Congenital and Inherited Diseases

Beta Mannosidosis

This heritable, lysosomal storage disease in goats is seen only in newborn kids of Nubian breeding and is character­ized by intention tremors and an inability to rise.

Epidemiology

The condition was first described as a neurovisceral storage disease with dysmyelinogenesis of unknown cause in new­born Anglo Nubian kids in Australia in 1973 (Hartley and Blakemore 1973). It was later characterized as beta man- nosidosis in Nubian kids in Michigan in 1981 (Jones and Laine 1981). It was long thought to occur only in the goat, but is now also recognized in humans (Dorland et al. 1988), the Salers breed of cattle (Abbitt et al. 1991), and German Shepherd dogs (Jolly et al. 2019). The specific molecular defect responsible for caprine beta mannosidosis has been identified and the associated cDNA coding region has been sequenced and characterized (Leipprandt et al. 1996). It involves a single base-pair deletion.

Currently the caprine disease is known only in the Nubian breed or Nubian crossbreds (Shapiro et al. 1985). It has been reported in Australia, New Zealand, Fiji, Canada, and the United States. Heterozygous carriers of the trait can be identified by intermediate plasma levels of beta mannosidase. An Australian survey identified 13.7% of 988 Anglo Nubians as carriers (Sewell and Healy 1985). This suggests a significant potential economic loss for Nubian breeders.

Pathogenesis

The lysosomal storage diseases result from an acquired or inherited deficiency of a catabolic lysosomal hydrolase. In cells where the hydrolase is missing, the substrate that is ordinarily catabolized accumulates in lysosomes, produc­ing marked vacuolation and destruction of cells. In the case of beta mannosidosis, the condition is inherited as an auto­somal recessive trait, transmitted with a frequency of 25% by the mating of two heterozygous parents, and the defi­cient hydrolase is beta mannosidase.

While vacuolation occurs in a wide variety of cell types, lesions are most severe in the CNS and clinical manifesta­tions of the disease in neonates are essentially neurologic. Vacuolation of neurons is accompanied by marked dysmy- elinogenesis in beta mannosidosis, but the exact relation­ship of these two findings is unresolved. One study has reported that greater accumulation of oligosaccharide at various locations in the CNS is not directly associated with the severity of myelin deficiency at those sites (Boyer et al. 1990).

Clinical Findings

The clinical presentation is consistent (Kumar et al. 1986). Affected kids of either sex are born alive. They are unable to rise and lie in lateral recumbency or drag themselves along if placed sternally. They have contracted tendons with carpal flexion, hindlimb extension, and hyperexten­sion of the pastern joints. Withdrawal reflexes are intact. There is a varying degree of facial dysmorphism, including a domed skull, an elongated and narrow muzzle, small slit­like palpebral fissures, enophthalmos, and a depressed nasal bridge. Most, if not all, affected kids are deaf, though this may be difficult to establish. Bilateral ptosis as part of Horner's syndrome is present. Pendular nystagmus and intention tremors may be observed. The skin is thickened, and the muscle mass may be decreased. Affected kids can see, smell, suckle, defecate, and urinate normally and may survive for several weeks with nursing care.

Clinical Pathology and Necropsy

The hemogram and serum chemistry profile are normal. Despite the facial dysmorphism and locomotor difficulties, radiographs of the skull, vertebrae, and long bones are nor­mal.

Techniques for measuring plasma beta mannosidase activity have been developed and can be used as an aid to distinguish normal goats from affected goats and heterozy­gous carriers (Healy and McCleary 1982; Cavanagh et al. 1983). Using a fluorometric technique, affected kids have markedly reduced or absent activity, with measure­ments below 0.2 U/L, while the activity of heterozygous car­riers is always below 2.4U/L and frequently below 1.7 U/L (Healy and McCleary 1982). Most normal, adult non-carrier goats have activity greater than 2.1 U/L, but some may meas­ure as low as 1.7U/L, giving false-positive results. In screen­ing for heterozygous carriers, false-positive identification rates as high as 12% can occur in goat populations when 2.1 U/L is used as the discriminant value and 2% when 1.7 U/L is used (Sewell and Healy 1985). Laboratory values for plasma beta mannosidase activity have also been reported for normal kids in the range of 66-222nmol/hour/mL (Cavanagh et al. 1982). Clinically affected homozygous kids have no beta mannosidase activity in plasma and heterozy­gous carriers have intermediate activity. In one study, hete­rozygous carriers had activity measurement that averaged 47% of that of normal goats (Sewell and Healy 1985).

While there is conflicting information on the effect of reproductive status and sex on beta mannosidase activity, the activity is known to decrease with increasing age, up to but not after sexual maturity (Dunstan et al. 1983; Sewell and Healy 1985). Severe stresses such as transport and shearing can reduce activity into the heterozygous suspect range, so blood samples should not be taken from goats immediately after obvious stressors (Mason 1986).

Affected kids also have the abnormal oligosaccharides betamannosyl-(1-4)-N-acetylglucosamine and betamannosyl- (1-4)-N-acetylglucosaminyl-(1-4)-N-acetylglucosamine pre­sent in the urine (Matsuura et al.

At necropsy, muscles appear pale and small. When the contracted tendons are cut, joint motion is unimpaired. The most prominent gross lesions are in the brain. Ventricular dilation is observed in association with a marked diminution of white matter because of a paucity of myelin, especially in the cerebrum. There is also polypoid hypertrophy of the middle ear mucosa (Jones et al. 1983).

Histologically, the disease is characterized by fine to coarse vacuolation of a wide variety of cell types in all tis­sues. These are lysosomal storage vacuoles. Fibroblasts, macrophages, and endothelial and perithelial cells are most consistently affected in all tissues. In the CNS there is vacuolation of virtually all cell types. In addition, there is marked demyelination, especially in the brain and to a lesser extent in the spinal cord, and axonal spheroids occur throughout the white matter. Mineralization may be seen, especially in the cerebellum and globus pallidus (Lovell and Jones 1983). Ocular lesions have also been described (Render et al. 1989).

Diagnosis

The diagnosis is based on the characteristic presentation in newborn kids of Nubian descent, confirmation of reduced beta mannosidase activity in plasma or abnormal oligosac­charides in urine, and characteristic histology at necropsy.

Differential diagnoses include hydrocephalus, congenital spinal malformations or trauma at birth, Akabane disease, Cache Valley virus infection, border disease, swayback, and mucopolysaccharidosis IIID, the other inherited lysosomal storage disease that occurs in the Nubian goat breed and presents with neurologic signs.

Treatment and Control

There is no treatment for this condition. Control in indi­vidual herds depends on diagnosis of the condition in new­born kids and removal of the parents of affected kids from the breeding program. Goat owners purchasing Nubian goats for breeding purposes may want to screen for hete­rozygous carriers by assaying plasma beta mannosidase activity.

Mucopolysaccharidosis IIID

Mucopolysaccharidosis IIID (MPS IIID) is an inherited lysosomal storage disease first described in human beings and later recognized in the Nubian breed of goats (Thompson et al. 1992). In human medicine the condition is also known as Sanfilippo D syndrome and Nubian goats are now used as a model for studying the human disease.

MPS IIID is caused by a deficiency in N-acetylglucosamine 6-sulfatase (G6S) activity in lysosomes that results from a nonsense mutation in the 5' region of the gene coding for expression of this enzyme. The result of this enzyme defi­ciency is that the catabolism of glycosaminoglycans (GAG) is disrupted, so that N-acetylglucosamine 6-sulfate and heparan sulfate accumulate in the tissues and urine of affected individuals. While multiple tissues are affected, the lysosomal accumulation of these GAG in the CNS is mostly responsible for the clinical manifestations seen in humans and Nubian goats. The key lesions seen in the CNS of affected goats are primarily the neuronal accumulation of heparan sulfate and the excess storage of gangliosides in cerebral cortical and spinal cord gray matter, as well as dys- myelination (Jones et al. 1998).

The pattern of inheritance for MPS IIID is autosomal recessive, with individuals homozygous for the defective gene expressing the disease condition. In a Michigan study of 552 Nubians using a G6S PCR-based mutation test, 25.2% of animals tested were identified as heterozygous carriers and 1.3% were homozygous for the mutation (Hoard et al. 1998).

There is phenotypic variation in MPS IIID disease expression, with mild and severe forms recorded in homozygous Nubian goats (Jones et al.

Differential diagnosis for newborn kids should include congenital copper deficiency, congenital skeletal abnor­malities such as hemivertebra, hydrocephalus, and beta mannosidosis, the other lysosomal storage disease that occurs only in Nubian goats. Akabane virus infection and Cache Valley virus infection can also produce kids unable to rise at birth, but these kids have arthrogryposis, which is not reported in MPS IIID. When progressive neurologic signs appear in adult goats, scrapie must be considered as well as coenurosis where it occurs. The differential diagno­sis for animals showing poor growth and decreased muscle mass should include the various nutritional, infectious, and parasitic diseases discussed in Chapter 15 relative to wasting.

Testing for the presence of the G6S mutation using RT- PCR can be performed on white blood cells harvested at the laboratory from 1 to 2 mL of blood collected in EDTA. The Texas Veterinary Medical Diagnostic Laboratory currently performs this test in the United States. The University of California Davis Veterinary Genetics Laboratory also offers a genetic test for this con­dition, but uses hair roots as the submitted sample rather than blood. The condition can be controlled through breeding based on the G6S mutation status of breeding stock determined through testing. There is no treatment for the condition.

Progressive Paresis of Angora Goats

Ataxia, first noted at approximately 4 months of age, has been seen in Angora goat kids from serial litters of the same parentage in Australia. Kids had normal mental status, cra­nial nerve function, and reflexes, but exhibited signs of weakness including difficulty in rising, a reluctance to move, and stumbling when forced to do so. Weakness was more apparent in the hindlimbs than the forelimbs.

Though clinically similar to enzootic ataxia or CAE, this condition has characteristic pathologic findings. No gross lesions were observed except muscle atrophy. Microscopic lesions were characterized by the occurrence of large cyto­plasmic vacuoles in large neurons of the midbrain, brain stem, and ventral horns of the spinal cord. Chromatolysis and pyknosis were also observed. The history of reoccur­rence of the condition in kids from serial litters of the same parentage suggested a hereditary basis for the condition, though the pathogenesis of the disease remains unclear (Lancaster et al. 1987).

Spastic Paresis

This condition is well known in cattle and is considered to be inherited in that species. Spastic paresis is charac­terized by intermittent unilateral or bilateral spastic contracture of the gastrocnemius muscle, leading to hyperextension of one or both hindlimbs. The hyperex - tension may be so extreme that the animal is unable to place the foot on the ground and the leg is carried straight behind. The hock is straight and the gastrocnemius mus - cle is palpably firm or knotted. It has been demonstrated that selective depression of gamma efferent neurons in the spinal cord by epidural administration of dilute pro - caine alleviates the condition, indicating that the disor­der occurs from overstimulation of the myotatic (stretch) reflex (De Ley and De Moor 1980).

Reports of the condition in goats are infrequent. The condition was first reported in Czechoslovakia in 1973 and involved a 3-year-old male Saanen (Kral and Hlousek 1973). The goat was reluctant to stand and when forced to do so remained on its carpi with rump in the air, hindlimbs over­extended with the hocks straight, and the gastrocnemius tendons palpably taut. Though the diagnosis could not be confirmed, tibial neurectomy, as frequently applied in cat­tle, corrected the condition.

The condition also has been reported in two familially related pygmy goats in the United States (Baker et al. 1989). In these cases, the diagnosis was supported by application of a dilute procaine epidural with subsequent alleviation of signs. Despite this evidence of spastic pare­sis in goats, the diagnosis must be made with caution because of the hereditary implications of the disease, which are not well defined in the caprine species. The author (DMS) has observed at least two goats with cla.ssi- cally described signs of spastic paresis that turned out to be cases of the arthritic form of CAE. The occurrence of joint pain without joint swelling is not uncommon in CAE and could lead to abnormalities of gait and posture that can mimic spastic paresis.

Hydrocephalus and Hydranencephaly

Hydrocephalus occurs sporadically in goats as a develop­mental anomaly resulting in improper drainage of the CSF. This causes increased intracerebral pressure, with thinning of the cerebral cortices, expansion of the ventri­cles, and possible distortion of the skull surrounding the brain. Affected kids can be delivered dead or alive. Live kids are usually dull and blind with pronounced muscular weakness; they are unable to stand unassisted or ambulate (Figure 5.8). Obvious doming of the skull is variable and does not have to be present to make a diagnosis of hydro­cephalus. Hydranencephaly, which is a normotensive hydrocephalus that results from necrosis or a failure of cell growth, occurs in goats in conjunction with arthrogryposis as a result of fetal Akabane virus infection or Cache Valley virus infection, as discussed in Chapter 4. Kids with hydra- nencephaly have neurologic deficits similar to those seen in hydrocephalus.