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Inherited Peripheral Neuropathies Mutation Database

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Inherited Peripheral Neuropathies


Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Soon after the original description by J.M. Charcot, P. Marie and H.H. Tooth in 1886, it became apparent that this syndrome is clinically and genetically heterogeneous. Several subtypes of inherited peripheral neuropathies were delineated and classified as hereditary motor and sensory neuropathies (HMSN), hereditary motor neuropathies (HMN) and hereditary sensory (and autonomic) neuropathies (HSAN). All these types are further subdivided in several subtypes. The classification provides a valuable framework for both diagnostic and research purposes.
In this classification, HMSN type I corresponds to CMT type 1 (CMT1, dominant, OMIM entries 118220, 118200, 302800, 601098) and CMT type 4 (CMT4, autosomal recessive, OMIM entries  214400, 601382, 604563, 601596, 601455, 604168, 609311, 611228) while HMSN type II corresponds to CMT type 2 (CMT2, OMIM entries 609260, 118210, 600882,  605588, 605589, 601472). Dejerine-Sottas syndrome (DSS,OMIM entry 145900 ) and congenital hypomyelinating neuropathy (CH, OMIM entry  605253 ) are included in HMSN type III.

Molecular genetic studies have been very successful in the field of the inherited peripheral neuropathies. Up to date, about 50 loci and 30 genes have been identified (see table).

Genes Loci

HMSN


Form Inheritance Locus Reference Gene Reference

CMT1


CMT1A AD 17p11.2 Vance et al., 1989 PMP22 Raeymaekers et al., 1991
Lupski et al., 1991
CMT1B, DSS,CH AD 1q22-q23 Bird et al., 1982 MPZ (P0) Hayasaka et al., 1993
Hayasaka et al., 1993
Hayasaka et al., 1993
CMT1C AD 16p13.1-p12.3 Street et al., 2001 LITAF (SIMPLE) Street et al., 2003
CMT1 (CMT1D), DSS, CH AD 10q21.1-q22.1 EGR2 Warner et al., 1998
CMT1 (CMT1E) AD 8p21 NEFL Jordanova et al., 2003
DSS AD 8qter Ionasescu et al., 1996 unknown

CMT4


CMT4A AR 8q13-q21 Ben Othmane et al., 1993 GDAP1 Baxter et al., 2002
CMT4B2 AR 11p15 Ben Othmane et al., 1999 SBF2 (MTMR13) Senderek et al., 2003
CMT4B1 AR 11q23 Bolino et al., 1996 MTMR2 Bolino et al., 2000
CMT4C AR 5q23-q33 LeGuern et al., 1996 SH3TC2 (KIAA1985) Senderek et al., 2003
CMT4D (HMSN-L) AR 8q24 Kalaydjieva et al., 1996 NDRG1 Kalaydjieva et al., 2000
CMT4E (CHN) AR 10q21.1-q22.1 EGR2 Warner et al., 1998
CMT4F (DSS) AR 19q13.1-q13.3 Delague et al., 2000 PRX Boerkoel et al., 2001
Guilbot et al., 2001
CCFDN AR 18q23-qter Angelicheva et al., 1999 CTDP1 Varon et al., 2003
CMT4G (HMSN-R) AR 10q23 Rogers et al., 2000 unknown
CMT4H AR 12p11.1-q13.11 De Sandre-Giovannoli et al., 2005 FGD4 Stendel et al., 2007
Delague et al., 2007
CMT4J AR 6q21 FIG4 Chow et al., 2007

DI-CMT


DI-CMTA AD 10q24.1-q25.1 Verhoeven et al., 2001 unknown
DI-CMTC AD 1p34-p35 Jordanova et al., 2003 YARS Jordanova et al., 2006
DI-CMT AD 1q22-q23 MPZ Mastaglia et al., 1999
HMSN-P AD 3q13.1 Takashima et al., 1997 unknown
slow NCV AD 8p23 Verhoeven et al., 2003 ARHGEF10 Verhoeven et al., 2003

CMT2


CMT2A AD 1p35-p36 Ben Othmane et al., 1993 MFN2 Züchner et al., 2004
CMT2A AD 1p35-p36 Ben Othmane et al., 1993 KIF1B Zhao et al., 2001
CMT2B AD 3q13-q22 Kwon et al., 1995 RAB7 Verhoeven et al., 2003
CMT2C AD 12q23-q24 Klein et al., 2003 unknown
CMT2D AD 7p14 Ionasescu et al., 1996 GARS Antonellis et al., 2003
CMT2E AD 8p21 Mersiyanova et al., 2000 NEFL Mersiyanova et al., 2000
CMT2F AD 7q11-21 Ismailov et al., 2001 HSPB1 (HSP27) Evgrafov et al., 2004
CMT2G AD 12q12-q13.3 Nelis et al., 2004 unknown
CMT2 AD 1q22-q23 MPZ De Jonghe et al., 1999
Marrosu et al., 1997
CMT2L AD 12q24 Tang et al., 2004 HSPB8 Tang et al., 2005

AR-CMT2 or CMT4C


AR-CMT2A (CMT4C1) AR 1q21.2-q21.3 Bouhouche et al., 1999 LMNA De Sandre-Giovannoli et al., 2002
AR-CMT2 (CMT4C2) AR 8q21.3 Barhoumi et al., 2001 unknown
AR-CMT2B (CMT4C3) AR 19q13.3 Leal et al., 2001 unknown
AR-CMT2 (CMT4C4) AR 8q21 Cuesta et al., 2002 GDAP1 Cuesta et al., 2002

CMTX


CMTX or CMT1X XR/XD Xq13.1 Gal et al., 1985 GJB1 (Cx32) Bergoffen et al., 1993
CMT2X or Cowchock syndrome XR Xq24-q26 Priest et al., 1995 unknown
CMT3X XR Xp22.2 Ionasescu et al., 1991 unknown
CMT4X XR Xq26-q28 Ionasescu et al., 1991 unknown
CMTX5 XR Xq21.32-q24 Kim et al., 2005 PRPS1 Kim et al., 2007

 

distal HMN


Form Inheritance Locus Reference Gene Reference
distal HMN II AD 12q24 Timmerman et al., 1996 HSPB8 (HSP22) Irobi et al., 2004
distal HMN V AD 7p Christodoulou et al., 1995 GARS Antonellis et al., 2003
distal HMN VI AR 11q13-q23 Grohmann et al., 1999 IGHMBP2 Grohmann et al., 2001
distal HMN VIIA AD 2q14 McEntagart et al., 2001 unknown
distal HMN VIIB AD 2p13 Puls et al., 2003 DCTN1 Puls et al., 2003
distal HMN / ALS4 AD 9q34 Chance et al., 1998 ALS4 (SETX) Chen et al., 2004
distal HMN-Jerash-type AR 9p21.1-p12 Christodoulou et al., 2000 unknown
congenital distal SMA AD 12q23-q24 van der Vleuten et al., 1998 unknown
distal HMN / Silver syndrome (SPG17) AD 11q13 Patel et al., 2001 BSCL2 Windpassinger et al., 2004
distal HMN X AR Xq13.1-q21 Takata et al., 2004 unknown
Autosomal recessive lower motor neuron disease with childhood onset AR 1p36 Maystadt et al., 2006 PLEKHG5 Maystadt et al., 2007

 

HS(A)N


Form Inheritance Locus Reference Gene Reference
HS(A)N I AD 9q22 Nicholson et al., 1996 SPTLC1 Bejaoui et al., 2001
Dawkins et al., 2001
HS(A)N II AR 12p13.33 Lafrenière et al., 2004 HSN2 Lafrenière et al., 2004
HS(A)N III AR 9q31-q33 Blumenfeld et al., 1993 IKBKAP Slaugenhaupt et al., 2001
HS(A)N IV / V AR 1q21-q22 NTRK1 (TRKA) Indo et al., 1996
Houlden et al., 2001
HSAN V AR 1p13.1 Einarsdottir et al., 2004 NGFB Einarsdottir et al., 2004
HSN I + cough + gastroesophageal reflux AD 3p22-p24 Kok et al., 2003 unknown
DI-CMTB AD 19p12-p13.2 Kennerson et al., 2001 DNM2 Züchner et al., 2005

 

Hereditary recurrent focal neuropathies


Form Inheritance Locus Reference Gene Reference
HNPP AD 17p11.2 Mariman et al., 1993 PMP22 Chance et al., 1993
HNA AD 17q25 Pellegrino et al., 1996 SEPT9 Kuhlenbäumer et al., 2005

 

Other forms


Form Inheritance Locus Reference Gene Reference
GAN AR 16q24.1 Ben Hamida et al., 1997 GAN Bomont et al., 2000
ACCPN (Andermann syndrome) AR 15q Casaubon et al., 1996 SLC12A6 (KCC3) Howard et al., 2002
CH + Waardenburg-Hirschsprung AD 22q13.1 SOX10 Pingault et al., 2000

 

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