Abiotrophy in Domestic Animals: a Review

Abiotrophy in Domestic Animals: A Review

Alexander de Lahunta

ABSTRACT and it allows us to concentrate our can be made to normal neuronal efforts on determining the specific development in which many popula- This review of abiotrophies in cytological defect that is present and tions of differentiated neurons die domestic animals has been organized ideally the genetic basis for its prematurely as a normal programmed by the predominate anatomical loca- occurrence. When we use abiotrophy developmental event. Some of the tion of the lesion. Secondary consider- to name a disease, we are only mechanisms may be common to both ations include the major signs of the describing the pathological process processes. This normal developmental clinical disorder and special neuropa- a concept of the mechanism resulting event occurs in the peripheral nervous thological features. Those abiotro- in the degeneration that is described. system when motoneurons from the phies that have an established genetic As the underlying cause of the ventral grey column fail to develop a basis are identifiled but the review abiotrophy is determined, this should normal motor end plate relationship includes degenerative disorders in be used in naming the disease. Using with a skeletal muscle fiber which is which the etiology is not yet the concept of abiotrophy in its the target organ. These neurons established. broadest sense it is applicable to any of degenerate. The ultimate size and the inherited degenerative diseases of shape of the ventral grey column the nervous system. This would reflects this normal degenerative Gowers in 1902 (1) gave a lecture include the numerous cerebellar process (2,3). In the central nervous entitled a "Lecture on Abiotrophy" in cortical degenerations about which we system the normal development of the which he developed and applied the have little knowledge of the primary mature visual system is a result of concept of abiotrophy as a pathologi- cellular defect in most instances. significant degeneration of retinal cal process. He applied this to the Abiotrophy also applies to the ganglion cells that failed to complete understanding of degenerative dis- numerous examples of storage disease normal synapses on dendrites and eases of the nervous system. These which affect neurons diffusely. In soma of neurons in the lateral diseases are characterized by the many of these the specific enzymatic geniculate nucleus (4). The viability of spontaneous degeneration of neurons defect is known as well as the the latter thalamic neurons is depend- prematurely. Once normal neurons mechanism of inheritance. These ent on their normal synaptic develop- are differentiated they continue to storage diseases are appropriately ment with neurons in the visual grow but do not divide and once identified by the specific enzyme system's cerebral cortex in the occipi- having completed their development deficiency. Nevertheless the patholog- tal lobe. are expected to last the lifetime of the ical process that results from this Our goal as veterinary scientists is individual. The premature degenera- enzyme deficiency is an abiotrophy. first to recognize and describe the tion of these cells reflects an intrinsic Where our knowledge includes a abiotrophy and then to study it further abnormality in their structure which unique feature of the abiotrophic to understand the intrinsic abnormality alters their metabolic activity resulting process, the disease has been named by on a structural, biochemical and genetic in their unexpected degeneration. that pathological feature such as basis. This will allow us to offer appro- Abiotrophy refers to this process. In neuraxonal dystrophy, neurofila- priate genetic counseling to prevent contrast with the broader connotation mentous disease and chromatolytic further occurrence of the disease and of the term atrophy, abiotrophy limits diseases. It must be remembered that ultimately to offer therapy for patients the cellular defect to an inborn these are just features reflecting the by restoring the defective mechanism. metabolic error of development and degeneration of the neuron which The use of gene transfer mechanisms is excludes exogenous insults that can have a large variety of causes. Many of now in its infancy but hopefully in the cause the demise of the cell. The these are exogenous toxicities. Abio- near future will permit the treatment of underlying cellular defect in most trophy refers simply to those processes what are presently lethal diseases (5). abiotrophies is inherited. that are intrinsic to the neuron and The use of domestic animals that have Abiotrophy is a pathological pro- limit its normal viability. diseases similar to those in people will cess by which we can classify a In considering a premature degener- be vital in these studies to achieve this degeneration in the nervous system ation as a disease process, comparison therapeutic success.

Department of Anatomy, New York State College of Veterinary Medicine, Cornell University, Ithaca, New York 14853. Submitted June 27, 1989.

Can J Vet Res 1990; 54: 65-76 65 In this review of domestic animal TABLE I. abiotrophies, I have excluded the Motoneuron numerous storage Degenerations diseases and leuko- Swedish Lapland dog - Sandefeldt 1973 (19) dystrophies caused by specific lyso- Saint Bernard - Great Dane - Bloodhound somal enzyme deficiencies. Biological Crosses - Stockard 1936 (20) processes often defy rigid systematic Brittany Spaniel - Lorenz 1979 (20, 21) categorization. Regardless ofthe choice Rottweiler - Shell 1987 (26) English Pointer - Inada 1978 (28) of classification, overlaps and excep- German Shepherd - Cummings 1989 (31) tions will occur. I have chosen primarily Multisystem Degenerations an anatomic approach based on where Cell Body the major lesion is located but this is Cocker Spaniel - Zaggy 1988 (32) Cairn Terrier - Palmer, Cummings 1988 (33-35) influenced secondarily by the major Angora Goat - Lancaster 1987 (36) presenting clinical signs or nature ofthe Processes pathological process (Table I). The Simmental - Harper, Hartley 1989 (37, 38) major groups include: 1) Motoneuron Limousin X - Palmer, 1988/ Harper 1989 (39, 40) degenerative diseases. 2) Multisystem Brown Swiss - Leipold 1973 (41) Smooth Fox Terrier - Bjorck 1957 (46) degenerations. These are further Jack Russell Terrier - Hartley 1973 (47) divided by the part of the neuron Bull Mastiff - Carmichael 1983 (49) involved cell body, process, myelin German Shepherd - Averill 1973 (50) only or by the major pathological Horses (Appaloosa) - Mayhew 1977 (56) feature that is present neuraxonal Myelin Rottweiler - Gamble 1984 (60) dystrophy, neurofilamentous accumu- Labrador Retriever - O'Brien 1985 (62) lations. 3) Cerebellar degenerations. 4) Dalmation - Bjerkas 1977 (64) Miscellaneous degenerations. All of the Afghan Hound - Cummings 1978 (65) diseases that are included here are Charolais - Palmer 1972 (67) Murray Gray - Richards 1986 (69) degenerative processes. All are consi- Hereford - Harper 1986 (71) dered to be abiotrophies at the present Neuraxonal Dystrophy level of our understanding. The genetic Suffolk, Merino, Romney basis for some has been established. In Coopworth, Perendale Sheep others, only the lesions have been -Cordy 1967, Harper 1986, Nuttal 1988 (74-76) Cat - Woodard 1974 (81) described but the cause remains Collie Sheep dog - Clark 1982 (77) unknown. Further investigation of Rottweiler - Cork 1983 (78) some of these may confirm an extrinsic Chihuahua - Blakemore 1985 (82) cause such as toxicity or nutritional Boxer - Griffiths 1980 (87) German Shepherd - Duncan 1977 (83) deficiency rather than a genetic basis, Morgan - Beech 1984 (93) and therefore exclude them from this Neurofilamentous Disease classification of abiotrophies. Yorkshire Pig - Higgins 1973 (97) Although this is a review of nervous Collie - de Lahunta 1975 (98) system abiotrophies the close clinical Cat - Vandevelde 1976 (99) Grant Zebra - Higgins 1977 (100) and morphological relationship of Hereford - Rousseaux 1983 (101) skeletal muscle to the nervous system Cerebellum warrants the observation that impor- Dog - Autosomal Recessive tant muscle abiotrophies exist. Kerry Blue Terrier - de Lahunta 1976 (106) Gordon Setter - de Lahunta 1980 (114) Although muscle cells have the capabil- Rough Coated Collie - Hartley 1978 (105) ity of regeneration, specific defects in Dog - Multiple litters their structural integrity can lead to Airdale Beagle their premature degeneration. In Bernese Mountain dog Samoyed domestic animals these structural Finnish Harrier Clumber Spaniel Brittany Spaniel Akita abnormalities can be morphologically Border Collie very subtle but clinically very profound Dog - Single animal or litter as in the congenital myotonic Miniature Poodle Golden Retriever myopathy recognized in goats (6) and Fox Terrier Great Dane Cairn Terrier Schnauzer x Beagle the Chow Chow dog (7). These are Cocker Spaniel Mongrel inherited disorders that are similar to Labrador Retriever Thomsen's disease in people. The other Cattle extreme in morphological deterioration Angus Shorthorn of Holstein Hereford muscle is the sex-linked recessive Ayrshire Charolais myopathy of male Golden Retrievers Sheep (8) and Irish Terriers (9). The disease in Merino Golden Retrievers has been found to be Welsh Mountain a nearly perfect animal model of Corriedale (Continued)

66 TABLE I. Concluded not aware that this disease has ever been seen under natural breeding Others Horse - Arabian, Gotland pony conditions. Yorkshire pig Cat Brittany Spaniel Miscellaneous In 1979 (21,22) Lorenz and Cork Peripheral - Schwann cell: Tibetan Mastiff - Cummings 1981 (121) provided the first description of an Spinal Ganglion: English Pointers - Cummings 1981 (123) Distal Axon: Doberman Pinschers - Chrisman 1985 (125) hereditary canine spinal muscle Astrocytes atrophy that occurs in Brittany Labrador Retriever - McGrath 1980 (127) Spaniels and is inherited as an Sheep - Fankhauser 1980 (126) autosomal dominant gene that has Scottish Terrier - Cox 1986 (128) three phenotypic expressions (23). The clinical signs consist of varying degrees of axial and appendicular Duchenne's muscular dystrophy in progressed to recumbency with severe neuromuscular weakness with young boys (10,11). In this disease the muscle atrophy causing joint immo- atrophy. The homozygous dominant specific gene locus has been found as bility especially distally. Neuronal form is expressed as an accelerated well as the structural cell membrane degeneration was characterized by neuromuscular weakness with onset protein - dystrophin that is chromatolysis, cell body shrinkage, around six weeks of age progressing to deficient in these muscle cells (12). A and neuronophagia. This occurred recumbency by three to four months third example of an inherited primarily in the ventral grey column of of age. The heterozygous form is myopathy occurs in young Labrador the intumescences of the spinal cord expressed either as an intermediate Retrievers. This autosomal recessive and in the Purkinje neurons of the type with onset of weakness around inherited disease causes varying degrees cerebellar cortex. Other affected six months of age and slow progres- of exercise intolerance and was neurons included those in spinal cord sion to three years of age or a chronic originally described as a Type II muscle dorsal grey column, spinal ganglia, type that is not recognized clinically fiber deficiency (13,14). A number of trigeminal ganglia and the trigeminal until around one year of age and clinical variations have been recognized mesencephalic nucleus. This heredi- progresses very slowly with mild signs in this breed and are under rigorous tary neuronal abiotrophy was com- of neuromuscular weakness. The study to determine the basic morpho- pared to the two common motoneu- degree of lesion development corre- logical defect and whether they all ron diseases in man: Werdnig- lates with the clinical expression and represent the same genetic abnormality Hoffman disease of infants (infantile consists of motoneuronal chromatoly- (15-18). spinal muscular atrophy) and the sis and proximal axonal swelling with Kugelberg-Welander disease which neurofilaments. Motoneurons are MOTONEURON DISEASE occurs after infancy. affected throughout the spinal cord In this classification the motoneuron ventral grey column and in brain stem is the general somatic efferent lower Saint Bernard X Great Dane X motor nuclei. Morphometric studies motor neuron (alpha motoneuron). Blood Hound have actually shown an increased The cell bodies are in the spinal cord In 1936 Charles Stockard described population of small neurons in the ventral grey column or motor nuclei in an inherited disease that became ventral grey column and axonal the brain stem. The axons are con- referred to as Stockard's paralysis atrophy in the ventral roots and spinal tained in all the spinal nerves and (20). In his breeding laboratory he was nerves. A defect in the normal specific cranial nerves (III-VII, IX- studying skeletal development of large programmed cell death that occurs XII). This group of motoneuron and giant breeds of dog with special during development may be involved diseases includes those diseases in interest in the acromegalic condition in this lesion. The neurofibrillary which the clinical expression reflects in Saint Bernards. He raised over 2000 changes result from an abnormality of signs of profound neuromuscular puppies from various cross breedings the motoneuron cytoskeletal constitu- disease and the major lesion is in the of Saint Bernards, Great Danes, and ents and impaired slow axonal motoneuron. In some, the disease Blood Hounds. In a few litters a transport (24). The latter has been process is restricted to motoneurons. In unique neuronal abiotrophy occurred confirmed in intercostal nerves (25). others multiple neuronal systems of the limited to the motoneurons of the central nervous system are affected. lumbar, intermediate and ventral grey Rottweiler columns. This caused a progressive At least three different nervous Swedish Lapland Dog paraparesis starting at 8 to 14 weeks of system abiotrophies have been One of the earliest diseases to be age that stopped after a few weeks and reported in the Rottweiler breed. One described as an abiotrophy was the some clinical compensation followed. is a spinal muscular atrophy reported autosomal recessive neuronal degener- The lesion consisted of an initial by Shell in 1987 (26). Neuromuscular ation of young Swedish Lapland dogs chromatolysis followed by neurono- weakness is first observed from birth by Sandefeldt in 1973 (19). Their phagia and gliosis. An inheritance to four weeks of age and progresses neuromuscular weakness began at five involving the interaction of three rapidly resulting in recumbency, to seven weeks of age and rapidly dominant genes was proposed. I am severe denervation atrophy and joint

67 immobility. Megaesophagus with two weeks of age the female developed 1982 and 1985. The disorder appears regurgitation also occurs. In this study a right forelimb weakness; the male to be widespread in the breed, of long- motoneuronal chromatolysis was was bilaterally weak. This was standing, and has all the implications associated with the accumulation of followed in both by a rapid denerva- of an inherited disorder. A repeat neurofilaments in the cytoplasm of the tion atrophy with a carpal valgus breeding in the United States using cell bodies. These degenerate moto- deformity and fixation of that joint in related parents produced one affected neurons occurred in the spinal cord flexion. A tenotomy was performed in dog. ventral grey column, especially the the unilaterally affected female and by The signs are variable but all have intumescences, and in brain stem five months of age she had good use of onset between 2.5 and 5 months of age motor nuclei and the red nucleus (27). this limb with some residual atrophy. and are progressive. In England, the At Cornell we have recently studied The bilaterally affected male was major signs appeared to be a cerebellar a similar disorder in one Rottweiler autopsied at eight weeks of age and ataxia and spinal cord spastic paresis puppy with onset of weakness at three extensive motoneuron lesions were and ataxia. The first dog studied at weeks of age. By eight weeks of age he found only in the ventral grey column Cornell was assumed to have cata- could only support weight on the of the seventh and eighth cervical plexy based on the owner's description forelimbs. Neuromuscular paresis was spinal cord segments. Many cell of brief episodes of pelvic limb evident in all four limbs without bodies were absent and replaced by collapse unrelated to exercise and the significant atrophy. At autopsy at ten gliosis. Others were chromatolytic or absence of any abnormality when weeks of age, the swollen chromato- vacuolated and axonal spheroids were examined by veterinarians. The lytic motoneuronal cell bodies con- present. The ultrastructural observa- second puppy began to first show tained widely dispersed endoplasmic tion of a significant decrease in ataxia and collapsing episodes at ten reticulum but few neurofilaments. The ribosomes suggests impaired protein weeks of age. The signs progressed affected neurons included those synthesis and decreased axonal rapidly and featured two clinical reported by Shell plus neurons in transport. entities. When the puppy was active spinal ganglia and many medullary the signs were those of a severe sensory neurons (vestibular, cochlear MULTISYSTEM -NEURONAL cerebellar disorder. During this nuclei) and the cerebellar nuclei. An CELL BODY exaggerated activity the dog would inherited basis is presumed but not A multisystem neuronal abiotrophy suddenly totally collapse and lay documented. that primarily affects neuronal cell completely atonic from which he bodies has been described in Cocker would recover spontaneously in a few English Pointers Spaniels, Cairn Terriers and Angora seconds or with stimulation. This In 1978 (28) Inada reported an goats. latter clinical entity was presumed to hereditary progressive neurogenic be cataplexy. muscular atrophy of English Pointers Cocker Spaniel The lesion in all these Cairn Terriers with onset of progressive neuromuscu- In 1988 (32) Zaggy reported on four consists of a widespread chromatoly- lar signs around five months of age. red-haired Cocker Spaniels with sis of multiple neuronal systems in the Usually by three months of progres- progressive signs of abnormal behav- central and peripheral nervous sys- sion, these dogs were recumbent and ior and ataxia that from the descrip- tems with widely dispersed endoplas- severely atrophied. The affected tion appears to be predominately a mic reticulum and loss of ribosomes. motoneurons were limited to the cerebellar ataxia. These signs began at Peripheral chromatolysis predomi- spinal cord ventral grey column and one year of age and progressed for nates in the spinal cord ventral grey spinal accessory nucleus and the months before autopsy. The lesion columns. Central chromatolysis is hypoglossal nucleus. The degenerative consisted of neuronal cell body loss, found in brain stem motor and sensory process was unique in that it was gliosis and dystrophic axons with nuclei and a patchy chromatolysis accompanied by the accumulation of widespread distribution in the grey occurs primarily in the spinal cord lipid granules in the cytoplasm ofthese and white matter of most all segments dorsal grey column, spinal ganglia, motoneurons that on ultrastructural of the brain. No specific topography enteric and autonomic ganglia. In study consisted of membranous was evident. Pedigree studies strongly addition, degenerate processes occur cytoplasmic bodies and zebra bodies support a familial basis. in the spinal cord lateral and ventral similar to those found in many of the funiculi with a unique necrosis of the lysosomal storage diseases (29). The Cairn Terrier substantia gelatinosa and adjacent presumed enzymatic deficiency is still In 1988 and 1989 Palmer and white matter primarily in caudal unknown. Breeding experiments Blakemore in England (33,34) and thoracic and cranial lumbar segments. suggest an autosomal recessive inher- Cummings at Cornell in New York It is important to differentiate this itance (30). State (35) simultaneously described a disease from the inherited globoid cell similar multisystem neuronal abio- leukodystrophy that also occurs in this German Shepherd trophy in Cairn Terriers. Correspon- breed. A very focal form of motoneuron dence with Farrow in Australia abiotrophy has recently been studied disclosed his experience with the same Angora Goats at Cornell in one of two affected condition. The report from England In 1987 (36) Lancaster described a German Shepherd puppies (31). At concerned three dogs seen in 1974, possibly inherited neuronal degenera-

68 tion in young Angora goats. Clinical referred to as "weavers" because of Bull Mastiff signs of a progressive spastic paresis their ataxic gait. This progressive In 1983 (49) Carmichael reported on and ataxia began from birth to four paraparesis and ataxia begin around a degenerative brain lesion with months and progressed to sternal five to eight months of age and hydrocephalus in Bull Mastiffs that recumbency and inability to stand in a predominately affect the pelvic limbs was inherited as an autosomal reces- few weeks. The lesion consists of causing a weaving type of gait. sive defect. These dogs were six to nine extensive vacuolation of neuronal cell Forelimb signs occur later in the weeks old when their signs began with bodies located diffusely throughout course of the disease. Progression a visual abnormality and a predomi- the spinal cord ventral grey column occurs over many months (42,43). The nately cerebellar ataxia most evident and multiple nuclei ofthe caudal brain major lesion is bilaterally symmetrical in the pelvic limbs. Some dogs stem and the red nuclei. degeneration of individual axons and developed head tremors, abnormal nystagmus and behavioral abnormal- MULTISYSTEM -PROCESSES their myelin in the spinal cord white matter especially in the thoracic ities. Hydrocephalus was described as A number of multisystem degenera- segments. Similar lesions also occur in moderate to severe, involving all tions in the nervous system predomi- the brain stem, cerebellum and ventricles and with no recognizable nate as focal or diffuse lesions subcortical white matter of the obstruction. Intramyelenic vacuoles involving the axons and myelin of cerebrum. A less prominent cell body created a spongiform change in all the neuronal processes. chromatolysis also occurs in the spinal cerebellar nuclei, the vestibular nuclei cord ventral grey column and medul- and caudal colliculi, accompanied by Simmental-Limousin lary olivary nuclei (44). Ultrastruc- gliosis and spheroids. A multifocal encephalopathy was tural lesions have been described in described in the Simmental breed of neuromuscular junctions and skeletal German Shepherd cattle in Australia and New Zealand in The German Shepherd is a breed 1989 (37,38). Purebred Simmentals in muscles (45). This abiotrophy is predisposed to a degenerative myelo- Australia developed a progressive thought to be an autosomal recessive pathy in older age. Affected dogs are ataxia and behavioral change at five to inherited condition. usually at least four or five years old eight months of age. The gait abnor- when they develop an insidiously mality progressed to recumbency with Smooth Fox progressive spastic paraparesis and opisthotonos and death by 12 months. and Jack Russell Terriers ataxia of the pelvic limbs. No forelimb In New Zealand both purebred A cerebellar ataxia primarily asso- deficits are observed. In 1973 (50) Simmentals and Simmental-Hereford ciated with a myelopathy was des- Averill described the clinical signs and cross cattle at seven months of age cribed in Smooth Fox Terriers in the associated diffuse degeneration of developed a progressive paresis and Sweden in 1957 (46) and in Jack neuronal processes scattered through ataxia. This involved primarily the Russell Terriers in Great Britain in all funiculi of the spinal cord. These pelvic limbs in the crossbreds and all 1973 (47). The signs begin between 2.5 lesions predominate in the thoracic four limbs in the purebreds. The lesion and 4 months of age and consist of a segments and do not resemble the consists of a unique bilaterally severe cerebellar ataxia that initially pattern expected with the process of symmetrical severe necrosis of paren- progresses rapidly and then becomes "dying back of the axons" (51). chyma with cavitation. Described as a static or progresses slowly. Walking Lesions also occur in rootlets and lysis the lesion occurred in the center becomes very difficult due to the spinal nerves but these are also found of each caudate nucleus, internal spasticity, delayed protraction and in clinically normal old animals (52). capsule, and putamen of the cerebrum dysmetria. The gait has been described A family of Siberian Huskies has been and various nuclei of the brain stem. as bouncing or dancing in quality. reported with this disease (53) and it A similar lytic lesion has been Despite the obvious cerebellar nature also occurs sporadically in other observed in Limousin-cross cattle in of the signs, no lesions have been breeds (54), especially larger breed Great Britain (39) in 1988 and described in the cerebellum. In the dogs (55). Australia (40) in 1989, but with wider Smooth Fox Terriers the only lesion is distribution including the optic an extensive bilaterally symmetrical Horses - Appaloosa chiasm, cerebellar peduncles and degeneration of the superficial tracts In 1977 (56), Mayhew described a spinal cord funiculi. The clinical signs of the lateral funiculi (spinocerebellar) degenerative myeloencephalopathy of begin at four months and consist of a and in the ventral funiculi on either young horses of many breeds. Onset of progressive ataxia and visual deficit. side of the ventral median fissure (48). a slowly progressive symmetrical No cause has been discovered for this The Jack Russell Terrier has the same spasticity, ataxia, and paresis of all encephalopathy. Ultimately this may spinal cord lesions but also extensive four limbs occurs before seven months turn out to be an environmental toxin degeneration in the central compo- in half the cases, between 7 and 14 and not an inherited abiotrophy. nents of the auditory system in the months in a quarter of the cases and brain stem. An autosomal recessive older than that for the rest. The lesion Brown Swiss genetic abnormality has been con- consists primarily of a degeneration of A progressive myeloencephalo- firmed for the Smooth Fox Terrier axons and myelin with extensive pathy has been recognized since 1973 and presumed for the Jack Russell replacement by astrogliosis. It is a (41) in Brown Swiss cattle that are T.errier. bilaterally symmetrical lesion most

69 pronounced in the superficial tracts of progressive cerebellar ataxia. Vacuo- Charolais the lateral funiculi (spinocerebellar) lated distended myelin sheaths with- A unique myelin abnormality in and ventral funiculi adjacent to the out macrophages were scattered Charolais cattle was first reported ventral surface and ventral median throughout all cerebellar white matter from England by Palmer in 1972 (67). fissure. All spinal cord segments are and to a much less degree in spinal These cattle develop a slowly progres- affected but often the lesion is most nerve myelin (63). The cause remains sive predominately thoracolumbar advanced in the thoracic segments. unknown. spastic paraparesis and ataxia some- Spheroids occur predominately in the time between 6 and 36 months of age. nucleus thoracicus and lateral cuneate Dalmation The lesion consists of focal areas of nuclei. Two causes have been pro- Bjerkas in 1977 (64) described an demyelination called plaques. These moted. An environmental insult such hereditary cavitating leukodystrophy plaques consist of clumps of para- as a nutritional deficiency or ingestion in Norwegian-bred Dalmations. At nodes where myelin sheaths are of a toxin could account for the three to six months of age, these dogs distended. These occur in hypertro- multiple cases often seen on the same developed a progressive visual defect phied processes of oligodendrocytes at property. A vitamin E deficiency has and undescribed locomotor abnor- these paranodes (68). Unmyelinated been supported by some studies (57) mality. Their lesions consisted of axons traverse these plaques which are but not others (58). A familial basis initially large foci of demyelination located throughout the central ner- has also been advanced and supported with axonal sparing in the centrum vous system: spinal cord ventral and in one study involving the Appaloosa semiovale of each cerebrum, the optic lateral funiculi, cerebellar medulla and breed (59). Further studies are needed nerves, and to a lesser degree the white peduncles, transverse fibers of pons, to determine this pathogenesis more matter tracts in the basal nuclei internal capsule in the cerebrum and accurately. (caudate nucleus and putamen) and in the corpus callosum. An inherited the spinal cord white matter. As the basis is presumed. MULTISYSTEM -MYELIN lesion progressed, grossly apparent A few abiotrophies have been cavities occurred in some of these sites. Murray Grey Cattle described in dogs and cattle that This disease was presumed to be In 1986 (69) Richards described a predominately affect central myelin inherited as an autosomal recessive progressive spinal myelopathy in with axonal sparing. defect. Murray Grey cattle in Australia. These cattle are usually affected at Rottweiler Afghan Hounds birth with a spastic paraparesis and Gamble in 1984 (60) reported on a In 1978 (65) Cummings described ataxia. A few calves were normal to 8 leukoencephalomyelopathy in United the primary myelinolytic lesion that to 12 months when signs first began. States' Rottweilers that showed occurs as an autosomal recessive The signs progress for weeks to progressive signs of a cervical spinal inherited disorder in young Afghan months and are associated with a cord disorder beginning between 1.5 hounds (66). The signs of white matter bilaterally symmetrical primary and 3.5 years of age. The predominant spinal cord disease begin between 3 demyelination in the spinal cord lesion was a bilaterally symmetrical and 13 months in the pelvic limbs with lateral and ventral funiculi and a primary demyelination with reactive a rapidly progressive spastic parapare- neuronal cell body chromatolysis in astrocytosis in the central part of the sis and ataxia. Paraplegia usually the spinal cord, brain stem and lateral funiculus of the entire spinal occurs in seven to ten days. Varying cerebellar nuclei. The cause has been cord or predominately the cranial degrees of forelimb deficit follow. The determined to be an autosomal cervical segments. Dorsal funiculi lesion consists of a bilaterally symmet- recessive inheritance (70). were variably involved and the same rical necrosis of myelin with preserva- lesion occurred in the medullary tion of axons that appears to start Polled Hereford pyramids and the cerebellar medulla. ventrally in the ventral funiculi and In 1986 (71) Harper described a In addition some spheroids occurred expand laterally into the lateral spongiform encephalopathy of new- in the general proprioceptive nuclei of funiculi. Symmetrical dorsal funiculi born polled Herefords due to a the medulla and spinal cord. The same lesions vary in their occurrence. In all deficiency of a branch-chain ketoacid disease has been reported in the dogs, the processes adjacent to the decarboxylase. A similar disease in Netherlands and a genetic transmis- grey matter (fasciculus proprius) are children is referred to as maple syrup sion has been proposed (61). spared. Only central myelin is urine disease. These calves are usually affected. Macrophages filled with normal at birth but within one to three Labrador Retriever degenerate myelin accumulate along days rapidly become dull, recumbent In 1985 (62) O'Brien described a axons and around blood vessels. A and opisthotonic. The lesions consist spongy degeneration of the cerebellar similar myelinolytic lesion occurs predominately of a swelling of myelin white matter in two Labrador around the dorsal nucleus of the sheaths around the terminal parts of Retriever littermates. Their signs trapezoid body in the medulla. axons therefore usually adjacent to began between four and six months of Paralyzed dogs can be maintained for populations of neurons. This occurs age and initially consisted of episodes months with no further progression of throughout the central nervous system of extensor rigidity and opisthotonos the disease and with persistence of and is probably identical to the (cerebellar seizures?) followed by a axonal preservation. hereditary neuraxial edema described

70 by Cordy in 1969 (72). Whereas the development. These sheep acquired a grey matter were characterized as morphological disturbance is weaving gait between one and six ballooned cell processes: olivary expressed mainly in specific areas of months that progressed from ataxia nuclei, lateral cuneate nuclei, thalamic central myelin the metabolic abnor- and trembling to severe paresis, nuclei, and mesencephalic reticular mality involves neurons diffusely collapse and death. Spheroids formation. Spheroids without bal- which accounts for the severe wide- occurred primarily in grey matter looning occurred in white matter: spread nature of the clinical signs (73). areas at the termination of axons: medial lemniscus, medial longitudinal spinal cord dorsal grey columns and fasciculus, central tegmental tract and MULTISYSTEM -NEURAXONAL nucleus thoracicus, brain stem-lateral dorsal rootlets. In addition, neuronal DYSTROPHY cuneate nucleus of medulla, midbrain cell body loss and gliosis occurred in Neuraxonal dystrophy is a neuronal colliculi, lateral geniculate nucleus of cerebellar Purkinje neurons, olivary degeneration manifested by axonal diencephalon, cerebellar nuclei, and nuclei, thalamic nuclei and spinal swellings called spheroids. These optic tracts. An inherited basis was ganglia. spheroids occur generally in one of proposed. three distributions. They may occur in Chihuahua the distal axon at a preterminal site Collie Sheep Dog In 1985 (82) Blakemore described a where they usually consist of tubular Clark in 1982 (77) reported on a neuraxonal dystrophy in two Chihua- and/or vesicular membranous orga- fairly limited development of sphe- huas that developed a progressive nelles. These are usually in or adjacent roids in young working Collie Sheep tremor and ataxia at seven weeks of to populations of neuronal cell bodies dogs. The dogs acquired a progressive age. Spheroids occurred in the internal (nuclei, cortex). They can occur cerebellar ataxia starting at two to capsule and cerebellar white matter proximally in the axon near the cell four months of age. Spheroids and a variety of nuclei: lateral body where the spheroid usually predominated in terminal axons in the geniculate, olivary, trapezoid body, consists of an accumulation of grey matter of cerebellar nuclei and and lateral cuneate. neurofilaments that are often disor- medullary vestibular nuclei. They also iented. A third location of spheroids is occurred in the white matter of German Shepherd at multiple sites along the axon. cerebellar peduncles and folia. An In 1977 (83) Duncan first reported autosomal recessive inheritance was on a giant axonal neuropathy in Sheep proposed. German Shepherds that was inherited In 1967 (74) Cordy described a as an autosomal recessive genetic neuraxonal dystrophy in Suffolk Rottweiler defect. These dogs developed a sheep that developed a progressive Cork in 1983 (78) reported a canine progressive pelvic limb paresis and spastic paresis and ataxia primarily form of neuraxonal dystrophy in ataxia starting around 15 months of related to a spinal cord lesion. The young adult Rottweilers. The few age. Neuromuscular signs predomi- onset of signs varied from 1.5 to 5 cases observed developed a slowly nated (84). Spheroids occurred cen- months. Spheroids occurred diffusely progressive cerebellar ataxia starting trally in the distal part of axons near in the central nervous system at the between one and two years of age (79). their termination in grey matter: termination of axons in grey matter There is one report of the same clinical spinal cord dorsal and intermediate areas: all spinal cord grey matter, and pathological syndrome in a puppy grey columns, medullary general especially nucleus thoracicus, brain whose signs began at ten weeks of age proprioceptive nuclei, and cerebellar stem medullary nuclei; cerebellar (80). In all dogs spheroids predomi- granule layer. Others occurred in long nuclei; rostral colliculi and lateral nated in distal axons in numerous grey white matter tracts near their termina- geniculate nuclei. An autosomal matter areas: spinal cord dorsal grey tion - cranially in dorsal funiculi, recessive inheritance was proposed for columns, especially the nucleus caudally in lateral corticospinal this disease in Suffolk sheep. thoracicus; Purkinje neuron layer of pathways, and in the caudal cerebellar In 1986 (75) Harper described a cerebellar cortex with significant loss peduncles, brachia of rostral colliculi, neuraxonal dystrophy in adult Merino of cell bodies; and medullary general and vestibulospinal tracts (85). Sim- sheep in Australia. The signs of proprioceptive nuclei. An autosomal ilar spheroids occurred in peripheral progressive diffuse spinal cord disease recessive inherited basis is suspected. nerves (86). All spheroids consisted of began between one and four years of abnormally oriented neurofilaments age. Spheroids occurred at multiple Cat which may reflect an abnormality in sites along axons and were found most Woodard in 1974 (81) described a slow axon transport from a primary commonly in areas of white matter: all diffuse neuraxonal dystrophy in axonal dysfunction or abnormal cell funiculi of spinal cord, cerebellar young cats that was inherited as an body metabolic activity. peduncles, transverse fibers of the autosomal recessive disease. Affected pons, tracts in the thalamus, internal cats had a coat color similar to the lilac Boxer capsule and corona radiata. Siamese in contrast to their normal In 1980 (87) Griffiths first reported In 1988 (76) Nuttall described a black-coated littermates. Signs of a on a diffuse axonopathy in young central nervous system degeneration progressive cerebellar ataxia began Boxers that is inherited as an auto- in Coopworth sheep in New Zealand around five weeks of age. The somal recessive disorder. These dogs that was characterized by spheroid spheroids that occurred in regions of develop a unique gait abnormality

71 sometime between one and seven mental model produced by iminodi- weeks of age the foal was recumbent, months of age (88). All four limbs are proprionitrile intoxication. This toxin severely atrophied and had immobile affected but the pelvic limbs are worse. impairs axonal transport resulting in joints. Neurofilamentous distention of The gait consists of a spastic paresis accumulation of neurofilaments prox- motoneurons predominated in the and severe general proprioceptive imally in large axons (95,96). spinal cord ventral grey column and deficit causing dysmetria. Reflexes brain stem cranial nerve motor nuclei. and tone are depressed but no atrophy Yorkshire Pig Other neurons involved were in the occurs. After weeks of progression the Higgins described a motoneuron reticular formation and red nuclei. signs may become static. Spheroids neurofilamentous accumulation in Myelopathy also occurred in each occurred both centrally and peripher- Yorkshire pigs in 1973 (97). These pigs lateral and ventral funiculus of the ally at multiple sites along the axon developed signs of progressive neuro- entire spinal cord. and consist of accumulated axonal muscular disease around five weeks of organelles and neurofilaments. Sites age. By ten weeks of age the signs were Hereford Cattle include the grey matter of cuneate severe. Chromatolysis with intracyto- In 1983 (101) Rousseaux described nuclei, dorsal nuclei of the trapezoid plasmic distention with neurofila- newborn horned Hereford calves as body, and the spinal cord. Affected ments predominated in the motoneu- "shakers" because of their diffuse white matter areas include lateral and rons of spinal cord ventral grey tremors associated with their unsuc- ventral funiculi of the spinal cord, columns and brain stem cranial nerve cessful attempts to stand. A progres- optic nerves, and spinal nerve rootlets motor nuclei. In addition these cell sive spasticity followed resulting in a and proximal nerves (89-91). The body lesions occurred in the brain few months in complete spastic rootlet spheroids contain disoriented stem reticular formation and red paraplegia. Neuronal cell body chro- neurofilaments with a depletion of the nucleus. A myelopathy with spheroids matolysis associated with neurofila- cytoskeletal protein tubulin, and also occurred in the spinal cord lateral mentous accumulations in the soma increased concentration of actin (92). and ventral funiculi An inherited basis and proximal axon occurred diffusely An inherited primary defect in slow was presumed. in numerous brain stem nuclei, axonal transport is the present cerebellar Purkinje neurons, retinal understanding of this disease. Collie ganglion cells, all parts of spinal cord In 1974 (98) Shively and I reported a grey matter, and sensory and visceral Morgan Horse diffusely distributed neuronal cell efferent (autonomic) ganglia of the In 1984 (93) Beech described a very body neurofilamentous distention peripheral nervous system. In addi- selective focal neuraxonal dystrophy including the proximal axons in a tion, a degeneration occurred in all limited to the lateral cuneate (acces- young Collie dog. This puppy had funiculi ofthe spinal cord as well as the sory cuneate) nuclei of the medulla of signs of a neuromuscular paresis at the ventral rootlets associated with young Morgan horses. Most of these time it started to walk and the signs spheroids. An autosomal recessive horses first developed a spastic progressed up to euthanasia at 12 inheritance was proposed for this paraparesis and pelvic limb ataxia weeks. Affected cell bodies included disorder (102). between 6 and 12 months of age. motoneurons of spinal cord ventral Occasionally the onset occurs later. grey columns and the oculomotor CEREBELLUM No forelimb signs were observed. This nuclei; neurons in multiple systems of One of the most common of the morphological lesion does not readily the medulla, pons, midbrain and domestic animal abiotrophies is that explain a pelvic limb deficit. Breeding diencephalon; cerebellar Purkinje which affects the cerebellar cortex studies have supported an inherited neurons and retinal ganglion cells. (103). Most of these are limited to the basis but the mechanism is not clear. A Purkinje neurons which appear to be polygenic defect or a dominant gene Cat excessively susceptible to intrinsic with variable expression have been Vandevelde reported in 1976 (99) on disturbances of their metabolic appa- proposed (94). a selective population of motoneurons ratus. Because the integrity of the in a kitten that were distended with granule cell neuron is dependent on its MULTISYSTEM -CELL neurofilaments. The kitten developed synaptic relationship with the den- BODY NEUROFILAMENTS progressive neuromuscular paresis of dritic zone ofthe Purkinje neuron, loss A number of degenerative diseases all four limbs from the time it could of the latter neuron usually results in a have been described in domestic walk until it was tetraplegic at ten secondary depletion of granule cell animals in which the major lesion is a weeks of age. Affected motoneurons neurons (104). With a few exceptions distention of the cytoplasm of neuro- were limited to the lateral part of the retrograde degeneration is not usually nal cell bodies with accumulated ventral grey column of each observed in other neuronal groups neurofilaments. Many of these pro- intumescence. that project to the cerebellar cortex foundly affect motoneurons and cause such as the olivary neurons (to signs of neuromuscular disease. This Grant Zebra Purkinje neurons) and pontine neu- neurofilamentous abnormality has In 1977 (100) Higgins described rons (to granule cell neurons). been studied in a variety of human and rapidly progressive signs of neuromus- The onset of progressive cerebellar spontaneously occurring animal dis- cular paresis in a Grant Zebra foal ataxia most commonly occurs in the orders and compared to the experi- starting at two weeks of age. By six first few weeks [Rough Coated Collie

72 (105)] or months [Kerry Blue Terrier following hypothesis has been pro- In 1981 (123) Cummings described a (106), Holstein calves (107)]. Occa- posed. The primary neuronal degener- presumably inherited abnormality of sionally it is present at birth [Samoyed ation that occurs is an excitotoxic the development and maintenance of (108) and Beagle dogs (109), Welsh degeneration involving neurons that somatic afferent nociceptive neurons Mountain (110) and Corriedale lambs have glutamate receptors and receive in English Pointers. This causes these (111), Shorthorn ( 112) and Hereford axon terminals that elaborate glu- puppies to be analgesic in their paws calves (113)]. In other instances the tamic acid as the excitatory neuro- so that at 11 to 12 weeks of age, they onset is delayed and occurs in young transmitter (120). Excessive glutamate start to lick and chew on their digits adult or older adult animals [Gordon stimulation will cause degeneration of causing mutilation with secondary Setter (114), Brittany Spaniel (115), the neuron stimulated. This could infections and fractures. Spinal Schnauzer x Beagle dogs ( 116), occur if excessive glutamate or an ganglia are grossly small from a Merino sheep (75), and Angus calves analog is released, astrocytic uptake of decreased population of cell bodies (1 17)]. Occasionally other populations glutamate is deficient, or the glutam- and degeneration of cell bodies and of neurons are involved in the primary ate receptors are abnormally excessive processes in the dorsal rootlets. There abiotrophy [Miniature poodle (1 18)]. or bind excessive glutamate. The is a depletion of the nociceptive In most instances when enough Purkinje neurons and neurons in the neurotransmitter, substance P, in the affected animals have been studied, an caudate nucleus have glutamate related dorsal grey column of the inherited autosomal recessive gene has receptors which are activated by the spinal cord where these nociceptive been implicated as the cause. Many glutamic acid released at synapses neurons terminate. In 1964 (124) a reports involve too few animals to from granule cell axons for Purkinje similar acral mutilation was described confirm a genetic mechanism or involve neurons and corticostriate axons for in European short-haired Pointers only a single animal or single litter. neurons in the caudate nucleus. The and called a toe necrosis. An auto- The neuronal abiotrophy of Kerry olivary and substantia nigra neuronal somal recessive inheritance was Blue Terriers that is inherited as an degenerations are proposed to be established for this latter disorder. autosomal recessive gene is especially secondary retrograde degeneration of In 1985 (125) Chrisman described a unique because of the additional cells that terminate on the neurons chronic distal neuropathy in the pelvic neuronal populations that are affected that have degenerated. The loss of limbs of adult Doberman Pinschers. besides the Purkinje neurons and the their target cells results in their At three years of age or later these plausible explanation for this unusual degeneration. Olivary neurons project dogs develop a peculiar overflexion of topography (106). Signs ofprogressive directly via climbing fibers on to the the pelvic limbs as they walk. One or cerebellar ataxia begin at 12 to 16 dendritic zones of Purkinje neurons. A both limbs can be affected with what weeks of age and progress usually to large population of neurons in the reads like a "stringhalt" type of gait. an inability to coordinate to stand substantia nigra project to neurons in This is associated with a mild atrophy near a year of age. Autopsies at the caudate nucleus - a nigrostriatal of caudal leg and thigh muscles. progressive intervals during the course pathway. The inherited recessive Axonal and myelin degeneration are ofthe disease reveal an initial Purkinje genetic defect is responsible for the present distally in neurons of the cell degeneration resulting in pro- biochemical or structural abnormality sciatic nerve. found loss of these cell bodies. As this involving the neurotransmitter, glu- A unique astrocyte abnormality has neuronal population degenerates, the tamic acid. been described in humans, sheep and granule cell layer shows a moderate dogs. These affected astrocytes are depletion of its cell bodies and after MISCELLANEOUS enlarged and they develop long one to two months of progression a A primary inherited Schwann cell processes which are distended with bilaterally symmetrical degeneration defect has been recognized in Tibetan intermediate filaments that give them occurs in the olivary nuclei. These cell Mastiffs and first reported by Cum- an eosinophilic appearance. These bodies become distended with multi- mings in 1981 (121). At a critical develop primarily in a perivascular ple large vacuoles and then disappear. period in the growth of these puppies, and subpial position where the At approximately two to three months when axons are rapidly elongating, enlarged processes have been called of progression of signs, a rapidly these defective Schwann cells cannot Rosenthal fibers. The perivascular progressive degeneration occurs bilat- keep up with the myelination of these lesions are distributed diffusely erally in the center of each caudate axons and episodes of demyelination throughout the central nervous system nucleus. Cell body degeneration is and remyelination occur resulting in a but predominately in subpial and followed by cavitation of these nuclei. hypertrophic neuropathy. The result- subependymal white matter where This nuclear degeneration is followed ing clinical signs of neuromuscular myelin loss may occur. This has given in a few weeks by a bilaterally paresis begin between 7 and 12 weeks rise to the term fibrinoid leukoence- symmetrical degeneration in each of age and usually stop progressing phalopathy and the eponym Alexand- substantia nigra (1 19). after six to seven weeks. Pelvic limb er's disease. In 1980 (126) Fankhauser Based on what is known about signs and lesions are worse and usually reported this lesion in a four year old neurotransmitters and neuroanatomic some residual pelvic limb deficit and Alpine sheep, and McGrath reported pathways and the results of injections deformity persists. This Schwann cell it in two six month old Labrador of kainic acid into neuronal popula- defect is inherited as an autosomal Retrievers (127). In 1986 (128) Cox tions in experimental animals, the recessive disease (122). described the lesion in a Scottish

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