Hereditary ataxia in the Jack Russell Terrier (JRT) is a

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1 J Vet Intern Med 2004;1:1 21 Hereditry Atxi in the Jck Russell Terrier Clinicl nd Genetic Investigtions Annette Wessmnn, Thoms Goedde, Andre Fischer, Peter Wohlsein, Henning Hmnn, Ottmr Distl, nd Andre Tipold Hereditry txi in the Jck Russell Terrier (JRT) is chrcterized by git disturbnce with symmetric generlized txi nd hypermetric nd spstic movements. Histopthology shows disese of the entire centrl nervous system, predominntly n xonopthy. In the present study, 3 cliniclly ffected dogs were exmined. Git bnormlities begn t 2 9 months of ge. Generlized seizures occurred in 13 dogs in ddition to the txi, nd dogs developed respirtory distress. Brin stem uditoryevoked potentils (BAEPs) were bnorml in 4 of exmined dogs, in which only wves I nd II were detected. Abnorml BAEPs suggest the possibility of hereditry txi in the JRT. Investigtions regrding the mode of inheritnce were performed by complex segregtion nlyses on 3 pedigrees with totl of 11 JRTs (2 cliniclly ffected dogs nd unffected littermtes nd ncestors). Different modes of inheritnce were tested, including monogenic, mixed, nd polygenic models, s well s model with environmentl effects only. Models with genetic effects explined the dt significntly better thn the environmentl model. The monogenic model hd to be rejected in this study becuse of n insufficient mtch of dt when compred to tht of the most generl model. The polygenic nd mixed mjor gene models explined the pedigree dt best nd therefore hve to be regrded s possible hypotheses for the mode of inheritnce of hereditry txi in the JRT. The polygenic model proved best suited to explin the segregtion pttern in the JRT, becuse it hd the fewest number of prmeters. Key words: Brin stem uditory-evoked potentils; Mode of inheritnce; Segregtion nlysis; Seizures; Spinocerebellr txi. Hereditry txi in the Jck Russell Terrier (JRT) is well-known but rrely described disese in smll niml prctice. 1,2 It occurs in both types of the JRT: the Prson Russell Terrier with greter height t the shoulder nd the Jck Russell Terrier. The disese cn be dignosed cliniclly by its chrcteristic git disturbnce with symmetric generlized txi nd hypermetric nd spstic movements similr to findings in nimls with cervicl lesions. 1 4 During ctivity or excitement, the clinicl signs worsen, nd muscle fscicultions my occur. 3 Git bnormlities re observed for the 1st time in dogs between 2 nd 6 months of ge, 2,4 but the course of the disese therefter is vrible. Severe spsticity nd txi my provoke bd flls fter few steps in most ffected dogs t 1 2 yers of ge. 1 4 The From The Queen Mother Hospitl for Animls, The Royl Veterinry College, Htfield, UK (Wessmnn); the Deprtments of Smll Animl Medicine nd Surgery (Tipold), Animl Breeding nd Genetics (Hmnn, Distl), nd Pthology (Wohlsein), School of Veterinry Medicine, Hnnover, Germny; the Fculty of Veterinry Medicine of the Ludwig Mximilin University, Munich, Germny (Fischer); nd the Veterinry Prctice, Piding, Germny (Goedde). Preliminry results hve been presented in Kleintierprxis 2001;46:6 0, by A. Wessmnn, O. Distl, T. Goedde, A. Fischer, S. Demierre, nd A. Tipold: Hereditry txi in the Jck Russell TerrierPreliminry results; presented s thesis, Annette Wessmnn, 2002, t the School of Veterinry Medicine, Hnnover, Germny: Hereditry txi in the Jck Russell TerrierClinicl nd genetic investigtions; s poster presenttion t the 20th Annul ACVIM Forum, Dlls, TX, 2002; s n bstrct t the 46th Annul Congress of The British Smll Animl Veterinry Assocition, Birminghm, UK, The uthors represent nd wrrnt tht their prt of the work s submitted will in no wy violte ny copyright or ny other right. Reprint requests: Andre Tipold, LDVM, Deprtment of Smll Animl Medicine nd Surgery, School of Veterinry Medicine, Bischofsholer Dmm 1, 3013 Hnnover, Germny; e-mil: ndre. tipold@tiho-hnnover.de. Submitted June 1, 2003; Revised November 6, 2003, nd Jnury 9, 2004; Accepted Februry 19, Copyright 2004 by the Americn College of Veterinry Internl Medicine /04/ /$3.00/0 disese is not considered lethl. 2,4 On histopthology, lesions chrcterized by bilterl xonopthy nd myelopthy re observed in the centrl nervous system. 1,4 Chnges re found minly in the dorsl nd ventrl funiculi of the cervicl spinl cord. 4 Similr lesions re found in the brin, predominntly in the centrl uditory pthwys of the midbrin nd the medull oblongt. The lterl lemniscus nd trpezoid body (olivry nucleus) re especilly ffected. 1,4 However, uditory function is not impired. 1,4 Occsionlly, the spinl gngli 1,4 of the lumbr spinl cord nd the cud equin re ffected. 1 In 1942, similr hereditry txi ws detected in Sweden in the Fox Terrier, breed involved in the development of the JRT. In tht study, histopthologic lesions were described only in the spinl cord.,6 Björck et l determined n incidence of 2.% of hereditry txi on the bsis of n evlution of 23 ffected litters with unffected prents, nd 2 test showed no significnt difference from the expected distribution (2% of ffected dogs) if monogenic utosoml recessive mode of inheritnce ws involved. The suspected mode of inheritnce ws confirmed by test mtings, for which ssisted or rtificil insemintion ws lwys necessry becuse of the Fox Terrier s severe git bnormlities. 6 In light of the comprble clinicl nd histopthologic chnges in the JRT, Hrtley nd Plmer 1 suspected the sme disese segregting with similr mode of inheritnce in these 2 breeds. The primry purpose of this study ws to evlute the clinicl signs nd brin stem uditory-evoked potentils (BAEPs) of ffected dogs to determine whether the degenertive lesions in the centrl uditory pthwys were responsible for bnorml BAEPs. The 2nd gol of this study ws to clrify the mode of inheritnce of hereditry txi in JRTs. Mterils nd Methods Clinicl Exmintions Thirty-five cliniclly ffected Prson Russell Terriers nd Jck Russell Terriers (both bbrevited JRT) were prospectively exmined.

2 16 Wessmnn et l Tble 1. Exmintions nd numbers of exmined dogs mong 3 Jck Russell Terriers with hereditry txi. Further Investigtions Neurologic exmintion Blood exmintion Rdiogrphy (ntive, vertebrl column) Cerebrospinl fluid nlysis Myelogrphy Computed tomogrphy (thecogrphy) Brin stem uditory-evoked potentils Histopthologic exmintion JRTs, Jck Russell Terriers. No. Affected JRTs Fig 2. Pedigree 2 contining ffected Jck Russell Terriers. mle unffected Jck Russell Terrier (JRT); femle unffected JRT; / ffected mle/femle JRT; j/m mle/femle JRT with unknown stte of helth regrding hereditry txi; rrow probnd (1st known ffected dog of the litter responsible for scertinment of the corresponding pedigree); P histopthologiclly confirmed cse of hereditry txi. Medicl histories, especilly with regrd to the course of the disese, were obtined by personl communiction with the owners. Every dog ws exmined cliniclly nd neurologiclly either t the Deprtment of Smll Animl Medicine nd Surgery, School of Veterinry Medicine Hnnover, or in other neurology centers in Germny (Deprtment of Smll Animl Medicine, University of Munich nd Smll Animl Prctice, Piding). To exclude the possibility of other diseses, further tests were performed, including routine CBC nd biochemistry test, n exmintion of the cerebrospinl fluid (totl cell count nd protein concentrtion), rdiogrphs of the vertebrl column, nd myelogrphy. In selected dogs (see Tble 1), computed tomogrphy ws performed fter injection of contrst medium (0.4 ml/kg Iopmidol b ) in the cerebellomedullry cistern to visulize the size of the cerebellum (thecogrphy). Computed tomogrphy ws employed insted of mgnetic resonnce tomogrphy, s the ltter technique ws not vilble t the time of this study. Histopthology ws performed in 9 of the exmined dogs to confirm the dignosis nd exclude cerebellr diseses. Tissue from the centrl nd peripherl nervous system ws fixed in 4% buffered formlin nd processed for prffin embedding. Sections of representtive res of the brin nd spinl cord were mounted on positively chrged slides c nd stined with hemtoxylin-eosin (HE). Becuse degenertive lesions lso cn be detected in the centrl uditory pthwys, 4 BAEPs were mesured in ffected JRTs between the ges of 12 nd 21 months with permission of the owners. BAEPs were mesured with commercilly vilble electrophysiologic unit d while dogs were under generl nesthesi. e Monurl clicks were delivered from click genertor through erplugs t 90-dB norml hering level (nhl) nd stimulus rte of 11.1 Hz. Erplugs tht were provided by Nicolet EBE prolonged the mesured ltency by 1 millisecond. A msking noise ws pplied to the contrlterl er t 0 db nhl. Between 00 nd 2,000 clicks were recorded, nd wves I V were nlyzed. Pek ltencies were determined for peks I, III, nd V s well s the interpek ltency between peks I III, III V, nd I V. For comprison, 30 cliniclly helthy JRTs ged between 3 months nd 11. yers were lso tested. Genetic Exmintions The mode of inheritnce ws evluted on the bsis of 2 of the 3 cliniclly ffected JRTs nd their 3 independent pedigrees (Figs 1 3). No pedigree dt were vilble for the remining dogs. The 1 ffected Prson Russell Terriers of pedigree 1 were registered either in the Prson Jck Russell Terrier Club Deutschlnd e.v. (PJRTCD) or the Club for Terriers e.v. (KFT), or else they were not registered. One litter of pedigree 2 with ffected Jck Russell Terriers ws listed in breeding club (Deutsches Hundestmmbuch, DHS). None of the dogs from the 3rd pedigree tht involved 4 ffected Jck Russell Terriers ws registered. Ancestors with descendnts of their own were grded s not ffected, becuse dogs suffering from hereditry txi re not ble to mte without help.,6 Littermtes of sires nd dms with n unknown phenotype were excluded from the study. The 3 pedigrees contined totl of 11 dogs: 2 ffected nd 23 not ffected littermtes, long with 6 ncestors (clerly not ffected, s they hd descendnts). The disese ws nlyzed s dichotomous trit by mens of regressive logistic models (not ffected 0, ffected 1) with the progrm REGD (Segregtion Anlysis of Discrete Trit under Regressive Logistic Model) of the progrm S.A.G.E. (Sttisticl Anlysis for Genetic Epidemiology). f The following models were tested to explin the occurrence of the hereditry txi in the JRT tht ws observed: no genetic effect, only 1 distribution ( -model, environmentl effects); 1-locus model with 2 lleles in Hrdy-Weinberg equilibrium Fig 1. Pedigree 1 contining 1 ffected Prson Russell Terriers. mle unffected Jck Russell Terrier (JRT); femle unffected JRT; / ffected mle/femle JRT; j/m mle/femle JRT with unknown stte of helth regrding hereditry txi; sme bitch, shown 2 times for survey purpose; rrow probnd (1st known ffected dog of the litter responsible for scertinment of the corresponding pedigree); P histopthologiclly confirmed cse of hereditry txi; 1 14 prents of ffected JRT of pedigree 1 (prent number).

3 Hereditry Atxi in the Jck Russell Terrier 1 with recessive, dominnt, or rbitrry genetic effect; polygenic model; nd mixed model with recessive, dominnt, or rbitrry mjor gene nd polygenic components. Two different submodels were specified for the polygenic nd mixed monogenic nd polygenic modes of inheritnce. Submodel 1 (type of fmilir correltion [FAM] ) included the effect of ffected prents nd mting prtners s well s of unffected prents nd mting prtners. Submodel 2 (FAM ) considered ffected nd unffected sires, dms, nd other mting prtners. The mting prtner effect hd to be included to ccount for multiple mtings. The result of ech segregtion nlysis ws compred with the generl model (sturted) s reference model. This sturted model yielded the lowest vlue for the mximized log-likelihood function ( 2lnL) with the fewest prmeters nd explined the presented dt best. Likelihood rtio test sttistics were used to compre the different models with the sturted model. The test is symptoticlly 2 distributed nd is clculted s the difference between the tested nd the generl models 2lnL. Degrees of freedom for the likelihood rtio test sttistic were obtined by the difference between the number of independently estimted prmeters for the compred models. The different models lso were compred by Akike s criterion (AIC), which identifies the most prsimonious nd best-fitting model (the model with the best fit to the dt observed nd the lowest number of prmeters used) by the lowest AIC, which is defined s AIC 2 log (likelihood) 2 (number of estimted prmeters). The 3 pedigrees (Figs 1 3) used for the segregtion nlyses originted from reported cliniclly ffected dogs nd therefore did not represent rndom smple of the popultions under investigtion. Thus, scertinment correction hd to be performed to consider the nonrndomly selected pedigrees (Figs 1 3) by conditioning the ncestors nd littermtes on the phenotype of the probnds. Ech probnd is the 1st reported ffected dog of litter responsible for the scertinment of the corresponding pedigree. The significnce used for ll sttisticl tests ws n error probbility of.0. Results Clinicl Findings Fig 3. Pedigree 3 contining 4 ffected Jck Russell Terriers. mle unffected Jck Russell Terrier (JRT); femle unffected JRT; / ffected mle/femle JRT; rrow probnd (1st known ffected dog of the litter responsible for scertinment of the corresponding pedigree); P histopthologiclly confirmed cse of hereditry txi. All 3 ffected dogs showed chrcteristic git bnormlities t 2 9 months of ge (men, 4.4 months). Once clinicl signs were observed (Fig 4), the dogs deteriorted progressively for the 1st few weeks. After this period, certin degree of stbiliztion with intermittent worsening occurred. In ddition, 13 dogs showed generlized seizures with or without foci of origintion, such s muscle twitching on the hed or limb between the ges of 4 nd 1 months (men,.9 months). Seizures lsted for 2 3 minutes. In dogs, respirtory distress occurred between the ges of 6 nd 11 months (men,. months). These dogs hd n bnormlly high respirtory rte with open-mouth brething fter smll mount of exercise for 10 1 minutes. Owners noticed exercise intolernce in 11 dogs tht resulted in incresed spsticity nd difficulty wlking. Furthermore, behvior chnges such s ggression or nxiety were observed by the owners of dogs. Signs progressively worsened in 34 of the 3 dogs until they were euthnized on the owners request (ged 4 42 months; men, 16.0 months). One dog died of respirtory distress. In 1 bitch (dog 3), milder form ws observed: txi ws noticed t 9 months of ge but remined stble fter yers of ge. The dog ws euthnized becuse of crdiovsculr filure t 1 yers of ge. Physicl exmintions were norml for ll dogs. Neurologic exmintion identified symmetric generlized txi with hypermetric nd spstic movements in ll 4 legs. Posturl rections were delyed nd hypermetric, nd proprioception ws bsent or reduced. Dogs frequently hd brsions on their toes from knuckling over while wlking. Spinl reflexes were norml or incresed, nd crnil nerves showed no bnormlities. The mence response ws reduced in 1 dog. In 6 dogs, fine tremor of the muscles of the hed or the legs ws observed. In ll ffected dogs, lesions were loclized to the cervicl spinl cord (C 1 C ), minly to the spinocerebellr trcts, bsed on hypermetric movements. Routine lbortory work, including the mesurement of Fig 4. Frequency of clinicl signs in hereditry txi of the Jck Russell Terrier.

4 1 Wessmnn et l Tble 2. Brin stem uditory-evoked potentils of ffected Jck Russell Terriers compred to those of 30 cliniclly helthy Jck Russell Terriers: the ltencies of wves I, III, nd V nd the interpek intervls (wves I III, III V, nd I V) in milliseconds. I (Lt ms) III (Lt ms) V (Lt ms) I III (IPI Lt ms) III V (IPI Lt ms) I V (IPI Lt ms) Affected Jck Russell Terriers Men vlue of the recorded wves Stndrd devition Reference group Men vlue of the recorded wves Stndrd devition 2.11/ / / / / / / / / / / / / / / /0.2 4./ / / / / / / /0.34 Left, recording of the left er; Right, recording of the right er; Lt, ltency; ms, milliseconds; IPI, interpek intervl. Affected Jck Russell Terriers: in 3 dogs, only wves I nd II were mesured, in 1 dog, wves I III were mesured. In 4 dogs, wves could be recorded. electrolytes nd n exmintion of the cerebrospinl fluid, showed no bnormlities. All exmintions tht used dignostic imging techniques, including myelogrphy nd computed tomogrphy, were norml. The BAEPs were bnorml. In dog 1 (Tble 2), flt isoelectric line ws observed when the BAEP from the right er ws recorded. Peripherl defness ws ssumed 9 nd is considered congenitl disorder in the JRT. 10 Thus, the results of the BAEP of the right er of dog 1 were not evluted in this study. Four of the ffected JRTs tht were exmined showed bnorml peks. Only wves I nd II (Fig, dog 3) were mesured in 3 dogs (dogs 2, 3, nd ). In the 4th dog (dog ), wves I III were detected, but wves IV nd V were missing. In the remining 4 dogs (dogs 1, 4, 6, nd ; Tble 2), wves could be recorded. In ll 30 cliniclly helthy JRTs (representing the reference group), ll wves could be mesured (Tble 2). Form nd ltencies corresponded to the BAEPs of mixed-breed dogs s described. 11,12 In ll ffected dogs, ltencies remined within the rnge of vlues recorded in the reference group (upper limit). However, the men vlues of the ltency of recorded wves I V were slightly longer thn the men vlues of the reference group (Tble 2). The men vlues of interpek intervls (dogs 1, 4, 6,, nd ) were slightly incresed (wves I III) or were comprble (wves III V) to the men vlues of the reference group. Histopthologic exmintion ws performed in 9 ffected dogs nd confirmed the clinicl dignosis. No mcroscopic bnormlities of the centrl nervous system were found, but histopthologic chnges were detected in the entire nervous system. A bilterl myelopthy, predominntly n xonopthy combined with myelin loss, ws present nd most profound in the dorsl nd ventrl or ventromedil funiculi. Swelling of xons nd dilttion of myelin sheths with loss of myelin djcent to mild strogliosis were observed primrily in the spinocerebellr trcts of the cervicl cord but were lso observed in ll prts of the brin. In the brin, lesions such s gliosis nd swollen xons nd depletion of myelinted fibers were minly seen in the midbrin nd the medull oblongt, especilly in the pons nd trpezius trcts, but lso in the dorsl olive, the lterl lemniscus, nd the cochler nuclei. Occsionlly, the peripherl nerves showed similr chnges. A tigrolysis with degenertion of ventrl nerve ws seen in 1 dog in spinl gnglion of the lumbr spinl cord. Slight degenertive chnges of the myelin sheth were noticed in the cud equin in 3 dogs. Genetic Findings Fig. The brinstem uditory-evoked potentil (BAEP) of 12- month-old ffected Prson Russell Terrier (dog 3, Tble 2)00 clicks, 90-dB norml hering level (nhl); wves I nd II re distinct, but wves III V were not nlyzble. Verticl division 0. V; horizontl division 1 millisecond. Segregtion nlyses of the 3 pedigrees (Tble 3) were consistent with genetic etiology. The model tht took into ccount only environmentl effects (the -model) ws rejected in fvor of the generl model (P.001). The monogenic models could not explin the distribution of the presented dt sufficiently well (P.001), nd these hypotheses lso were rejected. Considering equl prentl effects (FAM ) nd sire, dm, nd mting prtner effect (FAM ), the polygenic model nd the mixed models showed no significnt difference from the generl model. Following

5 Hereditry Atxi in the Jck Russell Terrier 19 Tble 3. Segregtion nlyses with scertinment correction for hereditry txi in the Jck Russell Terrier. Tested Hypothesis Generl model -Model Monogenic dominnt Monogenic recessive Monogenic rbitrry Fmilir Correltion df 2lnL AIC Polygenic model Mixed model with dominnt mjor gene Mixed model with recessive mjor gene Mixed model with rbitrry mjor gene Compred to the Generl Model 2 df P df, degrees of freedom; AIC, Akike (194) criterion; 2lnL, 2 log-likelihood function; 2, 2 -distributed likelihood rtio test sttistic, clculted by the difference of 2lnL of the compred models. P.0: significnt. the likelihood rtio test, the best fit to the generl model ws the mixed model with dominnt or rbitrry mjor gene effect. Considering the number of estimted prmeters by mens of AIC, the polygenic model hd the lowest AIC nd is therefore the most prsimonious of the models tht re not significntly different from the most generl model for the presented dt. Direct comprison of the bestfitting models, nmely the polygenic model (Tble 4) nd the mixed model with rbitrry mjor gene effect (Tble ), with ech other nd other hypotheses, such s environmentl effects (the -model) nd the monogenic rbitrry model, showed equivlent results. No significnt difference could be detected between the mixed model nd the polygenic model (Tble 4), but the monogenic s well s the model (environmentl effects) were not consistent with the segregtion nlysis (Tbles 4, ). Discussion Hereditry txi in the JRT is well-known but rrely described disese tht hs suspected hereditry bsis. 1 The Tble 4. Comprison between the polygenic model nd the hypothesis of environmentl effects ( -model), monogenic rbitrry, nd mixed model with rbitrry mjor gene effect. Hypothesis df 2lnL Compred to the Polygenic Model 2 df P Polygenic model (FAM ) Model Monogenic rbitrry Mixed model with rbitrry mjor gene (FAM ) df, degrees of freedom; FAM, fmilir correltion; 2lnL, 2 log-likelihood function; 2, 2 -distributed likelihood rtio test sttistic, clculted by the difference of 2lnL of the compred models. P.0: significnt. present study ws intended to elucidte the clinicl mnifesttions, investigte BAEPs in ffected JRTs, confirm the suspected hereditry nture of the disese, nd nlyze the mode of inheritnce. All ffected dogs showed typicl generlized txi with hypermetric nd spstic movements s described for hereditry txi in the JRT 1 nd Fox Terrier.,6 The git bnormlities cn best be explined s originting from degenertive lesions in the spinl cord, especilly in the spinocerebellr trcts in both breeds. 1,6 However, clinicl signs relting to degenertive lesions detected in the brin were observed in the JRT but not in Fox Terriers. More thn one third of the ffected JRTs exmined in the present study showed generlized seizures nd respirtory distress. To our knowledge, these findings hve not been described previously. The seizure ctivity my be cused by degenertive lesions in the brin. Functionl chnges re not lwys visible by HE stining methods, but they were clerly seen in the brin stem in the dogs of our study s described erlier. 4 Respirtory distress my be cused by brin stem lesions, Tble. Comprison between the mixed model with rbitrry mjor gene effect nd the hypothesis of environmentl effects ( -model) nd monogenic rbitrry model effect. Hypothesis df 2lnL Compred to the Mixed Model with Arbitrry Mjor Gene Effect 2 df P Mixed model with rbitrry mjor gene (FAM ) Model Monogenic rbitrry df, degrees of freedom; FAM, fmilir correltion; 2lnL, 2 log-likelihood function; 2, likelihood rtio test sttistic, clculted by the difference of 2lnL of the compred models. P.0: significnt.

6 20 Wessmnn et l but the uthors suspect tht the high respirtory rte nd open-mouth brething were the result of rpid ftigue ssocited with spstic, hypermetric movements. The disese cn be cliniclly dignosed with high certinty becuse of both the breed nd the ge of onset nd nture of the typicl clinicl signs. Specil exmintions re norml nd help exclude other diseses with similr signs. In 9 dogs with suspected hereditry txi, the dignosis ws confirmed by histopthology, supporting the observtion tht the disese hs typicl clinicl fetures. The life expectncy of JRTs suffering from hereditry txi is not predictble, becuse the disese hs vrible course. Affected dogs were usully euthnized t their owners request in their 1st yer of life becuse of poor prognosis or severe clinicl deteriortion, but the disese itself is not lethl, 2,4 s is shown in the present study by the observtion of bitch with mild course tht survived with git bnormlities for 1 yers. A mesurement of the BAEP cn be helpful to support the clinicl dignosis. BAEPs were bnorml in 4 of the ffected JRTs exmined, becuse only distinct wves I nd II were detectble. Absent wves III V could be cused by lesions in or by xonl conduction disturbnces to the presumed genertors of wves III V, nmely the trpezoid body (wve III) nd the lterl lemniscus (wve IV). 9,11 These sites show bnormlities with histopthologic exmintion in the hereditry txi of the JRT. However, bnorml BAEPs lso re described for dogs with different brin stem lesions (eg, tumor, trum, demyelintion, infections, encephlopthies, hydrocephlus, cerebrovsculr diseses). 13,14 Delyed or bsent wves were recorded in dogs with brin stem tumors, depending on their loction. 13,14 Dogs with tumors in the trpezoid body nd the dorsl olivry nucleus hd seprte derivtion of wves I nd II with possible delyed ltency of wve II. 14 The men vlues of the ltencies of recorded wves I V in ffected JRTs were slightly higher thn the men vlues of the reference group. Prolonged ltencies suggest decresed conduction velocity. 14 The lrge vritions in the BAEPs of ffected JRTs could be explined by the differing severities of lesions in the brin stem. No correltion could be estblished in the present study between the severity of the degenertive lesions nd the form of the BAEP, becuse only 2 of the dogs with recorded BAEPs were exmined histopthologiclly. However, correltion between the severity of lesions nd the ppernce of the BAEP hs lredy been described. 14 Consequently, the recording of either just wves I nd II or long ltencies of the recorded wves cn strengthen the clinicl dignosis of hereditry txi in the JRT with typicl clinicl signs but is neither sensitive nor specific finding. So fr, BAEP recording is the only dditionl dignostic procedure to indicte degenertions tht represent xonl conduction disturbnce in the brin stem in living ffected JRT. Norml BAEPs do not exclude the disese. Peripherl defness is considered congenitl disorder in the JRT 10 ; however, the BAEP in congenitl defness cn be esily differentited from the findings in JRTs with hereditry txi. In peripherl defness, flt isoelectric line (such s tht recorded in dog 1) is observed. 10 Similr results hve been found in humns with spinocerebellr diseses such s the mitochondril disese known s Friedreich txi. 1 1 Some BAEP studies reported prolonged interpek intervls for the wves I III nd III V, 1,1 but others could identify just wve I. 19 A correltion between the extent of degenertion in the centrl uditory pthwys nd the extent of bnorml BAEPs hs been proposed in humns. 1,20 The mesurement of BAEPs to estimte the severity of degenertion s well s to predict the course of the disese hs been discussed. 1,20 Signs comprble to those of hereditry txi in the JRT re described in humns with Friedreich txi, 1 1 nd similr git disturbnce begins primrily t puberty. 21,22 The histopthology of hereditry txi in the JRT is well described, nd our findings of chrcteristic bilterl symmetric myelopthy corresponded to findings reported in the literture. 1,4 Fox Terriers with hereditry txi show git disturbnce equivlent to tht observed in the JRT, but histopthologic chnges re seen only in the spinl cord. Therefore, vritions in this specific disese cn be ssumed to occur in the 2 terrier breeds. A similr xonopthy in the spinl cord nd in the brin lso is described in humn ptients with Friedreich txi, 23,24 leding to the specultion of similr pthogenesis. This ssumption must be evluted by dditionl studies. Clinicl investigtions hve reveled tht hereditry txi in the JRT cn be dignosed in the living dog, nd this observtion is the bsis for genetic studies. Hrtley nd Plmer 1 suspected hereditry bsis for txi in JRTs, becuse n utosoml recessive trit ws determined for the comprble hereditry txi in Fox Terriers,,6 which prticipted in the development of the JRT breed. 2 Complex segregtion nlyses were performed with 11 JRTs belonging to 3 independent fmilies. The nlyses showed genetic influence on the occurrence of the hereditry txi in the JRT, nd results of the segregtion nlysis were not consistent with n environmentl model. Considering AIC, the polygenic model best explined the dt. The mixed models with mjor gene effect nd polygenic components could not be excluded, becuse they explined the dt s well s the polygenic model. A direct comprison between these 2 types of models lso offered no differentition. The complex segregtion nlysis ws not consistent with the hypothesis of monogenic inheritnce. Whether the suspected polygenic influence is bsed on 2 or more genes could not be estblished by our segregtion nlysis. Although the sttisticl test bsed on AIC ws most comptible with the polygenic model, significnt difference from the mixed models cn be demonstrted only by use of lrger nd more informtive pedigrees. The present study estblished distinct differences from hereditry txi tht is observed in Fox Terriers.,6 In ddition to the identicl git disturbnce, ffected JRTs hd seizures nd respirtory distress. Histopthologic chnges in JRTs were observed not only in the spinl cord, s in Fox Terriers, but lso in the brin. Although the hereditry txi in Fox Terriers follows monogenic utosoml recessive inheritnce, the most likely mode of inheritnce in the JRT is polygenic or by mixed mjor gene on the bsis of the segregtion nlysis of the present study. Additionl studies will be necessry to determine if hereditry txi in the 2 breeds ctully represents 2 different diseses. Becuse the pthogenesis of hereditry txi in the JRT is

7 Hereditry Atxi in the Jck Russell Terrier 21 still unknown nd resembles Friedreich txi in humns, n evlution of cndidte genes such s frtxin possibly could help clrify the responsible muttions. However, results of the complex segregtion nlysis indicte tht more thn 1 gene my be involved in the pthogenesis of hereditry txi in the JRT. Therefore, dditionl genetic nlyses should not be solely bsed on single gene but should lso use genome scns with microstellites tht re eqully distributed over the whole genome. To mke such studies worthwhile, more pedigrees must be scertined. Footnotes Computed tomogrphy, Somtom AR.HP.X, Siemens, Erlngen, Germny b Iopmidol, Solutrst 200N, Byk Gulden Phrmceutic, Konstnz, Germny c Superfrost plus, Menzel-Gleser, Brunschweig, Germny d Electrophysiologic unit, Nicolet Viking IV D, Nicolet EBE GmbH, Kleinostheim, Germny e Isoflurn, Forne, Abbott GmbH, Wiesbden, Germny f S.A.G.E. version 3.0. (199): Sttisticl Anlysis for Genetic Epidemiology, Relese 3.0. Computer progrm pckge vilble from the Deprtment of Epidemiology nd Biosttistics, Rmmelkmp Center for Eduction nd Reserch, Metro Helth Cmpus, Cse Western Reserve University, Clevelnd, OH References 1. Hrtley WJ, Plmer AC. Atxi in Jck Russell Terriers. Act Neuropthol (Berl) 193;26: Brund KG. Textbook of Clinicl Syndromes in Veterinry Neurology, 2nd ed. St Louis, MO: Mosby-Yer Book, Inc; 1994:144, Chrismn CL. Textbook of Problems in Smll Animl Neurology, 2nd ed. Phildelphi, PA: Verlg Le & Febinger; 1991: Summers BA, Cummings JF, De Lhunt A. Textbook of Veterinry Neuropthology. St Louis, MO: Mosby-Yer Book, Inc; 199: Björk G, Dyrendhl S, Olsson SE. Hereditry txi in smoothhired Fox Terriers. Vet Rec 19;69: Björck G, Mir W, Olsson SE, Sournder P. Hereditry txi in Fox Terriers. Act Neuropthol (Berl) 1962;1(Suppl):4 4.. Bonney GE. Compound regressive models for fmily dt. Hum Hered 1992;42: Akike H. A new look t the sttisticl model identifiction. IEEE Trns Autom Control 194;19: Steffen F, Jggy A. Tubheit und ihre Dignose bei Hund und Ktze. Schweiz Arch Tierheilkd 199;140: Strin GM. Defness prevlence nd ssocited phenotypic mrkers in dogs with high risk. J Vet Intern Med 1996;10: Sims MH, Moore RE. Auditory-evoked response in the cliniclly norml dog: Erly ltency components. Am J Vet Res 194;4: Shiu JN, Munro KJ, Cox CL. Normtive uditory brinstem response dt for hering threshold nd neuro-otologicl dignosis in the dog. J Smll Anim Prct 199;3: Fischer A, Obermier G. Brinstem uditory-evoked potentils nd neuropthologic correltes in 26 dogs with brin tumors. J Vet Intern Med 1994;: Steiss JE, Cox NR, Hthcock JT. Brinstem uditory-evoked response bnormlities in 14 dogs with confirmed centrl nervous system lesions. J Vet Intern Med 1994;: Yokoym J, Aoygi M, Suzuki T, et l. Three frequency component wveforms of uditory evoked brinstem response in spinocerebellr degenertion. Act Otolryngol 1994;11(Suppl): Fujit M, Hosoki M, Miyzki M. Brinstem uditory evoked responses in spinocerebellr degenertion nd Wilson disese. Ann Neurol 191;9: De Pblos C, Bercino J, Cllej J. Brinstem-uditory evoked potentils nd blink reflex in Friedreich s txi. J Neurol 1991;23: Colletti V, Sittoni V, Crosr C, et l. BSER bnormlities inptients with spino-cerebellr degenertion. Clin Otolryngol 193;: Knezevic W, Stewrt-Wynne EG. Brinstem uditory evoked responses in hereditry spinocerebellr txis. Clin Exp Neurol 19; 21: Illrioshkin SN, Fedin PA, Ivnov-smolenski IA, Solov ev OI. Brin stem uditory evoked potentils in spinocerebellr degenertion. Zh Nevroptol Psikhitr Im S S Korskov 1992;92: Andermnn E, Remillrd GM, Goyer C, et l. Genetic nd fmily studies in Friedreich s txi. Cn J Neurol Sci 196;3: Winter RM, Hrding AE, Britser M, Brvery MB. Intrfmilil correltion in Friedreich s txi. Clin Genet 191;20: Lmrche JB, Lemieux B, Lieu HB. The neuropthology of typicl Friedreich s txi in Quebec. Cn J Neurol Sci 194; 11(Suppl): Jitpimolmrd S, Smll J, King RH, et l. The sensory neuropthy of Friedreich s txi: An utopsy study of cse with prolonged survivl. Act Neuropthol (Berl) 1993;6: Hller M. Jck-Russell-Terrier, 2nd ed. Hmburg, Germny: Verlg Pul Prey; 1994:9 19.