Inherited Peripheral Neuropathies
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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 |
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| Form | Inheritance | Locus | Reference | Gene | Reference |
CMT1 |
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| 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 |
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| 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 |
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| DI-CMTA | AD | 10q24.1-q25.1 | Verhoeven et al., 2001 | unknown |
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| 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 |
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| 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 |
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| CMT2L | AD | 12q24 | Tang et al., 2004 | HSPB8 |
Tang et al., 2005 |
AR-CMT2 or CMT4C |
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| 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 |
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| AR-CMT2B (CMT4C3) | AR | 19q13.3 | Leal et al., 2001 | unknown |
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| AR-CMT2 (CMT4C4) | AR | 8q21 | Cuesta et al., 2002 | GDAP1 |
Cuesta et al., 2002 |
CMTX |
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| 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 |
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| CMT3X | XR | Xp22.2 | Ionasescu et al., 1991 | unknown |
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| CMT4X | XR | Xq26-q28 | Ionasescu et al., 1991 | unknown |
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| CMTX5 | XR | Xq21.32-q24 | Kim et al., 2005 | PRPS1 |
Kim et al., 2007 |
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distal HMN |
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| 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 |
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| 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 |
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| Autosomal recessive lower motor neuron disease with childhood onset | AR | 1p36 | Maystadt et al., 2006 | PLEKHG5 |
Maystadt et al., 2007 |
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HS(A)N |
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| 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 |
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| 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 |
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| DI-CMTB | AD | 19p12-p13.2 | Kennerson et al., 2001 | DNM2 |
Züchner et al., 2005 |
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Hereditary recurrent focal neuropathies |
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| 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 |
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Other forms |
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| 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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