a neurologic syndrome in golden retrievers presenting as a sensory ataxic neuropathy

A Neurologic Syndrome in Golden Retrievers Presenting as aSensory Ataxic Neuropathy

K. Hultin Jaderlund, E. Orvind, E. Johnsson, K. Matiasek, C.N. Hahn, S. Malm, and A. Hedhammar

Background: A sensory ataxic neuropathy has been observed in Swedish Golden Retrievers recently.

Animals: Twenty-one affected Golden Retrievers.

Methods: Clinical and neurologic status, electrophysiologic, and pathologic status as well as pedigree analyses were

evaluated.

Results: Clinical signs had an insidious onset between 2 and 8 months of age and a slowly progressive course. Affected dogs

were ataxic and dysmetric. They had abnormal postural reactions and decreased spinal reflexes but no apparent muscle

atrophy. Clinical pathology, radiography, and electrophysiology of motor systems were all within reference values. Sensory

nerve conduction results of affected dogs were significantly different from those of a group of control dogs. Necropsy revealed

a chronic progressive central and peripheral sensorimotor axonopathy; the proprioceptive pathways were most severely

affected.

Conclusions and Clinical Importance: This disease in these Golden Retrievers is distinct from other canine breed-related

neurodegenerative diseases or hereditary neurodegenerative diseases described in humans. Pedigree analyses indicated

a hereditary background, but the mode of inheritance could not be established.

Key words: Axonopathy; Dog; Neurodegenerative disease; Sensory ataxic neuropathy.

B reed-related degenerative diseases affecting thenervous system are described in many breeds of

dogs.1–5 Over the past few years, a breed-relatedneurodegenerative disease presenting as a sensory ataxicneuropathy (SAN) has been recognized in a number ofrelated Golden Retrievers in Sweden. Clinically, thisdisease is distinct from other breed-related neurologicdiseases reported in dogs. The aim of this paper is todescribe the clinical, electrophysiologic, and pathologicfeatures of this disorder.

Materials and Methods

Sixteen (9 female, 7 male) ataxic Golden Retrievers were

examined by one of the authors (KHJ). Medical records from 5

other affected dogs (3 females, 2 males) were also evaluated.

The clinical pathology of 17 dogs included evaluation of muscle

enzyme activity (aspartate aminotransferase, creatine kinase,

n 5 16), glucose (n 5 2), fructosamine (n 5 7), and thyroid hormone

(n 5 17) as well as serology for Neospora caninum (n 5 9), Borrelia

burgdorferi (n 5 12), and Anaplasma phagocytophilum (n 5 12). The

presence of A phagocytophilum was further evaluated by polymerase

chain reaction techniques on blood (n 5 5). Cerebrospinal fluid

analyses and myelography were performed in 3 dogs, and plain

radiography of the vertebral column was evaluated in another 3

dogs. Complete neurologic examination, including assessment of

level of consciousness, behavior, posture, gait, cranial nerves,

postural reactions, spinal reflexes, muscle tone, and pain perception,

was performed on the dogs as previously described.6

Fourteen dogs were sedated with a combination of medetomi-

dinea and butorphanolb intramuscularly for electromyography

(EMG) (n 5 13), motor nerve conduction studies (MNCS)

(n 5 14), and sensory nerve conduction studies (SNCS) (n 5 11)

using neurophysiology equipment.c The EMG was conducted in

the proximal and distal pelvic and thoracic limb muscles using

concentric needle electrodes.d MNCS and SNCS of the ulnar,

peroneal, and tibial nerves were performed. SNCS were also

performed using the superficial radial nerve. Surface electrodese

were used to perform MNCS, whereas disposable, sensory, needle

electrodesf were used for SNCS. MNCS and SNCS were performed

at a skin temperature .30uC. The same testing procedures were

undertaken in 11 healthy 5- to 103-month-old (median, 39 months)

Golden Retrievers. Electrophysiologic parameters from the 2

groups of dogs (affected and healthy) were compared using a 2-

sample t-test. Statistical significance was set at P , .05 at

a confidence level of 95%.

Four of the dogs (Nos. 1 through 4) were euthanized and

autopsied at 11, 15, 23, and 30 months of age, respectively. Onset

of clinical signs in these dogs was 2, 6, 6, and 4 months of age,

respectively. Necropsy was performed immediately after euthana-

sia. Routine in-house postmortem examinations were performed,

including fresh muscle biopsies from quadriceps, triceps, cranial

tibial, and interosseus muscles from dog 2. In addition, fresh

muscle biopsies from the same muscles; fresh nerve biopsies from

ulnar, superficial radial, tibial, and peroneal nerves from dog 1;

formalin-fixed muscles, peripheral nerves, and spinal cord from

dogs 1 and 2; and formalin-fixed peripheral and central nervous

system from dog 4 were evaluated at the Neuromuscular Disease

Laboratoryg at the University of Edinburgh. Formalin-fixed

muscles and peripheral and central nervous system from dog 3

were evaluated at the Institute of Veterinary Pathology,h Ludwig-

Maximilians University of Munich. Fresh muscle biopsies were

frozen, and material was processed and stained using hematoxylin-

eosin (HE), Gomori’s trichrome, periodic acid-Schiff (PAS), PAS/

diastase, oil red O, acid phosphatase, alkaline phosphatase,

succinate dehydrogenase, cytochrome oxidase, and ATPase tech-

niques. Formalin-fixed material was also processed using HE, PAS,

From the Department of Clinical Sciences, Swedish University of

Agricultural Sciences, Uppsala, Sweden (Hultin Jaderlund, Hed-

hammar); the Department of Companion Animal Clinical Sciences,

Norwegian School of Veterinary Science, Oslo, Norway (Hultin

Jaderlund); and the Swedish Board of Agriculture, Varsta

Distriktsveterinarstation, Sweden (Orvind) and Morarp, Sweden

(Johnsson); General Pathology and Neuropathology, Institute of

Veterinary Pathology, Ludwig-Maximilians University, Munich,

Germany (Matiasek); the Neuromuscular Disease Laboratory,

University of Edinburgh, Scotland (Hahn); and the Department of

Animal Breeding and Genetics, Swedish University of Agricultural

Sciences, Uppsala, Sweden (Malm).

Reprint requests: Karin Hultin Jaderlund, DVM, DECVN, Depart-

mentofClinicalSciences,SwedishUniversityofAgriculturalSciences,Box

7054, SE-750 07 Uppsala, Sweden; e-mail: karin.hultin-jaderlund@

kv.slu.se.

Submitted May 31, 2007; Accepted June 20, 2007.

Copyright E 2007 by the American College of Veterinary Internal

Medicine

0891-6640/07/2106-0021/$3.00/0

J Vet Intern Med 2007;21:1307–1315

PAS/diastase, and Masson’s trichrome stained sections, as well as

Luxol fast blue, Woelcke-Spielmeyer-Schroder, Bodian, glial

fibrillary acidic protein (GFAP), and neurofilament (NF) staining

for spinal cord. Nerve biopsies were processed according to

standard protocols. Briefly, all samples underwent immersion in

2.5% glutaraldehyde followed by OsO4 postfixation, repeated

buffer rinses, and a graded alcohol series before being embedded

in epoxy resin. For routine histologic inspection, semi-thin sections

(0.5 mm) were mounted on triethoxysilane-coated glass slides and

stained with azur II-methylene blue-safranin. Additional OsO4-

stained probes were subjected to nerve fiber teasing. Three hundred

single nerve fibers with at least 5 internodes were considered

representative.

A preliminary genetic evaluation based on familial relationships

among affected animals was performed. Inbreeding coefficients,

based on nearly complete 5-generation pedigrees (Pedigree

Completeness Index between 92.5% and 100%) were calculated

for 20 of the dogs from 14 different litters using the software

package Pedig.i

Results

History and Course

All owners of these dogs had noticed an insidiousonset of abnormal movements, especially in the pelviclimbs, in 2- to 8-month-old dogs. Signs had been slowlyprogressive over months to years. Common signsreported by the owners were ‘‘bunny hopping’’ at highspeed, unsteadiness, ataxia, avoiding or easily slippingon slippery surfaces and stairs, wearing down of pelviclimb claws, male dogs urinating while standing on bothpelvic limbs, and hyperextension of the carpus. Threedogs developed urinary incontinence during the courseof the disease.

Neurologic examinations were performed on the dogsbetween 8 and 77 months of age (mean, 21 months;median, 16 months). Nine of the affected animals wereeuthanized at the owners’ request before they reached3 years old. The oldest dog still alive of those examinedhas been followed up to an age of 8 years.

Clinical and Neurologic Status at Presentation

Routine physical examination did not identify anyabnormalities except gait disturbances. Movements wereconsidered ataxic and dysmetric, varying intermittentlybetween hypermetria and hypometria in individuallimbs. Neurologically, proprioceptive placing reactionswere abnormal, and spinal reflexes generally weredepressed. Patellar reflexes were completely lost orseverely decreased in all affected dogs, whereas flexorreflexes in the thoracic limbs were best preserved.Overall, pelvic limbs were more affected than thoraciclimbs. Cranial nerves were not affected. Clinical testingrevealed no evidence of hyper- or hypoesthesia. Muscleatrophy was not evident (See Table 1 and the videoavailable online at http://dx.doi.org/10.1892/07-005v1).Although the pattern of clinical signs was very similar,severity of signs differed considerably among affecteddogs, regardless of the age at examination or time fromonset of signs. Clinical pathology and radiography didnot identify any abnormalities.

Electrophysiology

Mean values of SNCS velocity and amplitude wereconsidered within the reference range in the affecteddogs. However, when the affected dogs and the controlgroup of healthy Golden Retrievers were compared,a statistically significant difference was found in thesensory nerve conduction velocity (SNCV) in theperoneal nerve (P 5 .0011) as well as in the ulnar nerve(P 5 .017). Mean peroneal nerve SNCV for affecteddogs was 58.3 m/s (standard deviation [SD], 9.85), and74.8 m/s (SD, 10.3) for controls, whereas mean ulnarnerve SNCV for affected dogs was 67.0 m/s (SD, 10.2)and 77.6 m/s (SD, 8.83) for controls (Fig 1). Nosignificant differences in amplitudes were noted betweenthe groups. Motor nerve conduction studies (includingF-wave latencies) showed that velocity, amplitude, andlatencies were all within reference ranges, and nostatistical differences were found between affected dogsand control dogs. Needle EMG was considered normalin all but 5 dogs. Two affected dogs, aged 10 and15 months old, respectively, had prolonged insertionactivity in the extensor digitorum brevis muscle. The 3other dogs (2 aged 15 months and 1 aged 22 monthsold) had spontaneous activity in the abductor digiti Vmuscle (positive sharp waves in one 15-month-old dog,positive sharp waves and prolonged insertion activity inthe other 15-month-old dog, and fibrillation potentialsin the 22-month-old dog).

Pathology

No abnormalities were noted on gross inspectionof the tissues harvested from the 4 dogs that werenecropsied. Histopathology in these animals, however,revealed lesions in the central nervous system (CNS) andthe peripheral nervous system (PNS) and very mildneurogenic lesions in skeletal muscles.

All dogs were affected by a mild to moderate spinalwhite matter degeneration with multifocal myelin

Table 1. Neurologic signs in Golden Retrievers dia-gnosed with sensory ataxic neuropathy, as shown on thelinked video available online at http://dx.doi.org/10.1892/07-005v1.

Dog order

on video Signalement Demonstrating

1st 11-month-old male Severe ataxia and reluctance

to walk on floor

2nd 4-year-old female Mildly affected gait, with

reluctance to change

floors, severely reduced

proprioceptive placing

reaction in right pelvic

limb, and hyperextension

of the carpi

3rd 15-month-old female Spinal reflexes in left pelvic

limb

4th 11-month-old male Spinal reflexes in left thoracic

limb

1308 Hultin Jaderlund et al

ballooning, eosinophilic spheroids, intratubar macro-phages, and fiber loss associated with varying degrees ofastroglial proliferation. These changes were most pro-nounced in the fasciculus gracilis and the dorsal part ofthe lateral funiculus, followed by the fasciculus cuneatusand the ventral descending motor pathways (Figs 2–4).In the thoracic spinal cord of dog 2, a narrow zone ofmild degenerative changes could be traced around allspinal white matter adjacent to the pia. GFAP-positiveastrocytosis paralleled loss of Bodian and NF-positiveaxons in dorsal and dorsolateral fiber tracts (Fig 5).

Two animals (dogs 1 and 3) had a few weakly NF-stained and dysmorphic alpha-motor neurons in varioussegments of the ventral column of the spinal cord.Moreover, patchy loss of motor neurons was indicatedby empty beds and mild focal gliosis in dog 1 (Fig 2). In

contrast to the other animals, dog 3 had a mildly dilatedthoracolumbar central canal and multiple presynapticbuttons and axonal spheroids throughout the ventralcolumn of both the cervical and lumbar intumescence ofthe spinal cord.

On GFAP-stained slides, astroglial proliferationextended markedly into the dorsal rootlets (Fig 6).Moreover, GFAP immunohistochemistry identified anincreased number of GFAP-positive cells within the

Fig 2. Dog 1. Section of the thoracolumbar spinal cord stained

with luxol-fast-blue. Myelin ballooning (arrows) is scattered

throughout the dorsal and dorsolateral spinal white matter. Some

spinal segments show loss of single ventral horn cells (so-called

empty beds; arrowhead). Bar: 800 mm.

Fig 3. Dog 2. Thoracolumbar spinal cord stained with hematoxylin-

eosin. Note the dilated myelin cylinders (arrows) and scattered

intratubar macrophages (insert) within the ventral funiculus. Bar:

150 mm in main figure, 20 mm in insert.

Fig 4. Dog 3. Deep cervical spinal cord stained with myelin-

specific Wolcke-Spielmeyer-Schroder stain. In advanced stages,

loss of large myelinated fibers is indicated by mild pallor of

dorsolateral (arrrow) and ventral tracts (arrowhead). Bar: 2 mm.

Fig 1. Sensory nerve conduction velocities plotted against group of

dogs for nerves with statistically significant differences in mean veloc-

ity between groups. The bars immediately to the right of each group

indicate means and standard deviations. (1) Ulnar nerve velocities

in the group of healthy dogs (n 5 11). (2) Ulnar nerve velocities in

the group of affected dogs (n 5 11). (3) Peroneal nerve velocities in

the group of healthy dogs (n 5 11). (4) Peroneal nerve velocities in the

group of affected dogs (n 5 11).

Golden Retriever Sensory Ataxic Neuropathy 1309

dorsal roots of affected dogs compared with the ventralroots or dorsal roots of healthy control dogs (Fig 6).

Histologic examination failed to show substantialfiber loss in peripheral nerve samples of dogs 1, 2, and 4whereas dog 3 had a mild (,25%) to moderate (25–50%)decrease in myelinated nerve fiber density in mixed andsensory nerves, accompanied by moderate expansion ofendoneurial connective tissue and mild to moderatesubperineurial edema (Fig 7). Thus, large myelinatedfibers appeared disproportionately affected. Histologicsections and teased nerve fiber preparations of allanimals showed pronounced type B features7 consistingof axonal atrophy with shrunken axons, inner myelinloops, myelin sheath crenation, and wrinkling in 25–50%of A(alpha)-fibers throughout all peripheral nervesamples (Fig 8). Five percent (dogs 1, 2, and 4) to 10%(dog 3) of myelinated nerve fibers in the same spatialdistribution were undergoing Wallerian degeneration

resembling Dyck type E fibers7 (Fig 8). Throughout allnerve samples, a mild increase in subperineurial andendoneurial mast cells was observed. Neither teasedpreparations nor azur-II methylene blue or Wolcke-Spielmeyer-Schroder staining revealed signs of demyelin-ation, dysmyelination, or impaired myelin compaction.Moreover, none of the PNS segments had inflammatorychanges or vascular abnormalities.

Changes in muscle biopsy specimens were limited tomild fiber-size variation and rare examples of type IIangular and small group atrophy (Fig 9). There was noevidence of fiber type grouping.

Pedigree Analyses

The 21 affected dogs belonged to 15 different littersborn between 1997 and 2004. All females that yieldedaffected progeny belonged to the same maternal lineage,spanning 7 generations. The inbreeding coefficients forthe dogs in the 14 litters included in the calculationswere between 0 and 6.3%. The mean coefficient ofinbreeding for the 20 dogs was 1.6%. This result iscompared with an average inbreeding coefficient of 1.5%(based on 5 generations) for all Golden Retrievers bornbetween 1997 and 2004 and registered in the SwedishKennel Club. The pedigree analyses indicated that thisdisease had a hereditary background. Neither anautosomal recessive inheritance with 1 gene involvednor a polygenic inheritance influenced by several genesand environmental factors could be excluded withcertainty.

Discussion

The ataxia observed in the affected dogs wassuspected to be attributable to a lesion in the pro-prioceptive pathways. The decreased spinal reflexes,however, also suggested a lesion in the motor unit (lowermotor neuron, peripheral nerve, neuromuscular junc-tions, or muscles), but this suspicion was not sub-stantiated by the normal EMG and MNCS results andthe lack of overt muscle atrophy, increases in muscleenzyme activity, or paresis. Instead, these findings arecompatible with a sensory ataxic neuropathy withpartial involvement of peripheral axons. Sensory ataxicneuropathies in humans are characterized by a loss ofproprioceptive sensations, loss of tendon reflexes, andpreservation of muscle strength.8

The results of SNCS in the affected dogs were notconclusive, because values obtained were within thepublished reference ranges for healthy dogs.9 However,the normal reference range includes dogs of unknownsize and breed anesthetized with pentobarbital sodiumand atropine sulfate. To avoid bias because of breed,size, and drugs, our results were compared with a groupof healthy Golden Retrievers sedated using the sameprotocol, and significant differences between the groupswere found for the ulnar and peroneal nerves. Thedifferences in velocity (but not in amplitude) arecompatible with a neuropathic disease involving theperipheral portion of the sensory nerves examined.However, because sensory nerve conduction velocities

Fig 5. Glial fibrillary acidic protein staining of the dorsolateral

spinal white matter in a control dog (A) and in dog 4. Funicular

degeneration is accompanied by glial fibrillary acidic protein

immunopositive astrocytosis (B). Note multiple dilated myelin

cylinders, moderately increased axonal diameters, and occasional

intratubar macrophages (arrow, B). Bar: 25mm.


for a number of nerves in the affected dogs were close to,or within, published reference ranges, SNCS measure-ments alone are not confirmatory for this disease.Because the clinical signs are progressive, examinationof older affected dogs in the future may show moresubstantial alterations.

Although one of the most consistent findings was theloss of or severe reduction in patellar reflexes, the normalEMG of quadriceps muscle in all dogs examinedindicated a lesion in the sensory part of the relevantreflex arc. Five of these dogs had EMG changes in distallimb muscles. In the control group of healthy GoldenRetrievers, only 1 had spontaneous activity in theabductor digiti V muscle. It is not unusual to find mildabnormal spontaneous discharges in muscles of the distalextremities in many otherwise healthy dogs.10,11 However,changes because of the involvement of innervating motornerve fibers could not be excluded. Another possibleexplanation was the abnormal positioning of distal partsof the extremities (as described previously), which mayhave induced changes in the muscles at that level.However, abnormal discharges of muscle fibers in distallimb muscles were not common in the examined dogs,

and therefore should not be considered a necessaryfinding when diagnosing sensory ataxic neuropathy inGolden Retrievers.

At necropsy, pathologic changes were subtle, despitethe unambiguously abnormal neurologic status withonset in very young dogs, months to years earlier. Thisobservation was interpreted to indicate a disease associ-ated with an inborn error of the cellular metabolism ofthe malfunctioning nerve cells resulting in slowly pro-gressive damage to neurons. The progressive nature ofthese changes was supported by ongoing Walleriandegeneration of varying stages in CNS and PNS speci-mens. The observation that some fascicles in theperipheral nerves were more severely affected than othersconforms with the clinical findings, electrophysiologyresults, and muscle biopsy results suggesting that thisdisorder predominantly affects sensory fibers rather thannonselectively affecting large myelinated A(alpha)-fibers.The rare presence of anguloid myocyte profiles and somefiber-size variation suggest that some motor axons werealso affected, but not to a clinically relevant extent. Takentogether, these CNS and PNS changes are consistent witha chronic progressive, central and peripheral sensorimo-

Fig 6. Dog 1. Glial fibrillary acidic protein (GFAP) immunohistochemistry shows astrocytes densely infiltrating the proximal portion of

the lumbar dorsal root (A) if compared with control tissue (not shown) or the ventral roots of the same segment (C). Moreover, large areas

are strongly immunopositive for GFAP within the intradural dorsal root (B), whereas the ventral root reveals a typical Schwann cell pattern

(D). Bar: 50 mm in A, 25 mm in B–D.


tor axonopathy particularly affecting the proprioceptivepathways with very mild involvement of peripheral motoraxons.

In the spinal cord, dorsal and dorsolateral whitematter, but also ventromedial motor tracts, were mostlyaffected. Neurons within the nervous system areorganized in subgroups according to the functionalsystem (eg, pain perception, proprioceptive input) aswell as morphologically according to degree of myelina-tion and fiber diameter. In the dorsal white matter,ascending proprioceptive pathways consist of large-diameter, myelinated nerve fibers. Sensory nerve cells,with axons extending from the most distal part ofa pelvic limb, through the length of the limb and theentire spinal cord to the caudal brainstem areascontribute to these pathways. Degeneration of theseneurons can be expected to result in degenerativechanges in both the PNS and CNS, although clinicalsigns may reflect either a CNS sensory disorder asdescribed in Jack Russell Terriers and IbizanHounds2,12,13 or a PNS sensory disorder as described inBorder Collies, English Pointers, and long-hairedDachshunds.14–18 Additional minor involvement of

motor systems (only detected by histopathology) maynot be clinically evident.

Affected dogs were of the same breed, with relatedaffected animals and clustering of cases in some litters,which indicated a hereditary disease. The mode ofinheritance could not be determined from pedigreeinspection. Calculation of inbreeding coefficients for 20of the affected dogs did not identify any clear trend, andthe mean coefficient of inbreeding for the affected dogswas very similar to the average inbreeding coefficient forall Golden Retrievers registered in the Swedish KennelClub born during the same time period. The finding thatthe severity of neurologic signs varied among affecteddogs and was not correlated to age at examination andduration of signs, could indicate that a single nuclear genemutation is insufficient to produce the disease. Additionalmolecular genetic studies are in progress to analyze theinheritance and nature of this disease.

Some case reports of neuropathies of unknownetiology in Golden Retrievers have been published.19–21

The descriptions of the dogs in these reports do not fullyagree with our findings in the current study. Steiss et al19

described a dog with a gait disturbance similar to that of

Fig 7. Semi-thin sections of the common peroneal (A) and superficial radial (C) nerve in dog 3 compared with control tissue (B: common

peroneal nerve; D: superficial radial nerve). The common peroneal nerve shows a moderate reduction (25–50%) in myelinated nerve fiber

density accompanied by mild expansion of endoneurial connective tissue (A). The nerve fiber density in the superficial radial nerve is also

mildly (,25%) reduced (C). Moreover, the subperineurial space (SP) appears enlarged and is filled by a mucoid fluid. In all nerve specimens

the frequency of perineurial, subperineurial, and endoneurial mast cells (MC) is mildly increased. Note the absence of demyelinative

features. Bar: 25 mm in A, B, C; 20 mm in D. Stain: azur II-methylene blue-safranin.


our dogs, but the signs started at 2 years of age, and thedog was also unilaterally deaf and had severe impairmentof hearing on the other side. An EMG of this dog did notidentify any abnormal spontaneous activity, but motornerve conduction velocities from ulnar, sciatic, and tibialnerves were abnormally low. At necropsy, severe loss ofsensory neurons in the spinal ganglia was found, withresultant loss of fibers in the sensory tracts of the spinalcord and pronounced loss of fibers in sensory nerves,together with grey matter changes in the nucleuscuneatus and nucleus gracilis of the brainstem. Braundet al20 and Matz et al21 reported 3 siblings with onset ofclinical signs at 5 to 6 weeks of age. The aberrantmovements of the described dogs were similar to those ofthe dogs reported here, but electrophysiology performedon 2 of the dogs identified involvement of motor nervefibers, in contrast to our results. Hypomyelination ofperipheral nerves was the histopathologic diagnosis ofthe dogs in these reports.20,21

Breed-related neurodegenerative diseases with signsoriginating from deficits in the sensory parts of the nervoussystem have been described in other breeds.2,10–16,18,22–25

Common clinical signs are general dysmetria with sparedmuscle strength or signs of paresthesia with self-mutilation.Neither the clinical signs nor the severity and distributionof degenerative changes within the nervous system aresimilar to those of the Golden Retrievers reported here.Hereditary ataxia in the smooth-haired Fox Terrier, JackRussell Terrier, or Ibizan Hound is characterized bysymmetric generalized ataxia with severe hypermetria andspastic movements. Histopathologically, bilateral degen-erative changes are observed dorsolaterally and ventrome-dially in the spinal cord. In affected Jack Russell Terriers

Fig 8. Common findings in teased nerve fibers from various

mixed and sensory nerves postfixation in osmium tetroxide.

Between 25% and 50% of large myelinated fibers show inner

myelin loops (A; arrowheads) and myelin wrinkling (B), which

indicates axonal atrophy. Wallerian degeneration presents with

formation of myelin ovoids (C; arrowhead) and intratubar

macrophages (C; Ma) in 5–10% of large myelinated fibers. About

5% of large myelinated fibers reveal multiple paranodal thickenings

(D; PN 5 paranode; RN 5 node of Ranvier). Small myelinated

fibers are largely spared from pathology (E). They show regular

myelin contour, RN and Schmidt-Lanterman incisures (SLI). Bar:

25 mm in D, 10 mm in A, B, C, E. Stain: osmium tetroxide

Fig 9. Frozen, transverse section of quadriceps muscle stained

with ATPase pH 9.5 showing mild fiber size variation with rare

examples of type II angular fiber atrophy. 1003. First dog; 11-

month-old male with severe ataxia and reluctance to walk on floor.

Second dog; mildly affected 4-year-old female, demonstrating

reluctance to change floors, severely reduced proprioceptive-

placing reaction in right pelvic limb, and hyperextension of the

carpus. Third dog; mildly ataxic 15-month-old female dog, spinal

reflexes, left pelvic limb. Fourth dog; 11-month-old male with

spinal reflexes in left thoracic limb.


and Ibizan Hounds, central auditory pathways of the brainand peripheral nerves also display degenerativechanges.2,12,13,22,23,25 Neuroaxonal dystrophy in Rottweilersis a disease characterized by ataxia and hypermetria. Inaddition, head tremor, nystagmus, and menace deficitsmay develop. Microscopically, massive numbers of axonalspheroids are observed, especially in sensory axonterminals in grey matter of the CNS.10,11 Boxers withprogressive axonopathy are ataxic and have diminished orabsent postural reactions, muscle tone and spinal reflexes.Patellar reflexes are absent early in the course of thedisease. Marked degenerative changes are seen particularlyin lateral and ventral funiculi of the spinal cord, but also innerve roots, peripheral nerves, and optic pathways.24

Pointers, English Springer Spaniels, and French Spanielswith sensory neuropathy have loss of pain perception ofthe digits with self-mutilation, but intact proprioceptiveplacing reactions and normal patellar reflexes. Histopath-ologically, they may show degeneration of fibers in dorsalroots and peripheral nerves as well as reduced fiber densityand myelin staining in the dorsolateral fasciculus of thespinal cord.14,26,27 Long-haired Dachshunds and BorderCollies with sensory neuropathy have ataxia with loss ofpostural reactions and pain perception but normal orslightly decreased patellar reflexes. Sensory nerve conduc-tion velocities are decreased or absent. Histopathologicchanges with severe axonal degeneration occur in distalsensory nerves, and in Dachshunds, degenerative changesare also observed in the fasciculus gracilis of the spinalcord.15–18 Even among hereditary neurologic diseases withsensory signs in humans, none seem to have the samedistribution of clinical signs, course of disease, andelectrophysiologic and histopathologic findings.28,29 InFriedreich’s ataxia, the most frequent hereditary ataxiaof humans, there are similarities to the Golden Retrieversdescribed here in neurologic presentation, but otherfindings, such as cardiomyopathy and diabetes mellitus,also occur in many of these patients,30 and pathologicchanges occur first in dorsal root ganglia with loss of largesensory neurons.31 Thus, none of these diseases hasa disease phenotype that resembles SAN in GoldenRetrievers.

In conclusion, a neurologic syndrome presentingclinically as a sensory ataxic neuropathy has been identifiedin Golden Retrievers in Sweden. The clinical history, breed,age at onset, pattern of neurologic signs, and progressionof signs, together with electrophysiologic and histopatho-logic findings, were sufficient to make the diagnosis insuspected cases. Histopathologically, the disease is charac-terized as a subtle degenerative disorder of sensory andmotor axons of both the PNS and CNS, predominating inCNS sensory afferents. Additional studies are in progressthat may provide information about the clinical nature andthe molecular basis of this disease.

Footnotes

a Domitor vet 1 mg/mL, 0.01 mL/kg, Orion, Sollentuna, Swedenb Torbugesic 10 mg/mL, 0.01 mL/kg, ScanVet, Animal Health AS,

Fredensborg, Denmark

c Counterpoint MK2, Medtronic A/S, Skovlunde, Denmarkd Myoline 40 mm, Judex, Aalborg, Denmarke Medelec Gold Disc Electrodes part. no. 54426T, Cephalon,

Norresundby, Denmarkf 15 mm*0,70 mm (22G), Medtronic A/S, Skovlunde, Denmarkg Neuromuscular Disease Laboratory, Royal (Dick) School of

Veterinary Studies, University of Edinburgh, Scotlandh Institute of Veterinary Pathology, Ludwig-Maximilians Univer-

sity, Munich, Germanyi Boichard D. (2002). Pedig: A fortran package for pedigree analysis

suited for large populations. 7th WCGALP, Montpellier, France,

Communication No. 28–13

Acknowledgments

This work was carried out in Sweden at the University ofAgricultural Sciences. This study was supported by AgriaInsurance Company, Sweden, and the Golden RetrieverClub of Sweden. The authors thank Dr Brian Summers,Dr Pall Leifsson, and the pathologists at the SwedishVeterinary Institute for their assistance with pathology andAnn Bavner for her assistance with statistics.

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a neurologic syndrome in golden retrievers presenting as a sensory ataxic neuropathy

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