NEUROLOGICAL REVIEW SECTION EDITOR: DAVID E. PLEASURE, MD Finding the Causes of Inherited Neuropathies Steven S. Scherer, MD, PhD he genetic causes of inherited neuropathies and their classification are the topics of this review. The large number of disorders as well as cumbersome and even inconsis- tent nomenclature make this a daunting task. Owing to limited space, I will not elabo- rate on the clinical features or diagnostic approaches of these disorders, and the pri- Tmary literature is not referenced; these topics are more fully discussed elsewhere.1-4 In addition, much information can be found in Online Mendelian Inheritance in Man (OMIM) (http://www .ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM; the 6-digit OMIM numbers of various disorders are given in the text and in the Table), the Mutation Database of Inherited Peripheral Neuropa- thies (http://www.molgen.ua.ac.be/CMTMutations), and the Neuromuscular Disease Center of Wash- ington University (http://www.neuro.wustl.edu/neuromuscular). WHAT IS without segmental demyelination or CHARCOT-MARIE-TOOTH DISEASE? remyelination. These findings were ex- tended by several groups, including More than a century ago, Charcot, Marie, Harding and Thomas,5 who proposed that and Tooth described patients who, as we forearm motor conduction velocities of now understand it, have a dominantly in- 38 m/s separated CMT1 from CMT2 herited, progressive neuropathy that af- (Figure 1A), a heuristic aid that can be fects myelinated motor and sensory axons misleading if applied too rigidly. in a length-dependent manner. This dis- This classification underscored the idea order is usually called Charcot-Marie- that CMT1 might be caused by muta- Tooth disease (CMT). Soon thereafter, re- tions in genes that are expressed by my- cessive cases of more severely affected individuals (with Dejerine-Sottas neuropa- elinating Schwann cells whereas CMT2 thy [DSN]) as well as kindreds with X- might be caused by mutations in genes ex- linked CMT type 1 (CMT1X) were de- pressed by neurons. This possibility was scribed. Dyck and colleagues introduced first formally demonstrated by Aguayo et the currently used classification scheme, al,6 who grafted nerve segments from although they used the term hereditary mo- Trembler mice (which have a domi- tor and sensory neuropathy rather than nantly inherited demyelinating neuropa- CMT. They demonstrated that most kin- thy) into the sciatic nerves of normal mice. dreds had CMT1, characterized by slowed The host axons that regenerated into the motor conduction velocities (10-40 m/s) donor nerve grafts were abnormally my- in the arms and histological evidence of elinated by the donor Schwann cells, segmental demyelination and remyelin- thereby demonstrating that the demyelin- ation in addition to axonal loss. The CMT2 ation defect was intrinsic to the Schwann kindreds tended to have a later age at on- cells. This concept is supported by the set, little if any slowing of nerve conduc- demonstration that myelinating Schwann tions, and loss of myelinated axons but cells or neurons express the genes that cause demyelinating or axonal neuropa- Author Affiliation: University of Pennsylvania Medical School, Philadelphia. thies, respectively. (REPRINTED) ARCH NEUROL / VOL 63, JUNE 2006 WWW.ARCHNEUROL.COM 812 Downloaded from www.archneurol.com at University of Pennsylvania, on June 13, 2006 ©2006 American Medical Association. All rights reserved. Table. Genetics of Nonsyndromic Inherited Neuropathies A Dominantly Inherited Neuropathies Disease (OMIM No.) Linkage or Gene Motor Sensory CMT1, autosomal or X-linked dominant demyelinating HNPP (162500) PMP22 CMT1 HMSN I CMT1A (118220) PMP22 Demyelinating Demyelinating CMT1B (118200) MPZ Axonal Axonal CMT1C (601098) LITAF/SIMPLE HMSN II CMT1D (607687) EGR2 CMT2 CMT1X (302800) GJB1 DI-CMT DI-CMTA (606483) 10q24.1-25.1 DI-CMTB (696482) DNM2 DI-CMTC (608323) YARS CMT2, autosomal dominant axonal or neuronal B Inherited Demyelinating Diseases CMT2A1 (118210) KIF1B CMT2A2 (609260) MFS2 Motor Sensory CMT2B (600882) RAB7 CMT2C (606071) 12q23-24 CMT2D (601472) GARS CMT1 CMT2E (162280) NEFL CMT 4 CMT2F (606595) HSPB1 Metachromatic and Globoid-Cell LD CMT2G (608591) 12q12-q13.3 Waardenburg IV Syndrome CMT2 (604484) 3q13.1 Cockayne Syndrome CMT2-P0 (118200) MPZ CMT2L (608673) HSPB8 Syndromic CMT4, AR demyelinating neuropathy CMT4A (214400) GDAP1 CMT4B-1 (601382) MTMR2 Pelizaeus-Merzbacher Disease CMT4B-2 (604563) MTMR13 Pelizaeus-Merzbacher–like Disease CMT4C (601596) KIAA1985 CMT4D (601455) NDRG1 CMT4F (605260) PRX Nonsyndromic Nonsyndromic CNS HMSN-R (605285) 10q23.2 CMT4H (609311) 12p11.21-q13.11 CMT4 (605253) EGR2 AR-CMT2, AR axonal neuropathy C Inherited Axonal or Neuronal Diseases or CMT2B AR-CMT2A (605588) LMNA Motor Sensory AR-CMT2B (605589) 19q13.1-13.3 CMT2K (607831) GDAP1 Hereditary Hereditary Congenital AR axonal neuropathy 5q deletion Motor CMT2 Sensory HSAN Neuropathy AR-CMT 2 Neuropathy HSAN1 (162400) SPTLC1; dominant HSAN1B (608088) 3p22-24; dominant Complicated SPG HSAN2 (201300) HSN2; recessive GAN HSAN3 (223900) IKBKAP; recessive NAD HSAN4 (256800) TRKA; recessive ALS4 HSAN5 (162030) NGFB; recessive Syndromic SPG17 Ataxias Primary erythermalgia (133020) SCN9A; dominant Cold-induced sweating (272430) CRLF1; recessive Pure SPG HMN HMN I (606595) Dominant HMN II (158590) HSPB8; dominant HMN II (608634) HSPB1; dominant Nonsyndromic Nonsyndromic CNS HMN III (607088) 11q13; recessive HMN IV Recessive HMN V (600794) GARS, dominant; BSCL2, dominant Figure 1. The relationships of inherited neuropathies to each other and other HMN VI/SMARD1 (604320) IGHMBP2; recessive syndromes. These Venn diagrams depict that dominantly inherited HMN VII (158580) DCTN1 neuropathies can be separated into demyelinating and axonal forms (A); that HMN/ALS4 (602433) SETX; dominant inherited demyelinating diseases can be separated into those that cause Congenital distal SMA (600175) 12q23-q24; dominant peripheral nervous system and/or central nervous system (CNS) HMN Jerash (605726) 9p21.1-p12; recessive dysmyelination or demyelination (B); and that inherited axonal diseases can be separated into those that cause combinations of a motor neuropathy, Abbreviations: ALS4, amyotrophic lateral sclerosis type 4; AR, autosomal sensory neuropathy, or both sensory and motor neuropathy, each of which recessive; CMT, Charcot-Marie-Tooth disease; DI, dominant intermediate; may also involve CNS axons. CMT indicates Charcot-Marie-Tooth disease; HMN, hereditary motor neuropathy; HMSN, hereditary motor and sensory HMSN, hereditary motor and sensory neuropathy; LD, leukodystrophy; neuropathy; HNPP, hereditary neuropathy with liability to pressure palsies; AR, autosomal recessive; SPG, spastic paraplegia; GAN, giant axonal HSAN, hereditary sensory and autonomic neuropathy; OMIM, Online neuropathy; ALS, amyotrophic lateral sclerosis; and NAD, neuroaxonal Mendelian Inheritance in Man; SMA, spinal muscular atrophy; dystrophy. SMARD1, spinal muscular atrophy with respiratory distress type 1. (REPRINTED) ARCH NEUROL / VOL 63, JUNE 2006 WWW.ARCHNEUROL.COM 813 Downloaded from www.archneurol.com at University of Pennsylvania, on June 13, 2006 ©2006 American Medical Association. All rights reserved. DOMINANT KINDS OF CMT fundamental disturbance caused by DNM2 mutations af- fects neurons or axons, Schwann cells, or both. Mapping the genetic loci of different kindreds led to the identification of the causative genetic defects and the re- RECESSIVE KINDS OF CMT alization that multiple genes cause CMT1, CMT2, and DSN. This began with the discovery that the PMP22 gene Recessive types of CMT are less common than domi- (which encodes an intrinsic membrane protein of com- nantly inherited neuropathies and are mainly caused by pact myelin, peripheral myelin protein 22) is duplicated mutations in a different group of genes (Table). The de- in CMT1A and deleted in hereditary neuropathy with li- myelinating forms (CMT4) are caused by mutations in ability to pressure palsies. Mutations in genes already MTMR2 or MTMR13 (which likely interact to form a phos- known to be expressed by myelinating Schwann cells were phatase), EGR2, PRX (which encodes periaxin, part of a found to cause other kinds of dominantly inherited de- dystroglycan complex), and NDRG1 or KIAA1985 (which myelinating neuropathies—myelin protein zero (MPZ), encode proteins of unknown function). Myelinating which encodes the major adhesive protein of compact Schwann cells express all of these genes, and the avail- myelin, and EGR2, which encodes a transcription fac- able data indicate that each of the corresponding pro- tor. Charcot-Marie-Tooth disease type 1 was also found teins likely has an essential role in Schwann cells so that to be caused by mutations in genes not previously known recessive mutations result in demyelination. Although re- to be expressed by myelinating Schwann cells—GJB1, cessive GDAP1 mutations cause a neuropathy with some which encodes the gap junction protein connexin32, and demyelinating features, the neuropathy appears to be axo- LITAF/SIMPLE, which encodes a protein that may be in- nal in other kindreds. The basis of this discrepancy re- volved in the degradation of intracellular proteins. mains to be determined. Charcot-Marie-Tooth disease type 2 is less common Besides GDAP1, pure recessively inherited axonal neu- than CMT1, and it also results from diverse genetic causes. ropathies are rare.7 Recessive mutations in LMNA (which A dominant mutation in KIF1B, which encodes a kine- encodes lamin A/C) cause