J Vet Intern Med 2007;21:13071315

A Neurologic Syndrome in Golden Retrievers Presenting as a Sensory 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.

reed-related degenerative diseases affecting the nervous system are described in many breeds of dogs.15 Over the past few years, a breed-related neurodegenerative disease presenting as a sensory ataxic neuropathy (SAN) has been recognized in a number of related Golden Retrievers in Sweden. Clinically, this disease is distinct from other breed-related neurologic diseases reported in dogs. The aim of this paper is to describe the clinical, electrophysiologic, and pathologic features 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

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 Ja derlund); and the Swedish Board of Agriculture, Va rsta 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

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 medetomidinea 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 2sample 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 euthanasia. 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 LudwigMaximilians University of Munich. Fresh muscle biopsies were frozen, and material was processed and stained using hematoxylineosin (HE), Gomoris trichrome, periodic acid-Schiff (PAS), PAS/ diastase, oil red O, acid phosphatase, alkaline phosphatase, succinate dehydrogenase, cytochrome oxidase, and ATPase techniques. Formalin-fixed material was also processed using HE, PAS,

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Table 1. Neurologic signs in Golden Retrievers diagnosed with sensory ataxic neuropathy, as shown on the linked video available online at http://dx.doi.org/ 10.1892/07-005v1.
Dog order on video 1st 2nd Signalement 11-month-old male 4-year-old female Demonstrating Severe ataxia and reluctance to walk on floor Mildly affected gait, with reluctance to change floors, severely reduced proprioceptive placing reaction in right pelvic limb, and hyperextension of the carpi Spinal reflexes in left pelvic limb Spinal reflexes in left thoracic limb

Clinical and Neurologic Status at Presentation

Routine physical examination did not identify any abnormalities except gait disturbances. Movements were considered ataxic and dysmetric, varying intermittently between hypermetria and hypometria in individual limbs. Neurologically, proprioceptive placing reactions were abnormal, and spinal reflexes generally were depressed. Patellar reflexes were completely lost or severely decreased in all affected dogs, whereas flexor reflexes in the thoracic limbs were best preserved. Overall, pelvic limbs were more affected than thoracic limbs. Cranial nerves were not affected. Clinical testing revealed no evidence of hyper- or hypoesthesia. Muscle atrophy was not evident (See Table 1 and the video available 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 affected dogs, regardless of the age at examination or time from onset of signs. Clinical pathology and radiography did not identify any abnormalities.

3rd 4th

15-month-old female 11-month-old male

PAS/diastase, and Massons 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 OsO4stained 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

Electrophysiology
Mean values of SNCS velocity and amplitude were considered within the reference range in the affected dogs. However, when the affected dogs and the control group of healthy Golden Retrievers were compared, a statistically significant difference was found in the sensory nerve conduction velocity (SNCV) in the peroneal nerve (P 5 .0011) as well as in the ulnar nerve (P 5 .017). Mean peroneal nerve SNCV for affected dogs was 58.3 m/s (standard deviation [SD], 9.85), and 74.8 m/s (SD, 10.3) for controls, whereas mean ulnar nerve SNCV for affected dogs was 67.0 m/s (SD, 10.2) and 77.6 m/s (SD, 8.83) for controls (Fig 1). No significant differences in amplitudes were noted between the groups. Motor nerve conduction studies (including F-wave latencies) showed that velocity, amplitude, and latencies were all within reference ranges, and no statistical differences were found between affected dogs and control dogs. Needle EMG was considered normal in all but 5 dogs. Two affected dogs, aged 10 and 15 months old, respectively, had prolonged insertion activity in the extensor digitorum brevis muscle. The 3 other dogs (2 aged 15 months and 1 aged 22 months old) had spontaneous activity in the abductor digiti V muscle (positive sharp waves in one 15-month-old dog, positive sharp waves and prolonged insertion activity in the other 15-month-old dog, and fibrillation potentials in the 22-month-old dog).

Results
History and Course
All owners of these dogs had noticed an insidious onset of abnormal movements, especially in the pelvic limbs, in 2- to 8-month-old dogs. Signs had been slowly progressive over months to years. Common signs reported by the owners were bunny hopping at high speed, unsteadiness, ataxia, avoiding or easily slipping on slippery surfaces and stairs, wearing down of pelvic limb claws, male dogs urinating while standing on both pelvic limbs, and hyperextension of the carpus. Three dogs developed urinary incontinence during the course of the disease. Neurologic examinations were performed on the dogs between 8 and 77 months of age (mean, 21 months; median, 16 months). Nine of the affected animals were euthanized at the owners request before they reached 3 years old. The oldest dog still alive of those examined has been followed up to an age of 8 years.

Pathology
No abnormalities were noted on gross inspection of the tissues harvested from the 4 dogs that were necropsied. Histopathology in these animals, however, revealed lesions in the central nervous system (CNS) and the peripheral nervous system (PNS) and very mild neurogenic lesions in skeletal muscles. All dogs were affected by a mild to moderate spinal white matter degeneration with multifocal myelin

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Fig 1. Sensory nerve conduction velocities plotted against group of dogs for nerves with statistically significant differences in mean velocity 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).

ballooning, eosinophilic spheroids, intratubar macrophages, and fiber loss associated with varying degrees of astroglial proliferation. These changes were most pronounced in the fasciculus gracilis and the dorsal part of the lateral funiculus, followed by the fasciculus cuneatus and the ventral descending motor pathways (Figs 24). In the thoracic spinal cord of dog 2, a narrow zone of mild degenerative changes could be traced around all spinal white matter adjacent to the pia. GFAP-positive astrocytosis paralleled loss of Bodian and NF-positive axons in dorsal and dorsolateral fiber tracts (Fig 5). Two animals (dogs 1 and 3) had a few weakly NFstained and dysmorphic alpha-motor neurons in various segments of the ventral column of the spinal cord. Moreover, patchy loss of motor neurons was indicated by empty beds and mild focal gliosis in dog 1 (Fig 2). In

Fig 3. Dog 2. Thoracolumbar spinal cord stained with hematoxylineosin. 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.

contrast to the other animals, dog 3 had a mildly dilated thoracolumbar central canal and multiple presynaptic buttons and axonal spheroids throughout the ventral column of both the cervical and lumbar intumescence of the spinal cord. On GFAP-stained slides, astroglial proliferation extended markedly into the dorsal rootlets (Fig 6). Moreover, GFAP immunohistochemistry identified an increased 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 4. Dog 3. Deep cervical spinal cord stained with myelinspecific 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.

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resembling Dyck type E fibers7 (Fig 8). Throughout all nerve samples, a mild increase in subperineurial and endoneurial mast cells was observed. Neither teased preparations 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 inflammatory changes or vascular abnormalities. Changes in muscle biopsy specimens were limited to mild fiber-size variation and rare examples of type II angular and small group atrophy (Fig 9). There was no evidence of fiber type grouping.

Pedigree Analyses
The 21 affected dogs belonged to 15 different litters born between 1997 and 2004. All females that yielded affected progeny belonged to the same maternal lineage, spanning 7 generations. The inbreeding coefficients for the dogs in the 14 litters included in the calculations were between 0 and 6.3%. The mean coefficient of inbreeding for the 20 dogs was 1.6%. This result is compared with an average inbreeding coefficient of 1.5% (based on 5 generations) for all Golden Retrievers born between 1997 and 2004 and registered in the Swedish Kennel Club. The pedigree analyses indicated that this disease had a hereditary background. Neither an autosomal recessive inheritance with 1 gene involved nor a polygenic inheritance influenced by several genes and environmental factors could be excluded with certainty.

Discussion
The ataxia observed in the affected dogs was suspected to be attributable to a lesion in the proprioceptive pathways. The decreased spinal reflexes, however, also suggested a lesion in the motor unit (lower motor neuron, peripheral nerve, neuromuscular junctions, or muscles), but this suspicion was not substantiated by the normal EMG and MNCS results and the lack of overt muscle atrophy, increases in muscle enzyme activity, or paresis. Instead, these findings are compatible with a sensory ataxic neuropathy with partial involvement of peripheral axons. Sensory ataxic neuropathies in humans are characterized by a loss of proprioceptive sensations, loss of tendon reflexes, and preservation of muscle strength.8 The results of SNCS in the affected dogs were not conclusive, because values obtained were within the published reference ranges for healthy dogs.9 However, the normal reference range includes dogs of unknown size and breed anesthetized with pentobarbital sodium and atropine sulfate. To avoid bias because of breed, size, and drugs, our results were compared with a group of healthy Golden Retrievers sedated using the same protocol, and significant differences between the groups were found for the ulnar and peroneal nerves. The differences in velocity (but not in amplitude) are compatible with a neuropathic disease involving the peripheral 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.

dorsal roots of affected dogs compared with the ventral roots or dorsal roots of healthy control dogs (Fig 6). Histologic examination failed to show substantial fiber loss in peripheral nerve samples of dogs 1, 2, and 4 whereas dog 3 had a mild (,25%) to moderate (2550%) decrease in myelinated nerve fiber density in mixed and sensory nerves, accompanied by moderate expansion of endoneurial connective tissue and mild to moderate subperineurial edema (Fig 7). Thus, large myelinated fibers appeared disproportionately affected. Histologic sections and teased nerve fiber preparations of all animals showed pronounced type B features7 consisting of axonal atrophy with shrunken axons, inner myelin loops, myelin sheath crenation, and wrinkling in 2550% of A(alpha)-fibers throughout all peripheral nerve samples (Fig 8). Five percent (dogs 1, 2, and 4) to 10% (dog 3) of myelinated nerve fibers in the same spatial distribution were undergoing Wallerian degeneration

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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 BD.

for a number of nerves in the affected dogs were close to, or within, published reference ranges, SNCS measurements alone are not confirmatory for this disease. Because the clinical signs are progressive, examination of older affected dogs in the future may show more substantial alterations. Although one of the most consistent findings was the loss of or severe reduction in patellar reflexes, the normal EMG of quadriceps muscle in all dogs examined indicated a lesion in the sensory part of the relevant reflex arc. Five of these dogs had EMG changes in distal limb muscles. In the control group of healthy Golden Retrievers, only 1 had spontaneous activity in the abductor digiti V muscle. It is not unusual to find mild abnormal spontaneous discharges in muscles of the distal extremities in many otherwise healthy dogs.10,11 However, changes because of the involvement of innervating motor nerve fibers could not be excluded. Another possible explanation was the abnormal positioning of distal parts of the extremities (as described previously), which may have induced changes in the muscles at that level. However, abnormal discharges of muscle fibers in distal limb muscles were not common in the examined dogs,

and therefore should not be considered a necessary finding when diagnosing sensory ataxic neuropathy in Golden Retrievers. At necropsy, pathologic changes were subtle, despite the unambiguously abnormal neurologic status with onset in very young dogs, months to years earlier. This observation was interpreted to indicate a disease associated with an inborn error of the cellular metabolism of the malfunctioning nerve cells resulting in slowly progressive damage to neurons. The progressive nature of these changes was supported by ongoing Wallerian degeneration of varying stages in CNS and PNS specimens. The observation that some fascicles in the peripheral nerves were more severely affected than others conforms with the clinical findings, electrophysiology results, and muscle biopsy results suggesting that this disorder predominantly affects sensory fibers rather than nonselectively affecting large myelinated A(alpha)-fibers. The rare presence of anguloid myocyte profiles and some fiber-size variation suggest that some motor axons were also affected, but not to a clinically relevant extent. Taken together, these CNS and PNS changes are consistent with a chronic progressive, central and peripheral sensorimo-

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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 (2550%) 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.

tor axonopathy particularly affecting the proprioceptive pathways with very mild involvement of peripheral motor axons. In the spinal cord, dorsal and dorsolateral white matter, but also ventromedial motor tracts, were mostly affected. Neurons within the nervous system are organized in subgroups according to the functional system (eg, pain perception, proprioceptive input) as well as morphologically according to degree of myelination and fiber diameter. In the dorsal white matter, ascending proprioceptive pathways consist of largediameter, myelinated nerve fibers. Sensory nerve cells, with axons extending from the most distal part of a pelvic limb, through the length of the limb and the entire spinal cord to the caudal brainstem areas contribute to these pathways. Degeneration of these neurons can be expected to result in degenerative changes in both the PNS and CNS, although clinical signs may reflect either a CNS sensory disorder as described in Jack Russell Terriers and Ibizan Hounds2,12,13 or a PNS sensory disorder as described in Border Collies, English Pointers, and long-haired Dachshunds.1418 Additional minor involvement of

motor systems (only detected by histopathology) may not be clinically evident. Affected dogs were of the same breed, with related affected animals and clustering of cases in some litters, which indicated a hereditary disease. The mode of inheritance could not be determined from pedigree inspection. Calculation of inbreeding coefficients for 20 of the affected dogs did not identify any clear trend, and the mean coefficient of inbreeding for the affected dogs was very similar to the average inbreeding coefficient for all Golden Retrievers registered in the Swedish Kennel Club born during the same time period. The finding that the severity of neurologic signs varied among affected dogs and was not correlated to age at examination and duration of signs, could indicate that a single nuclear gene mutation is insufficient to produce the disease. Additional molecular genetic studies are in progress to analyze the inheritance and nature of this disease. Some case reports of neuropathies of unknown etiology in Golden Retrievers have been published.1921 The descriptions of the dogs in these reports do not fully agree with our findings in the current study. Steiss et al19 described a dog with a gait disturbance similar to that of

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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; 11month-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 proprioceptiveplacing 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.

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 510% 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

our dogs, but the signs started at 2 years of age, and the dog was also unilaterally deaf and had severe impairment of hearing on the other side. An EMG of this dog did not identify any abnormal spontaneous activity, but motor nerve conduction velocities from ulnar, sciatic, and tibial nerves were abnormally low. At necropsy, severe loss of sensory neurons in the spinal ganglia was found, with resultant loss of fibers in the sensory tracts of the spinal cord and pronounced loss of fibers in sensory nerves, together with grey matter changes in the nucleus cuneatus and nucleus gracilis of the brainstem. Braund et al20 and Matz et al21 reported 3 siblings with onset of clinical signs at 5 to 6 weeks of age. The aberrant movements of the described dogs were similar to those of the dogs reported here, but electrophysiology performed on 2 of the dogs identified involvement of motor nerve fibers, in contrast to our results. Hypomyelination of peripheral nerves was the histopathologic diagnosis of the dogs in these reports.20,21 Breed-related neurodegenerative diseases with signs originating from deficits in the sensory parts of the nervous system have been described in other breeds.2,1016,18,2225 Common clinical signs are general dysmetria with spared muscle strength or signs of paresthesia with self-mutilation. Neither the clinical signs nor the severity and distribution of degenerative changes within the nervous system are similar to those of the Golden Retrievers reported here. Hereditary ataxia in the smooth-haired Fox Terrier, Jack Russell Terrier, or Ibizan Hound is characterized by symmetric generalized ataxia with severe hypermetria and spastic movements. Histopathologically, bilateral degenerative changes are observed dorsolaterally and ventromedially in the spinal cord. In affected Jack Russell Terriers

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c

and Ibizan Hounds, central auditory pathways of the brain and peripheral nerves also display degenerative changes.2,12,13,22,23,25 Neuroaxonal dystrophy in Rottweilers is a disease characterized by ataxia and hypermetria. In addition, head tremor, nystagmus, and menace deficits may develop. Microscopically, massive numbers of axonal spheroids are observed, especially in sensory axon terminals in grey matter of the CNS.10,11 Boxers with progressive axonopathy are ataxic and have diminished or absent postural reactions, muscle tone and spinal reflexes. Patellar reflexes are absent early in the course of the disease. Marked degenerative changes are seen particularly in lateral and ventral funiculi of the spinal cord, but also in nerve roots, peripheral nerves, and optic pathways.24 Pointers, English Springer Spaniels, and French Spaniels with sensory neuropathy have loss of pain perception of the digits with self-mutilation, but intact proprioceptive placing reactions and normal patellar reflexes. Histopathologically, they may show degeneration of fibers in dorsal roots and peripheral nerves as well as reduced fiber density and myelin staining in the dorsolateral fasciculus of the spinal cord.14,26,27 Long-haired Dachshunds and Border Collies with sensory neuropathy have ataxia with loss of postural reactions and pain perception but normal or slightly decreased patellar reflexes. Sensory nerve conduction velocities are decreased or absent. Histopathologic changes with severe axonal degeneration occur in distal sensory nerves, and in Dachshunds, degenerative changes are also observed in the fasciculus gracilis of the spinal cord.1518 Even among hereditary neurologic diseases with sensory signs in humans, none seem to have the same distribution of clinical signs, course of disease, and electrophysiologic and histopathologic findings.28,29 In Friedreichs ataxia, the most frequent hereditary ataxia of humans, there are similarities to the Golden Retrievers described here in neurologic presentation, but other findings, such as cardiomyopathy and diabetes mellitus, also occur in many of these patients,30 and pathologic changes occur first in dorsal root ganglia with loss of large sensory neurons.31 Thus, none of these diseases has a disease phenotype that resembles SAN in Golden Retrievers. In conclusion, a neurologic syndrome presenting clinically as a sensory ataxic neuropathy has been identified in Golden Retrievers in Sweden. The clinical history, breed, age at onset, pattern of neurologic signs, and progression of signs, together with electrophysiologic and histopathologic findings, were sufficient to make the diagnosis in suspected cases. Histopathologically, the disease is characterized as a subtle degenerative disorder of sensory and motor axons of both the PNS and CNS, predominating in CNS sensory afferents. Additional studies are in progress that may provide information about the clinical nature and the molecular basis of this disease.

Counterpoint MK2, Medtronic A/S, Skovlunde, Denmark Myoline 40 mm, Judex, Aalborg, Denmark e Medelec Gold Disc Electrodes part. no. 54426T, Cephalon, Norresundby, Denmark f 15 mm*0,70 mm (22G), Medtronic A/S, Skovlunde, Denmark g Neuromuscular Disease Laboratory, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Scotland h Institute of Veterinary Pathology, Ludwig-Maximilians University, Munich, Germany i Boichard D. (2002). Pedig: A fortran package for pedigree analysis suited for large populations. 7th WCGALP, Montpellier, France, Communication No. 2813
d

Acknowledgments
This work was carried out in Sweden at the University of Agricultural Sciences. This study was supported by Agria Insurance Company, Sweden, and the Golden Retriever Club of Sweden. The authors thank Dr Brian Summers, Dr Pall Leifsson, and the pathologists at the Swedish Veterinary Institute for their assistance with pathology and Ann Bavner for her assistance with statistics.

References
1. deLahunta A. Comparative cerebellar disease in domestic animals. Compend Contin Educ Pract Vet 1980;2:819. 2. Summers BA, Cummings JF, deLahunta A. Heredity, familial and idiopathic degenerative diseases. In: Summers BA, Cummings JF, deLahunta A, eds. Veterinary Neuropathology. St Louis, MO: Mosby Year Book 1995;281350. 3. Summers BA, Cummings JF, deLahunta A. Degenerative diseases of the peripheral nervous system. In: Summers BA, Cummings JF, deLahunta A, eds. Veterinary Neuropathology. St Louis, MO: Mosby Year Book 1995;437453. 4. Braund KG. Degenerative Disorders of the Central Nervous System. In: Vite CH, ed. Braunds Clinical Neurology in Small Animals: Localization, Diagnosis and Treatment. Ithaca, NY: International Veterinary Information Service, 2003. 5. Braund KG. Neuropathic disorders. In: Vite CH, ed. Braunds Clinical Neurology in Small Animals: Localization, Diagnosis and Treatment. Ithaca, NY: International Veterinary Information Service, 2003. 6. Lorenz MD, Kornegay JN. Neurologic history and examination. In: Lorenz MD, Kornegay JN, eds. Handbook of Veterinary Neurology, 4th ed. St. Louis, MO: Elsevier Science, USA; 2004:1038. 7. Dyck PJ, Stevens JC, Mulder DW, Espinosa RE. Frequency of nerve fiber degeneration of peripheral motor and sensory neurons in amyotrophic lateral sclerosis. Morphometry of deep and superficial peroneal nerves. Neurology 1975;25:781785. 8. Illa I, Rojas R, Gallardo E, et al. Chronic idiopathic sensory ataxic neuropathy: immunological aspects of a series of 17 patients. Rev Neurol (Paris) 2001;157:517522. 9. Redding RW, Ingram JT, Colter SB. Sensory nerve conduction velocity of cutaneous afferents of the radial, ulnar, peroneal, and tibial nerves of the dog: reference values. Am J Vet Res 1982;43:517521. 10. Cork LC, Troncoso JC, Price DL, et al. Canine neuroaxonal dystrophy. J Neuropathol Exp Neurol 1983;42:286296. 11. Chrisman CL, Cork LC, Gamble DA. Neuroaxonal dystrophy of Rottweiler dogs. J Am Vet Med Assoc 1984;184:464467.

Footnotes
a b

Domitor vet 1 mg/mL, 0.01 mL/kg, Orion, Sollentuna, Sweden Torbugesic 10 mg/mL, 0.01 mL/kg, ScanVet, Animal Health AS, Fredensborg, Denmark

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