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Congenital and Inherited Multifocal Disorders of the Nervous System in Animals

By

Rebecca A. Packer

, MS, DVM, DACVIM (Neurology), College of Veterinary Medicine and Biomedical Sciences, Colorado State University

Last full review/revision Sep 2020 | Content last modified Sep 2020

Large Animals

Shaker calf syndrome is a neurodegenerative disorder that is seen in Hereford calves. Affected animals show a marked tremor within hours of birth, difficulty in rising, a stiff gait, and loss of voice; signs progress to spastic paraplegia. There is excessive accumulation of neurofilaments within neurons of the central, peripheral, and autonomic nervous systems.

Vitamin A deficiency of sows can cause incoordination, head tilt, pelvic limb paralysis, paddling, and ocular lesions in piglets. Severe eye, skull, and brain abnormalities are seen in congenitally-affected calves born from vitamin A-deficient dams. Because these are congenital abnormalities in offspring of vitamin-deficient sows or dams, there is no treatment for the affected offspring. Treating deficient sows and dams may prevent this congenital abnormality in offspring.

Generalized Metabolic and Lysosomal Storage Disorders

Maple syrup urine disease is an autosomal recessive disease that causes an amino aciduria as a result of a deficiency of the mitochondrial enzyme branched-chain ketoacid decarboxylase (BCKADH) in Hereford calves. Affected calves are dull, become recumbent in 2–4 days, and terminally have opisthotonos. The histologic lesions are severe and consist of generalized status spongiosus in the CNS.

Sphingolipidoses

Globoid cell leukodystrophy is an inherited disease characterized by lesions in the cerebellum, pons, medulla, and spinal cord, characterized by demyelination and named for the perivascular accumulation of macrophages (globoid cells). reported in polled Dorset sheep 4–18 months old. Exaggerated tendon reflexes, ascending paralysis, and cerebellar signs may be seen. Galactosylceramide beta-galactosidase enzyme activity in affected animals is <6% of controls.

GM1gangliosidosis is seen in inbred Friesian calves. Clinical signs become evident during the first week of life and include depression, swaying of the hindquarters, reluctance to move, and stiffness. Death occurs in 6–8 months.

GM2gangliosidosis causes hypermetria and weakness in Yorkshire piglets within the first 3 months of life. Death occurs in 4–6 months.

Glycoproteinoses

Alpha-Mannosidosis (autosomal recessive) is seen in Angus, Murray Grey, and Galloway breeds. It produces ataxia, head tremor, aggression, and failure to thrive. There may also be abortions and neonatal death. Most affected calves die within the first year, sometimes shortly after birth. Affected (homozygous) calves have an absolute deficiency of alpha-mannosidase, and heterozygotes are partially deficient. Mannosidosis can be controlled by identifying and eliminating heterozygotes on the basis of biochemical testing. Two mutations have been identified in cattle, one lethal and one nonlethal (but pathologic).

Beta-Mannosidosis occurs in Nubian goats and Salers calves. Clinical signs may be apparent at birth and include the inability to stand, intention tremors, joint contractures, facial dysmorphisms, domed skull, and hypothyroidism. The condition is usual fatal within hours of birth, with some animals surviving weeks to months with supportive care.

Mucopolysaccharidoses

Bovine mucopolysaccharidosis type IIIB has been reported in a herd of cattle. Onset is typically from 2 years of age and consists of progressive ataxia, stumbling, and swaying. Signs progress over the lifespan of the animal. Disease is caused by a missense mutation in the NAGLU gene.

Glycogen Storage Disorders

Polysaccharide storage myopathy (PSSM)Type I and Type II, is an autosomal dominant inherited glycogen storage disorder identified in several breeds of horses, including Warmbloods, Quarter horses, Cob Normand and Belgian draft horses, and others. A gain of function mutation in the GYS1 gene is associated with disease. Muscle glycogen concentrations are often increased in Type I, and this form is a common cause of exertional rhabdomyolysis. Type II horses often exhibit stiffness and gait abnormalities despite normal CK and AST levels and may have increased muscle glycogen concentrations. Clinical signs begin at approximately 6 years of age with a decline in performance. A diet with long-chain fatty acids as opposed to triheptanoin or corn oil minimizes the insulin stimulation and clinical signs of PSSM.

Other Storage Disorders

Neuronal ceroid lipofuscinosis (Batten disease) is seen in sheep, cattle, and goats, characterized by brain and retinal atrophy and deposition of lipofuscin. A number of genetic mutations in the lysosomal coding genes have been identified in various species and breeds (CLN1, CLN5, CLN 6, et al). Clinical signs may vary among species. Young Nubian goats show cerebellar signs. Rambouillet sheep show blindness and decreased mentation from 8 months of age. South Hampshire lambs 9–12 months old show blindness, depression, head and thoracic limb tremor, and facial twitching and die by 30 months of age. Devon cattle become blind and weak by 14 months and die by 4 years of age. Currently, no treatment exists, although gene therapies are being investigated.

Small Animals

Canine multiple system degeneration has been identified in Kerry Blue Terriers and Chinese Crested dogs. Clinical signs reflect both cerebellar and brain stem dysfunction, including ataxia, dysmetria, and festination. The disorder is inherited as an autosomal recessive mutation. Onset of clinical signs is approximately 4 months, with severe progression by 12–18 months of age. There is no treatment.

Multisystemic chromatolytic neuronal degeneration in Cairn Terriers causes paraparesis in young puppies that progresses rapidly to produce cerebellar involvement with bouts of cataplectic collapse. Degeneration of neurons is widespread in the brain, spinal cord, and sensory ganglia.

Multisystem neuronal degeneration has also been reported in red-haired Cocker Spaniels and causes abnormal behavior and cerebellar signs. Neuronal changes are found in various brain-stem nuclei. A similar condition is seen in Miniature Poodles (3–4 weeks) with signs characterized by rolling from side to side, inability to stand or right into sternal position, periodic opisthotonos, intention tremors, and lack of a menace response associated with neuronal degeneration in the cerebral cortex and cerebellum.

Familial cerebellar ataxia with hydrocephalus in Bull Mastiffs is an inherited disorder that results in blindness, abnormal behavior, and cerebellar signs. Bilaterally symmetric spongiform lesions and astrogliosis are found in the deep cerebellar nuclei. Some reported cases also show abnormal myelin.

Dalmatian leukodystrophy is a rare inherited condition that causes visual deficits with progressive ataxia and tetraparesis at 3–6 months of age. There is dilatation of ventricles, cavitation of cerebral white matter, and widespread loss of myelin.

Central axonopathy in Scottish Terriers causes tremors, ataxia, and paraparesis in affected dogs. It shows similarities to the neuroaxonal dystrophies. Histopathology shows diffuse white matter degeneration in the brain and spinal cord. Onset of clinical signs is 10–12 weeks of age, and signs are progressive. No treatment is available.

Fibrinoid leukodystrophy (Alexander disease) is an inherited disease affecting the brain and spinal cord and has been described in Labrador Retrievers, Scottish Terriers,Miniature Poodles,Bernese Mountain dogs, and French Bulldogs. Age of onset is 2 months to 4 years. Clinical signs include progressive ataxia and tetraparesis with personality changes. Rosenthal fibers are found around blood vessels of the CNS, and the cause seems to be a disorder of astrocyte function. Prognosis is poor. Several mutations have been identified, most of which are associated with the GFAP protein.

Spongiform degenerative conditions have been described in young dogs and cats (breeds include Labrador Retriever, Shetland Sheepdog, Samoyed, Silky Terrier, Bull Mastiff, Saluki, Cocker Spaniel, Malinois-Shepherd crosses, Rottweiler, Border Terriers, and Egyptian Mau and Burmese kittens) and are often associated with signs of ataxia/hypermetria, head tremors, intermittent contractures, postural abnormalities, and behavioral changes. The underlying pathology relates to spongy degeneration of either white or gray matter. The pathogenesis of these disorders remains uncertain, although a genetic mutation has been identified for a family of Australian Cattle Dogs, Shetland Sheepdogs, and Belgian Shepherd dogs. Prognosis is poor.

Hereditary quadriplegia and amblyopia in Irish Setters is an autosomal recessive, homozygous lethal mutation. Clinical signs include head tremor, visual impairment, nystagmus, inability to stand, and seizures beginning at birth. Animals are called "swimmers" due to their method of moving around on their bellies.

Alaskan Husky encephalopathy (Leigh-like syndrome) is an autosomal recessive disease resembling Leigh syndrome. The disease is caused by a mutation in a thiamine transporter gene (SLC19A3), which results in encephalopathy due to impaired thiamine uptake. Onset of clinical signs is 7 months to 2.5 years, and signs consist of acute onset ataxia, seizures, behavioral abnormalities, blindness, facial hypalgesia, and difficulty eating. Histologic lesions are bilaterally symmetric and identified in cerebrum, thalamus, basal nuclei, midbrain, pons, medulla, and cerebellum. Yorkshire Terriers have been described with a similar disease, although a genetic mutation has not yet been identified in this breed.

Degenerative encephalopathy of Nova Scotia Duck Tolling Retrievers is an autosomal recessive, inherited disease resulting in neurologic dysfunction and a rapid eye movement (REM) sleep disorder. Onset of clinical signs is 2 months to 5 years, Lesions are bilaterally symmetric and affect gray matter in the brain. Caudate nuclei are primarily affected, with axonal dystrophy in the brain stem and spinal cord. Clinical signs are progressive and most prominently include an REM sleep disorder, in which motor function is not suppressed by the brain stem during REM sleep. Additional clinical signs may include anxiety and obsessive-compulsive tendencies, ataxia, tetraparesis, and mild hypermetria. A genetic test is available.

L-2-hydroxyglutaric aciduria is an inherited metabolic disease caused by a mutation in the L2HGDH gene. Diagnosis is supported by increased concentrations of L-2-hydroxyglutaric acid in the urine on organic acid screens. Clinical signs may include seizures, ataxia, aggression, and hyperactivity and appear at approximately 8 months of age. Lesions are bilaterally symmetric and apparent in gray matter of the thalamus, cerebral cortex, and cerebellum. Yorkshire Terriers, Staffordshire Bull Terriers, and West Highland White Terriers are known to be affected, though a mutation has not been described in West Highland White Terriers.

Lysosomal Storage Disorders

This clinically rare group of conditions results from deficiency of an enzyme that is essential for the metabolism of a protein, carbohydrate, or lipid substrate, or results from buildup of a byproduct that can be toxic to cells. Clinical signs usually appear early in life, although occasionally the onset is delayed. Specific diseases have been associated with a particular breed, but in theory, any breed could develop any one of these disorders, and many have been described in more than one breed. Considerable phenotypic variation should be expected beyond the classic signs described below.

Prognosis is poor for all of these disorders, although gene replacement therapies are being actively investigated. Diagnostic testing is limited except for those diseases in which the enzyme or mutation has been identified or the pattern or organic acids has been recognized. Currently, many lysosomal storage disorders have DNA or enzymatic tests available. Abnormal MRI findings may be detected in some lysosomal storage disorders but are not sensitive or specific. Testing often includes urine metabolic screening, lysosomal enzyme screening, histopathology for specific characteristics in tissue biopsy, or DNA testing for known mutations. Genetics laboratories should be checked for current testing availability.

Sphingolipidoses

Globoid cell leukodystrophy (Krabbe disease) is an inherited disease characterized by loss of galactosylceramide beta-galactosidase enzyme activity. The disease is seen mainly in Cairn and West Highland White Terriers as well as several other breeds of dogs and cats. Clinical signs are variable and multifocal, and either an ascending paralysis is seen by itself or combined with a cerebellar disturbance. Death occurs 2–3 months after the onset of signs. Total protein content of CSF may be increased. Large globoid cells are distributed perivascularly throughout the white matter of the spinal cord and brain. Antemortem diagnosis may be made by genetic testing. Adeno-associated viral gene therapy has shown some amelioration of signs in dogs.

GM1gangliosidosis (Derry disease) is a fatal, progressive disease caused by mutation in the beta-galactosidase (GLB1) gene. The disease is seen primarily in cats, particularly Oriental breeds, and in Beagles, Portuguese Water Dogs, English Springer Spaniels, Alaskan Huskies, and Shibas. Signs of cerebellar dysfunction predominate, and corneal clouding may develop. Diagnosis is made by genetic testing. Intraventricular cerebral injection of adeno-associated virus (AAV) gene therapy may result in partial response.

GM2gangliosidosis or familial amaurotic idiocy (Sandhoff disease, Tay-Sachs disease) has been seen in German Shorthaired Pointers, Japanese Pointers, Shiba Inu, Japanese Chin, mixed-breed cats, and Korat cats. Clinical signs seen at 6 months of age include behavioral change and visual disturbances. Progressive ataxia and dementia develop later. Clinical signs of ataxia, hypermetria, head tremor, and corneal opacity develop in kittens at ~3 months of age. Tay-Sachs disease is associated with a mutation in the HEXA gene, and Sandhoff disease is associated with a mutation in the HEXB gene. A genetic test is available for antemortem diagnosis.

Niemann-Pick disease is an inherited disease in cats caused by a mutation in the NPC2 gene, and it results in cerebellar dysfunction with an associated abdominal enlargement due to hepatosplenomegaly. The neurologic deficits tend to vary with the six subtypes of this disease, ranging from severe cerebellar-like signs (types A and C) to neuropathic signs (type A variant). Intrathecal infusion of 2-hydroxylpropyl-beta-cyclodextrin in cats with Type C1 may stabilize the disease.

Glucocerebrosidosis (Gaucher disease) is a rare disorder of Australian Silky Terriers that produces multifocal signs, with cerebellar ataxia, tremors, and hyperactivity predominating. The onset of clinical signs is 4–6 months of age.

Glycoproteinoses

Fucosidosis of English Springer Spaniels has been reported in Australia, New Zealand, the UK, and North America. It is characterized by clinical signs of ataxia, personality change, dysphonia, dysphagia, hearing/visual deficits, and seizures. Signs tend to progressively develop from 6 to >24 months of age, and the disease is ultimately fatal. A high proportion of peripheral lymphocytes may show cytoplasmic vacuolation. DNA testing is available. Prognosis is poor, and the only currently available treatment in dogs, although impractical, is bone marrow transplantation. Intracisternal enzyme infusion is being investigated.

Alpha-Mannosidosis has been seen mainly in cats and cattle and less commonly in guinea pigs. Clinical signs include retinal and skeletal abnormalities as well as neurologic deficits. Cerebellar signs are the most consistent feature of the otherwise somewhat variable neurologic deficits. Mutations have been identified in cattle and guinea pigs in association with this disease. Adenoviral-based gene therapy administered intrathecally has shown promise in cats.

Beta-Mannosidosis is more commonly identified in goats, cattle, and humans. One dog has been reported with central and peripheral neuropathy as a result of this condition. the age of onset in dogs is unknown because this case was found as a stray at approximately 1 year of age. A duplication mutation in the MANBA gene was identified.

Mucopolysaccharidoses (Types I, II, III, VI, VII)

Mucopolysaccharidosis is primarily a disorder of cats, although some subtypes affect dogs. This disorder is associated with a flattening of the face, corneal clouding, and multiple bone dysplasias. Plott hounds can also be affected. Several types of this disease are reported; type VI is associated with mutation in the ARSB gene and is often associated with progressive paraparesis secondary to focal bony protrusions into the vertebral canal. Type VII is associated with mutations in the beta-d-glucoronidase (GUSB) gene, resulting in accumulation of glycosaminoglycans. One of the earliest signs of Type VII is failed initiation of secondary ossification centers in the vertebrae and long bones. The skeletal changes are nonprogressive after 9 months of age, and decompressive surgery may improve the neurologic deficits. A genetic test is available. Enzyme replacement therapy or adenoviral- and retroviral-based gene therapy may have some benefit in some types of mucopolysaccharidosis.

Glycogen Storage Disorders

Glycogenosis (types II, III, IV, VII) is not well described. Glycogen storage diseases can cause muscle weakness and exercise intolerance in young dogs and cats. Examples include glycogenosis types II (Lapland dogs), III (German Shepherds and Akitas), IV (autosomal recessive in Norwegian Forest cats), and VII (English Springer Spaniels). Clinical signs generally include generalized myopathy, weakness, exercise intolerance, muscle tremors, or dysphagia.

Mucolipidosis II is an autosomal recessive disease that affects Domestic Shorthaired cats and generally causes skeletal malformations. Clinical signs are apparent from birth and include dull mentation, failure to thrive, facial dysmorphia, and ataxia. Radiographically, metaphysial flaring, radial bowing, joint laxity, and vertebral fusion may be seen. Retinal degeneration and blindness may occur by 4 months of age.

Other Storage Disorders

Neuronal ceroid lipofuscinosis (Batten disease) is an autosomal recessive disease identified in many breeds, including English Setters, Tibetan Terriers, Australian Cattle dogs, Border Collies, American Bulldogs, American Staffordshire Terriers, Miniature Schnauzers, Cocker Spaniels, Longhaired Chihuahuas, and Border Collies, and many additional breeds of dogs, as well as Siamese cats. Clinical signs are characterized by behavior changes, aggression, and central blindness. Some animals may also exhibit ataxia, hypermetria, tremors, or seizures. This is a late-onset disease, with clinical signs typically appearing at 12–24 months old, with some forms occurring earlier or later. Clinical signs slowly progress over several years. The condition is an autosomal recessive trait in many breeds, including English Setters, Tibetan Terriers, Australian Cattle Dogs, Border Collies, American Bulldogs, American Staffordshire Terriers, Miniature Schnauzers, Cocker Spaniels, Longhaired Chihuahuas, Dachshunds, Border Collies, and many additional breeds of dogs, as well as Siamese cats. Genetic mutations (CLN5, CLN7, CLN8, MFSD8, PPT1, et al), have been identified in several breeds of dogs, and genetic tests are available for many breeds. Ultimately, the disease is fatal. No treatment is available yet, although gene therapy is being investigated.

Lafora disease occurs most commonly in miniature Wirehaired Dachshunds but also can affect other breeds, such as Bassett Hounds, Beagles, Poodles, Chihuahuas, and mixed-breed dogs. It is most well known in the miniature Wirehaired Dachshund, but genetic mutations in the NHLRC1 gene have been identified in several breeds (Beagles, Chihuahuas, and miniature Wirehaired Dachshunds), and diagnosis by genetic testing is available. Clinical signs can include late-in-life onset myoclonic seizures that can, in some cases, be triggered by visual or auditory stimuli. Other clinical examination findings are not commonly reported.

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