This chapter introduces the second part of the book dealing with the biol- ogy, genetics, clinical features and therapy of specific hereditary neuropa- thies. The classification and overview presented in the chapter serve as a framework for the following chapters, dealing with specific genetic entities.
5.1 History
The history of hereditary peripheral neuropathies can be divided into four periods: the first ranging from the first concise description in 1886 to 1956 [44]. This period was devoted to the clinical and pathological description of the disease. The second period ranging from 1956 to 1982 applied elec- trophysiologic techniques and refined pathological methods, especially electron microscopy, for the study of hereditary neuropathies. The third period, lasting from 1982 to today is concerned with the genetic mapping and elucidation of causative genetic defects. The genetic defects underlying most major forms of hereditary neuropathies are now known and we are already in the middle of the fourth period focussing on the understanding of the biology and pathobiology of the peripheral nerve based on the knowledge of the causative genetic defects which will be followed by the development of effective therapeutic approaches.
In 1886, J.M. Charcot, P. Marie and, independently, H.H. Tooth concisely described for the first time a hereditary peripheral neuropathy [12, 46].
The main symptoms were distal weakness and atrophy affecting mainly the legs and especially the small foot muscles and peroneal muscles. In addi- tion, fasciculations, frequent cramps and preservation of the proximal mus- cles were noted. Only a few years later the description of clinically distinct forms (e.g., Djerine-Sottas syndrome (DSS), also called HMSN III) showed that hereditary neuropathies are a heterogeneous group of diseases [16]. In the following decades numerous descriptions of clinically and genetically distinct forms of hereditary neuropathies were published and led to the first attempt of a classification by Dawidenkow in 1927 [14, 15]. The intro- duction of the measurement of motor nerve conduction velocities (MNCV)
neuropathies and rare unclassified forms
G. Kuhlenbåumer
into the clinical evaluation of patients with neuromuscular disease allowed the distinction between patients with severely reduced and nearly normal NCVs [30]. These were later termed hereditary motor and sensory neuro- pathy type I (HMSN I or CMT1) and hereditary motor and sensory neuro- pathy type II (HMSN II or CMT2) [20]. Improved pathologic methods showed that severely reduced MNCVs correlate with de- and remyelination in sural nerve biopsies [18]. The detailed neurophysiological and micro- scopic examination of large families allowed further subclassification [19].
In 1980, Bird and coworkers were the first to find a genetic linkage with the Duffy blood group antigens on chromosome 1 in a family with Char- cot-Marie-Tooth disease [5]. This finding was the advent of the molecular genetic era. The first causative genetic defect ± the CMT1A causing dupli- cation on chromosome 17p11 ± was identified in 1991 [32, 42]. This genet- ic defect turned out to be the most common cause of hereditary neuropa- thies accounting for between 50 and 70% of all hereditary peripheral neu- ropathies [36]. The underlying genetic defects for most common forms of hereditary peripheral neuropathies have now been identified. At present, animal and cellular models ± most of them based on the genes identified by genetic research ± are fundamentally changing our understanding of the biology of the peripheral nerve and the pathomechanisms underlying hereditary peripheral neuropathies. In the future, these models will lead to the development of novel therapeutic tools. The first successful trials of as- corbic acid and a progesterone antagonist in animal models of CMT1A give hope that this goal will be attainable in the not too far future [39, 43].
5.2 Clinical and electrophysiological phenotype of hereditary motor and sensory neuropathies (HMSNs)
A detailed account of the clinical and electrophysiological features of he- reditary neuropathies is given in the corresponding chapters. This section provides only the most essential information needed to understand the ge- netics and classification of HMSNs.
HMSNs are clinically characterized by slowly progressive distal muscle weakness and atrophy that primarily affect the small foot muscles, pero- neal muscles and later those of the hands and forearms. In all cases, distal, usually symmetrical sensory deficits are present. Most patients have foot deformities, mostly pes cavus and clawtoes/hammertoes. The tendon re- flexes are diminished or absent, especially the ankle jerk. The course of these diseases is often benign, and most patients do not ± or only very late in life ± become wheelchair dependent.
Slowed motor nerve conduction velocities (MNCVs) in patients with HMSN were described for the first time in the 1950s [30]. Later it was shown that the MNCVs of HMSN patients follow a nearly bimodal distri-
tal and predominantly demyelinating neuropathy (HMSN I or CMT1). The other group has normal or only slightly reduced MNCVs (above 38 m/s) cor- responding to a predominantly axonal neuropathy (HMSN II or CMT2) [22].
The cut-off value between CMT1 and CMT2 was originally defined as a MNCV of the median nerve of 38 m/s [22]. The amplitude of the compound motor nerve action potential (CMAP) is severely reduced in CMT2 patients but nearly all adult CMT1 patients also have reduced CMAPs due to second- ary axonal damage [28]. The amplitude of the sensory nerve action potentials (SNAP) is severely reduced or the potentials are not recordable at all. Patients with an X-linked mode of inheritance (CMTX) caused by mutations in the gap junction protein beta 1 gene (GJB1) can exhibit a CMT1, a CMT2 or an intermediate phenotype with MNCVs that do not allow for unequivocal allocation to the categories CMT1 or CMT2.
Electromyographic examination of distal muscles (e.g., the anterior tibial muscle) often shows signs of chronic denervation and sometimes, pathologic spontaneous discharges in all forms of HMSN.
5.3 Classification of hereditary neuropathies (Table 5.1) 5.3.1 The HMSN classification by Dyck, Chance, Lambert and Carney The HMSN classification is mainly a clinical one. Although not always in good agreement with the more recently defined molecular genetic entities anymore, it remains a landmark in the scientific exploration of hereditary neuropathies and a valuable tool in clinical practice; thus, an outline will be presented here. Hereditary motor and sensory neuropathies had been subdivided by Harding and Thomas into a group with motor nerve con- duction velocities (MNCV) below 38 m/s (HMSN I or CMT1) and a group with MNCVs above 38 m/s (HMSN II or CMT2) [22]. This electrophysiol- ogy-based classification is still valid. In the literature HMSN I and HMSN II are commonly referred to as Charcot-Marie-Tooth disease type 1 and 2 (CMT1 and CMT2).
HMSN III is equivalent to Djerine-Sottas syndrome (DSS) [16, 21]. DSS is clinically defined as a severe, demyelinating neuropathy manifesting in infancy. Nerve conduction velocities are strongly reduced and the protein content of the cerebrospinal fluid is elevated in some cases. The inheritance of DSS was formerly assumed to be exclusively autosomal recessive. Today, we know that DSS is not a genetic entity and that many of the presumably recessive cases turned out to be caused by dominant de novo mutations in a number of different genes. Nevertheless, the term DSS remains useful for the clinical description of a severe demyelinating peripheral neuropathy
Table5.1.Classificationofhereditaryneuropathies FormTypicalfeaturesInheritanceFrequencyLocusGeneOMIMAcc. Nr. HMSNhereditarymotorandsensoryneuropathiesADandAR CMT1dominanthypertrophic-demyelinatingCMT (mNCV<38m/s)ADcommon zCMT1AtypicalHMSN,childhood±typicallyonsetin2nd decade,optionaltremor,+deafnessalsocalled CMT1E
ADcommon17p11.2PMP22A:118220;E: 118300 zHNPPrecurrentpainlesspressurepalsiesandentrapment syndroms,histology:tomacula,onsetveryvariableADcommon17p11.2PMP22162500 zCMT1BoftenmoreseverethanCMT1A,congenitalto2nd decadeonsetADcommon1q22-q23MPZ(P0)118200 zCMT1CtypicalCMT1,childhood±onsetinseconddecadeADrare16p13.1-p12.3LITAF/SIMPLE601098 zCMT1DoftenmoreseverethanCMT1A,congenitalorfirst decadeonsetADrare10q21.1-q22.1EGR2607678 zCMT1FCMT1oftensevere,earlyonset,NEFLmutations causealsoCMT2EADrare8p21NEFL607734 CMT4recessivehypertrophic-demyelinatingCMT (mNCV<38m/s)ARrare zCMT4Asevereneuropathy,onsetinfirstdecade,Tunisian families(allelictoCMT4C4)ARrare8q13-q21GDAP1214400 zCMT4B1focallyfoldedmyelin,earlychildhoodonset (~34months),ItalianfamiliesARrare11q23MTMR2601382 zCMT4B2focallyfoldedmyelin,onsetinfirstor2nddecade, Tunisianfamilies,MIM:607739:withearlyonset glaucoma
ARrare11p15MTMR13/SBF2
604563; +Glauc
oma 607739
zCMT4CclinicallyCMT1like,onsetmostlyin1stdecade, scoliosis,peculiarmyelinpathologyARrare5q32 transcript KIAA1985
601596 zCMT4D(HMSN-L)progressivedeafness,onsetinfirstdecade, BulgarianGypsies(fromthetownofLom)ARrare8q24NDRG1601455 zCMT4E(CH)severeneuropathy,hypomyelination,congenital onsetARrare10q21.1-q22.1EGR2605253 zCMT4F(MIM:DSS)severeneuropathy,earlychildhoodonset(12±24 months),prominentsensorydeficit,(focallyfolded myelin)
ARrare19q13.1-q13.3PRXDSS:145900; PRX:605725 zCCFDNcongenitalcataractsfacialdysmorphismand neuropathy,WallachianGypsiesARrare18q23-qterCTDP1604186 zHMSN-Rsevereform,onsetinfirstorseconddecade, BulgarianGypsies(typeRusse)ARrare10q23unknown, EGR2605285 DI-CMT(dom. intermediate)dominantintermediateforms,intermediate mNCVADrare zDI-CMTAtypicalCMT,axonalandmyelinpathology,inter- mediatemNCV,onsetinfirstdecadeADrare10q24.1-q25.1unknown606483 zDI-CMTBtypicalCMT,axonalandmyelinpathology,inter- mediatemNCV,onsetinfirstdecadeADrare19p12-p13.2unknown606482 zDI-CMTCtypicalCMT,medianmNCVsbetween30m/sand normal,onset10±60yearsADrare1p34-p35unknown608323 zDI-CMTDtypicalCMT,ulnarmNCVsbetween33±48m/s, somesensoryandproximalmuscleinvolvementADrare1q22-q23MPZ(P0)607791 zDI-CMTnoclinicalsymptoms,mNCV*27±45m/s, normalCMAPs,slightlyreducedSNAPsADrare(?)8p23ARHGEF10608236
Table5.1(continued) FormTypicalfeaturesInheritanceFrequencyLocusGeneOMIMAcc. Nr. zHMSN-P (MIM: Okina
waty.)
proximalformofCMT,mNCV*38m/s,onset in3rddecade±rapidprogressADrare3p14.1-q13unknown604484 CMT2mNCV>38m/s,autosomaldominantADcommon zCMT2A1typicalCMT,onset1±52years,medianmotorNCVs 40-62m/s,noproximalinvolvement,notwheelchair bound
ADcommon(?)1p35-36MFN2118210 zCMT2A2similartoclassicalCMT,adultonset (mean*20years)ADrare1p35-p36KIF1B(beta)118210 zCMT2Bmainlysensoryneuropathy,acralulcerations,onset in2ndor3rddecade(couldbeclassifiedasHSAN)ADrare3q13-q22RAB7600882 zCMT2Cearlyonsetpredominantlymotor,axonalneuropathy withvocalcordandrespiratorymuscleinvolvementADrare12q23-q24unknown606071 zCMT2Dpredominantupperlimbsandmotorneuropathy, onsetin2ndor3rddecade,slowprogression (allelictodHMN5)
ADrare7p14GARS601472 zCMT2EtypicalCMT,intermediatemNCVs,onsetinthe2nd or3rddecade,NEFLmutationscausealsoCMT1EADrare8p21NEFL607684 zCMT2FallelictoHMN(1),similartoclassicalCMTbut trophicchanges,onsetin2ndor3rddecade, Russianfamily
ADrare7q11-21HSBP1(HSP27)606595 zCMT2GtypicalCMT,onsetmostlyinseconddecade,CMAP andSNAPSreducedADrare12q12-q13.3unknown608591
zCMT2I and
Jhearingloss,pupillarydysfunctioninsomeCMT2J pat.(couldbeclassifiedasDI-CMT),onsetin4thor 5thdecade
ADrare1q22-q23MPZ(P0)I:607677; 607736 zCMT2Lonset15-33years,clinicallytypicalHMSN,normal NCVs,candidateregionoverlapswithdHMN2regionADrare12q24HSBP8(HSP22)608014 CMT4Cor AR-CMT2autosomalrecessiveformsofCMT2ARrare zCMT4C1 (MIM:
CMT2B1)severeneuropathywithproximalmuscleinvolve- ment,onsetinthe2nddecade,Moroccanand Algerianfamilies
ARrare1q21.2-q21.3LMNA605588 zCMT4C2 (MIM:
CMT2H)signsofuppermotorneuroninvolvement,onsetin firstdecade,couldbeallelictoCMT4C4orCMT4A, Tunisian
ARrare8q21.3unknown607731 zCMT4C3 (MIM:
CMT2B2)typicalHMSN,onsetin4thdecade,onlyoneCosta RicanfamilyknownARrare19q13.3unknown605589 zCMT4C4 (MIM:
CMT2K)severeneuropathy,childhoodonset,vocalcord paralysis,allelictoCMT4AARrare8q21GDAP1607706 CMTXX-linkedformofCMT,oftenintermediate mNCVXRandXDcommon zCMTXorCMTX1classicalX-linkedCMT,femalesoftenlessseverely affectedthanmalesXR/XDcommonXq13.1GJB1(Cx32)302800 zCMTX2mentalretardation,infantileonsetXRrareXp22.2unknown302801 zCMTX3pyramidalsigns,onsetin2nddecadeXRrareXq26-q28unknown302802 zCMTX4(NADMR orCowchockSy.)severedistalweakness,deafness,mentalretarda- tion,congenitalorearlychildhoodonsetXRrareXq24-q26unknown310490
Table5.1(continued) FormTypicalfeaturesInheritanceFrequencyLocusGeneOMIMAcc. Nr. distalHMNhereditarymotorneuropathies (nosensory deficit,mostlynormalNCV)
ADandARrare zdistalHMNIallelictoCMT2F,juvenileonset,distalmuscle atrophy(notfullydescribedyet)ADrare7q11-21HSBP1(HSP27)608634 zdistalHMNIIdistalparesisandatrophy,onsetin3rdor4th decadeADrare12q24HSBP8(HSP22)158590 zdistalHMNIVlowerlimbpredominance,distaltoproximal,onset 0±20years,unabletowalkbetween12and>30 years
ARrare11q13±607088 zdistalHMNVapredominantupperlimbinvolvement,onsetin2nd decade(allelictoCMT2D)ADrare7pGARS600794 zdistalHMN Vb/SPG17alsocalledSilverSy.,onset:8±40years,spastic paraplegia,predominantupperlimbADrare11q12-14
BSCL2 (P270685 rot:Seipin) zdistalHMNdiaphragmaticspinalmuscularatrophy(SMARD1),ARrare11q13-q23IGHMBP2604320 VI(SMARD1)earlydeath,onsetinthefirstmonthoflife zdistalHMNVIIAvocalcordparalysis,onsetin2nddecadeADrare2q14unknown158580 zdistalHMNVIIBonsetearlyadulthood,vocalcordparalysis,ADrare2p13DCTN1607641 (MIM:PLMND)breathingdifficulties,facialweakness zdistalHMNpyra-distalweaknessandatrophy,pyramidaltractsigns,ADrare9q34SETX602433 midal/ALS4ageofonsetvarieswidelybetweenfamilies zdistalHMN-pyramidalinvolvement,onsetinfirstdecadeARrare9p21.1-p12unknown605726 Jerash-type
HSAN/HSNhereditarysensoryand/orautonomous neuropathiesARrare zHSAN1lancinatingpain,lossofpainandtemperature sensation,acralulcerations,onset~20yearsADrare9q22SPTLC1162400 zHSAN2gloveandstockingdist.,earlyonset,absenceof cutaneoussensoryreceptors/fibers, noautonomoussymptoms
ARrare12p13.33HSN2201300 zHSAN3Riley-Daysyndrome,familialdysautonomia, neonatalonset,ªcommonºinAshkenazijews (1/3700livebirths)
ARrare9q31-q33IKBKAP223900 zHSAN4congenitalinsensitivitytopainandanhidrosis (CIPA),fever,mentalretardation,earlychildhood onset
ARrare1q21-q22NTRK1(TrkA)256800 zHSN1with coughandrefluxHSN1phenotypewithoutulcerations,withadult onsetchroniccoughandesophagealrefluxADrare3p22-p24±608088 zHSNchildhoodonset,severereductionofdeeppain sensation,Charcotjoints,normalsweatingARrare1p11.2-p13.2NGFB± Hereditaryrecurrentfocalneuropathies zHNArecurrentpainfulbrachialplexuspalsies, nogeneralizedneuropathy,onsetinfirst to3rddecade
ADrare17q25unknown162100
Table5.1(continued) FormTypicalfeaturesInheritanceFrequencyLocusGeneOMIMAcc. Nr. Unclassifiedperipheralneuropathies zGAN (Giant
Axonal Neuropathy)
PNSandCNSinvolvement,giantaxonsfilledwith neurofilaments,onsetinfirstdecadeARrare16q24.1GAN256850 zACCPN
(Anderman syndr
ome)
agenesisofcorpuscallosumwithperipheral neuropathy,mentalretardation,dysmorphic features
ARrare15q13-q14SLC12A6 (KCC3Pro)218000 zCHandHirsch- sprungdiseasevariable:congenitalhypomyelination,CNS dysmyelination,intestinal(pseudo)obstruction, deafness
ADrare22q13.1SOX10
602229, 609136
zPeripheral neur
opathyand deafness
pred.sensory,demyelinatingneurop.,trophic changes,mNCVs30±55m/s,mildhearingloss, only1family
ADrare1p34.3GJB3(Cx31)603324 zMinifascicular neuropathywithpartialgonadaldysgenesis,demyelination andªminifasciclesºADrare12q13.12DHH607080
HMSN IV is equivalent to Refsum's disease, a complex neurological dis- order characterized by polyneuropathy, cerebellar ataxia, cardiac abnormal- ities and retinitis pigmentosa. Refsum's disease is a phytanic acid storage disease. Because of these features, Refsum's disease is usually considered as a complex neurological storage disease and not classified with the heredi- tary peripheral neuropathies any more.
The categories HMSN V, VI and VII stand for polyneuropathies with ad- ditional clinical features but do not represent single known genetic entities.
HMSN V describes the relatively rare combination of an inherited periph- eral motor and sensory neuropathy combined with spastic paraparesis. The inheritance is described as autosomal dominant. Only a few pedigrees have been reported and no chromosomal loci or genetic defects are known. A re- port describes exclusion mapping of known HMSN and hereditary spastic paraplegia (HSP) loci in families with HMSN V [34]. Troyer's syndrome ± a form of complicated HSP with an additional peripheral neuropathy ± could be regarded as a complicated autosomal recessive form of HMSN V. It is caused by mutations in the spartin gene (SPG20) [40]. Some forms of HMSN show signs of involvement of the first motor neuron without pronounced spastic paraplegia [13, 26, 50].
The category HMSN VI is used for HMSN associated with optic atrophy.
The first family was reported by Vizioli in 1879, but very few families with this entity have been reported since [48]. The chromosomal loci and under- lying genetic defects are not known. Four relatively recent descriptions report that inheritance may be autosomal dominant or recessive and that the neuro- pathy is of the HMSN II type [10, 11, 27] and one of the families is large en- ough to hopefully allow the elucidation of the underlying genetic defect [49].
HMSN VII stands for HMSN with retinitis pigmentosa. Pure HMSN VII is most likely exceedingly rare and to our knowledge no pedigrees have been reported recently.
5.3.2 Classification of primary hereditary neuropathies according to clinical subgroups and genetic entities
In recent years numerous hereditary neuropathies were mapped chromoso- mally and the underlying genetic defect was identified. It became clear that the earlier classifications are often discordant with the newly defined mo- lecular genetic entities. This led to continuously changing, sometimes con- fusing classifications. Some authors continued to use clinically oriented classifications while others preferred classification systems solely based on genes and mutations [2, 35]. In this book, a hierarchical classification sys- tem is used, which tries to take into account clinical as well as genetic in- formation. The hereditary neuropathies are first grouped into categories based on clinical similarities. For this purpose, the principal categories of
the classification system developed by Dyck and colleagues are used. The primary hereditary neuropathies are subdivided clinically into the heredi- tary motor and sensory neuropathies (HMSN), the hereditary sensory and autonomic neuropathies (HSAN) and the hereditary motor neuropathies (HMN) [1]. Another clinically distinct group are the hereditary recurrent focal neuropathies (HNPP ± hereditary neuropathy with liability to pres- sure palsy and the HNA ± hereditary neuralgic amyotrophy) [51]. In our classification, the HNPP will be grouped with the HMSNs because refined clinical methods revealed that the HNPP is a generalized neuropathy with focal exacerbations caused by pressure on nerve trunks and because the HNPP is caused by genetic defects affecting the same gene as the HMSN IA/CMT1A. This leaves only HNA as a recurrent focal neuropathy in the true sense. Further subdivisions are named ªCMTº and numbered or indicated by letters if no other names were given by the first describers.
The HMSN is further subdivided into CMT1 and CMT2 according to elec- trophysiological criteria (see section ªClinical and electrophysiological phe- notype of hereditary motor and sensory neuropathies (HMSNs)º). Subdivi- sions are made according to the mode of inheritance (autosomal dominant
± AD, autosomal recessive ± AR, X-linked ± XR) and finally according to the causative defective genes, respectively chromosomal loci if the genes are not known. A few genetic entities that do not fit any of these categories are placed in separate categories. Numerous unmapped clinical subtypes of hereditary neuropathies have been described over the years, but without linkage data it is difficult to determine whether these subtypes represent truly novel genetic entities. The clinically defined categories Djerine-Sot- tas syndrome (DSS or HMSN III) and congenital hypomyelination (CH) are genetically very heterogeneous and are therefore not listed as separate ge- netic entities in Table 5.1 but are regarded as severe forms of clinically dif- fering neuropathies resulting from mutations in the same genes.
Even though it is for clinical purposes necessary to distinguish between demyelinating and axonal polyneuropathies, it is quite clear that most he- reditary neuropathies affect both components of the peripheral nerve. Dif- ferent mutations in the same gene may cause either a predominantly de- myelinating phenotype or a predominantly axonal phenotype (see e.g., CMT1B due to mutations in MPZ or CMTX due to mutations in GJB1).
This may be due to the specific effect of the mutation if the protein is ex- pressed both in the Schwann cell and in the axon or it may be caused by a disturbed interaction between the Schwann cell and the axon (e.g., MPZ mutation causing a predominantly axonal phenotype despite the fact that MPZ is not expressed in the axon: see chapter 3.3.3 and 4.4). In the last de- cade, it is an emerging theme that genetic defects in the Schwann cell al- most invariably affect the axon as well and vice versa (e.g., see chapter 4.1.1).
Table 5.1 gives a rough overview of the classification used in this book including the most prominent clinical features, genetic features, and the Online Mendelian Inheritance in Man accession numbers (OMIM; http://
ternet resource is the ªInherited Peripheral Neuropathies Mutation Data- baseº (IPNMDB; http://www.molgen.ua.ac.be/CMTMutations/) which pro- vides a comprehensive and frequently updated list of all currently known mutations causing hereditary peripheral neuropathies.
5.4 Rare forms of hereditary peripheral neuropathies which do not fit into the current classification schemes
Numerous rare inherited multisystem diseases cause a peripheral neuropa- thy among a plethora of other organ manifestations. Some of them are sometimes assigned to the group of hereditary peripheral neuropathies and will be shortly discussed here but it has to be borne in mind that this selection is somewhat arbitrary and not comprehensive.
5.4.1 Giant axonal neuropathy ± gigaxonin (GAN) (OMIM 256850) z Clinical features: Giant axonal neuropathy (GAN) is an autosomal reces- sive neurological disease affecting both the PNS and the CNS and probably the most common disease of the ones described in this chapter [4]. GAN has been described in many countries and usually manifests in childhood with retardation of psychomotor development. The children develop a se- vere, progressive axonal peripheral neuropathy involving the cranial nerves, ataxia, dysarthria, nystagmus and dementia. The EEG is often ab- normal and MRI of the brain shows a disturbance of the myelin formation in the CNS. Very characteristic and diagnostically important is dull curly hair not resembling the hair of the healthy parents. The prognosis is poor.
Most patients are wheelchair-bound in the first or second decade and die before the age of 30 years. The combination of CNS and PNS symptoms with the characteristic appearance of the hair in a young child with healthy parents is highly diagnostic. The differential diagnosis includes several toxic substances including n-hexane and polyacrylamide which may cause similar neuropathologic changes in the PNS. Menkes disease (OMIM 3909400) is an X-linked disorder with hair changes resembling GAN and severe CNS pathology. Most children with Menkes disease die before the age of two years. Infantile neuroaxonal dystrophy (Seitelberger disease, OMIM 256600) and metachromatic leukodystrophy (OMIM 250100) are two other diseases affecting the CNS and the PNS which have been men- tioned as possible differential diagnosis. Both diseases do not cause the characteristic hair changes.
z Electrophysiology:GAN patients show signs of a severe, predominantly ax- onal peripheral neuropathy with severely reduced CMAPs and absent SNAPs. NCVs are normal to moderately reduced. The EEG often shows in- creased slow wave activity and auditory evoked potentials (AEP), visual evoked potentials (VEP) and somatosensory evoked potentials (SSEP) are often abnormal.
z Pathology, genetics and pathomechanism: Nerve biopsies show giant axons
± distorted nerve fibers with large axonal swellings ± with an increase of neurofilaments [37]. Giant axons are also found in the CNS of GAN pa- tients. Giant axons are not exclusively found in giant axonal neuropathy but have also been demonstrated in an Italian family with a so far unclassi- fied CMT2 syndrome [33]. Giant axonal neuropathy is caused by mutations in the gigaxonin gene (GAN) on chromosome 16q24 [3, 6, 8, 29]. GAN be- longs to the family of so called BTB/kelch proteins. GAN does most likely play a role in the crosstalk between intermediary filaments (IF) and micro- tubules (MT) in the axon [7].
5.4.2 Agenesis of the corpus callosum with peripheral neuropathy (ACCPN) or Anderman syndrome or hereditary motor
and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) ± solute carrier family 12 member 6 gene
(SLC12A6 coding for the protein: KCC3) (OMIM 218000)
z Clinical features: ACCPN is an autosomal recessive condition with early childhood onset which is quite common in parts of the province Quebec (Canada) but has rarely been reported worldwide. The main clinical symp- toms are a predominantly axonal sensorimotor but also demyelinating neu- ropathy (average onset of walking 3.8 years, average loss of ambulation at 14 years), mild to moderate mental retardation and psychotic episodes with delusions and hallucinations [17]. The neuropathy also affects the cranial nerves (ptosis, palsy of upward gaze). Achilles tendon retractions and scol- iosis are common. Tendon reflexes are usually absent. Partial or complete agenesis of the corpus callosum is found in approximately 70% of patients on CT examination. The average age of death is around 30±35years.
z Electrophysiology: Median MNCVs are very variable reaching from 11±39 m/s in adults [17]. SNAPs are usually absent and chronic neurogenic changes predominate on needle EMG.
z Pathology, genetics and pathomechanism:Sural nerve biopsies show mainly a lack of large myelinated fibers and signs of axonal loss. Cranial nerves as well as dorsal and ventral roots display swollen axons [17]. ACCPN was mapped to chromosome 15q13-q14 [9]. Mutations in the SLC12A6 gene en- coding the KCC3 K+-Cl± cotransporter were found in Canadian patients
root ganglia and ischiatic nerve. Heterologous expression of a mutated channel shows that the channel is expressed but does not function [23].
KCC3 is most likely involved in ion homeostasis (Cl± equilibrium).
SLC12A6 deficient mice show a peripheral neuropathy and deficits in be- havioral tests but the corpus callosum appears histologically normal [23].
A theory explaining the pathomechanism of ACCPN will have to bring to- gether the co-existence of developmental (ACC) and degenerative (periph- eral neuropathy) defects caused by mutations in one gene.
5.4.3 Congenital hypomyelinating neuropathy, central dysmyelination and intestinal (pseudo) obstruction
(Waardenburg-Hirschsprung disease) ±
SRY like box 10 transcription factor (SOX10) (OMIM 602229) z Clinical features: Mutations in the SOX10 gene cause a variety of pheno- types, most of them featuring intestinal (pseudo)obstruction. A number of dominant mutations have been described which cause a neurologic pheno- type including the following features: (1) intestinal (pseudo)obstruction;
(2) CNS myelin-related pathology; (3) a congenital hypomyelinating (CH) peripheral neuropathy and (4) deafness [24, 25, 41]. The onset is congeni- tal and the clinical features varied widely.
z Electrophysiology:NCVs varied widely. At least in one case the symptoms and electrophysiologic parameters improved with increasing age [41]. Brain stem-evoked potentials were also abnormal.
z Pathology, genetics and pathomechanism: Pathologic examination of pe- ripheral nerves showed nearly complete absence of myelin and myelinated fibers in an autopsy case [24]. The disease is caused by mutations in the transcription factor SOX10 which plays an important role in initiating CNS as well as PNS myelination by turning on other transcription factors (e.g., OCT6 and EGR2), which in turn activate myelin genes like PLP (CNS), PMP22 and MPZ (PNS).
5.4.4 Hereditary peripheral neuropathy and deafness ± gap junction protein 3 (GJB3 or connexin 31)
z Clinical features:This neuropathy is characterized by a variable degree of hearing loss and peripheral, predominantly sensory and demyelinating neuropathy [31]. In some cases ulceromutilating changes with chronic skin ulcers and osteomyelitis leading to amputation were found. So far only one family has been described.
z Electrophysiology: NCVs are only mildly reduced. CMAPs as well as SNAPs were reduced.
z Pathology, genetics and pathomechanism:Sural nerve biopsy in one patient demonstrated a demyelinating phenotype [31]. This neuropathy is autoso- mal dominant and caused by the deletion of one amino acid (D66del) of the GJB3 gene [31]. GJB3 encodes the pore forming connexin 31 protein.
Mutations in a number of other connexins have been identified as the cause of sensorineural deafness and mutations in GJB1 cause X-linked CMT. Mutations in GJB3 cause in most cases isolated dominant or recessive deafness.
5.4.5 Minifascicular peripheral neuropathy, partial gonadal dysgenesis ± desert hedgehog ± (DHH) (OMIM 607080)
z Clinical features: To our knowledge, only one patient with this phenotype has been reported. The patient showed premature female genitalia and a sparsely characterized peripheral neuropathy [47].
z Pathology, genetics and pathomechanism: The sural nerve biopsy demon- strated extensive formation of so called ªminifasciclesº. Minifascicles con- tain several axon-Schwann cell units that are separated by one-to-several layers of flattened cell processes with the morphology of perineurial cells, which are normally found surrounding large nerve fascicles. The possibili- ty of a mutation in the desert hedgehog (DHH) gene was suggested by a similar phenotype of the DHH-deficient mouse [38]. A point mutation in the translation initiation codon of the DHH gene was found in the patient.
A very similar phenotype without a mutation in the coding region of the DHH gene was described recently [45].
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