-Marie-Tooth disease type 2 (CMTX2) has been linked to an unknown gene on chromosome arm Xq24-26.

Mutations in the zinc-finger domain containing transcription factor EGR2 were linked to CMT1D and CHN.

DSS, a severe infantile neuropathy, was associated with PMP22 and MPZ mutations. Autosomal recessive DSS can be caused by mutations in the PRX gene on chromosome arm 19q13.13-2, which is regulated by EGR2.

CMT2A was linked to a loss-of-function mutation in the KIF1B gene on chromosome arm 1p36-35, which appears to be a motor protein involved in anterograde mitochondrial transport.

The gene responsible for CMT2B remains unknown, but linkage has been established to a 10-cM interval locus on chromosome arm 3q13-q22.

A linkage has yet to be identified for CMT2C. [23]

CMT2D is linked to an unknown gene on chromosome arm 7p14. [24]

Mutations in the neurofilament light subtype gene on chromosome arm 8p21 are the cause of CMT2E.

Several new disease genes have recently been identified: 2 signal transduction genes, the N-myc downstream-regulated gene-1 on chromosome arm 8q24.3 for the Lom form of autosomal recessive HSMN; the gene for the phosphatase myotubularin–related protein-2 on chromosome arm 11q22 for autosomal recessive HSMN; and the gene for a serine palmitoyltransferase subunit on chromosome arm 9q22 for HSN1.

Two different loci have been associated with the so-called intermediate nerve conduction forms of CMT: 10.7-Mb interval on chromosome arm 10q24.1-q25.1 and chromosome arm 19p12-p13.2.

Table 1. Genetics of CMT and Other HMSN Types (Open Table in a new window)

Disorder

Gene

Locus

CMT1: Dominant; Demyelinating

CMT 1A

PMP-22

17p11

CMT 1B

P0

1q22

CMT 1C

LITAF

16p13

CMT 1D

EGR2

10q21

CMT 1F

NF-L (NF-68)

8p21

CMTX1

Connexin-32

Xq13

CMTX2

Unknown

Xp22.2

CMTX3

Unknown

Xq26

HNPP

PMP-22

17p11

Dejerine-Sottas (HMSN 3)

PMP-22

8q23

EGR2

17p11

8q23

10q21

DI-CMT (Intermediate nerve conduction velocities)

DNM2

10q24

1p34

P0

CMT-X

19p12

10q24

1p34

1q22

Xq13

CMT2: Dominant; Axonal

DNM2

19p13.2-p12

CMT 2A

KIF1Bß

1p36

CMT 2A2

Mitofusin 2

1p36

CMT 2B

RAB7

3q13-q22

CMT 2B2

 

Unknown

19q13.3

CMT 2C

TRPV4

12q24.13

CMT 2D

GARS

7p14

CMT 2E

NF-68

8p21

CMT 2F

 

HSPB1 (HSP 27)

7q11

CMT 2G

Unknown

12q12

SMT 2H

GDAP1

8q21.3

CMT 2L

HSPB8

12q24

CMT 2 P0

P0

1q22

AR-CMT2: Recessive; Axonal

 

 

AR-CMT2A

Lamin A/C

1q21

AR-CMT2B

 

19q13

CMT 4A

GDAP1

8q13-21

CMT 4B1

MTMR2

11q23

CMT 4B2

SBF2/MTMR13

11q15

CMT 4C

SH3/TPR

5q23

CMT 4D (Lom)

NDRG1

8q24

CMT 4E

EGR2

10q21

CMT 4F

Periaxin

19q13

CMT 4G

HK1

10q23.2

CMT 4H

FIG4

6q21

Dejerine-Sottas (HMSN 3)

P0 CMT 4F

Autosomal

Congenital hypomyelinating neuropathy

P0

EGR2

PMP-22

Autosomal

CCFDN

CTDP1

18q23

Giant axonal neuropathy

Cytoskeletal protein gigaxonin

Unknown


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