Generalized Metabolic and Degenerative Disorders in Dogs and Cats
Canine Multiple System Degeneration
Canine multiple system degeneration has been identified in Kerry Blue Terriers and Chinese Crested dogs.
Clinical signs reflect both cerebellar and brainstem dysfunction, including ataxia, dysmetria, and festination (a quick, shuffling, short-stepped gait).
The disorder is inherited as an autosomal recessive mutation.
The age of onset is approximately 4 months, with severe progression by the age of 12–18 months.
There is no treatment.
Multisystemic Chromatolytic Neuronal Degeneration in Cairn Terriers
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.
No treatment is available, and this disease typically results in euthanasia or death.
Multisystemic Neuronal Degeneration in Dogs
Multisystemic neuronal degeneration has been reported in red-haired Cocker Spaniels and causes abnormal behavior and cerebellar signs. Neuronal changes occur in various brainstem nuclei.
A similar condition occurs in Miniature Poodles at the age of 3–4 weeks with signs of rolling from side to side, an inability to stand or right itself into a sternal position, periodic opisthotonos, intention tremors, and lack of a menace response associated with neuronal degeneration in the cerebral cortex and cerebellum.
Regardless of the dog breed affected, no treatment is available, and this disease typically results in euthanasia or death.
Familial Cerebellar Ataxia With Hydrocephalus in Bullmastiffs
Familial cerebellar ataxia with hydrocephalus in Bullmastiffs (mitochondrial fission encephalopathy) has autosomal recessive inheritance and results in blindness, abnormal behavior, and cerebellar signs. Bilaterally symmetrical spongiform lesions and astrogliosis occur in the deep cerebellar nuclei. Some reported cases also show abnormal myelin.
No treatment is available, and this disease typically results in euthanasia or death.
Hereditary Cavitating Leukodystrophy in Dalmatians
Dalmatian leukodystrophy is a very rare inherited condition that causes visual deficits with progressive ataxia and tetraparesis at the age of 3–6 months.
Clinical signs include dilatation of ventricles, cavitation of cerebral white matter, and widespread loss of myelin.
No treatment is available, and this disease typically results in euthanasia or death.
Central Axonopathy in Scottish Terriers
Central axonopathy in Scottish Terriers causes tremors, ataxia, and paraparesis in affected dogs. It shows similarities to neuraxonal dystrophies.
Histological evaluation shows diffuse white matter degeneration in the brain and spinal cord.
The age of onset is 10–12 weeks, and signs are progressive.
No treatment is available.
Fibrinoid Leukodystrophy in Dogs
Fibrinoid leukodystrophy (Alexander disease) is an inherited disease affecting the brain and spinal cord that has been described in Labrador Retrievers, Scottish Terriers, Miniature Poodles, Bernese Mountain Dogs, and French Bulldogs. The age of onset is 2 months to 4 years.
Clinical signs include progressive ataxia and tetraparesis, with personality changes. Rosenthal fibers occur around blood vessels of the CNS, and the cause seems to be a disorder of astrocyte function.
The prognosis is poor.
Several mutations have been identified, most of which are associated with the GFAP protein.
Spongiform Degenerative Conditions in Dogs and Cats
Spongiform degenerative conditions have been described in young dogs and cats and are often associated with signs of ataxia/hypermetria, head tremors, intermittent contractures, postural abnormalities, and behavioral changes.
Affected dog breeds include the Labrador Retriever, Shetland Sheepdog, Samoyed, Silky Terrier, Bullmastiff, Saluki, Cocker Spaniel, Malinois-Shepherd crosses, Rottweiler, and Border Terrier; cat breeds include the Egyptian Mau and Burmese.
The underlying pathological basis relates to spongy degeneration of either white or gray matter. The pathogenesis of spongiform degenerative disorders remains uncertain; however, a genetic mutation has been identified for a family of Australian Cattle Dogs, Shetland Sheepdogs, and Belgian Shepherd dogs.
The prognosis is poor.
Hereditary Quadriplegia and Amblyopia in Irish Setters
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" because of the way they move around on their bellies.
No treatment is available, and this disease typically results in euthanasia or death.
Alaskan Husky Encephalopathy
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.
The age of onset is 7 months to 2.5 years.
Clinical signs consist of acute-onset ataxia, seizures, behavior abnormalities, blindness, facial hypalgesia, and difficulty eating. Histopathological lesions are bilaterally symmetrical and identified in the cerebrum, thalamus, basal nuclei, midbrain, pons, medulla, and cerebellum.
No treatment is available, and this disease typically results in euthanasia or death.
A similar disease has been described in Yorkshire Terriers, but a genetic mutation has not yet been identified in this breed.
Degenerative Encephalopathy in Nova Scotia Duck Tolling Retrievers
Degenerative encephalopathy of Nova Scotia Duck Tolling Retrievers is an autosomal recessive, inherited disease resulting in neurological dysfunction and a rapid eye movement (REM) sleep disorder. The age of onset is 2 months to 5 years.
Lesions are bilaterally symmetrical and affect gray matter in the brain. Caudate nuclei are primarily affected, with axonal dystrophy in the brainstem and spinal cord.
Clinical signs are progressive and most prominently include a REM sleep disorder, in which motor function is not suppressed by the brainstem during REM sleep. Additional clinical signs can include anxiety and obsessive-compulsive tendencies, ataxia, tetraparesis, and mild hypermetria.
The prognosis is guarded, but supportive care and antiepileptic medications might help.
A genetic test is available.
-2-Hydroxyglutaric Aciduria in Dogs
L-2-Hydroxyglutaric aciduria is an inherited metabolic disease of dogs that is 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 can include seizures, ataxia, aggression, and hyperactivity.
The age of onset is approximately 8 months.
Lesions are bilaterally symmetrical 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; however, a mutation has not been described in West Highland White Terriers.
No treatment is available, and this disease typically results in euthanasia or death
Lysosomal Storage Disorders
Lysosomal storage disorders are a clinically rare group of degenerative conditions that result either from deficiency of an enzyme essential for the metabolism of a protein, carbohydrate, or lipid substrate, or from buildup of a by-product that can be toxic to cells.
Clinical signs usually appear early in life; occasionally, however, the onset is delayed.
Each specific lysosomal storage disorder has been associated with a particular breed. In theory, however, any breed could develop any one of these disorders, and many of them have been described in more than one breed.
Considerable phenotypic variation should be expected beyond the typical signs described below.
The prognosis is poor for any small animal that has a lysosomal storage disorder; however, gene replacement therapies are being actively investigated.
Diagnostic testing is limited, except for diseases in which the enzyme or mutation has been identified or the pattern of organic acids has been recognized. DNA or enzymatic tests are available for many lysosomal storage disorders.
Abnormal MRI findings can be detected in some lysosomal storage disorders; however, they are not sensitive or specific. Testing often includes urine metabolic screening, lysosomal enzyme screening, histological evaluation for specific characteristics in tissue biopsy, or DNA testing for known mutations. Genetics laboratories should be consulted for current testing availability.
Sphingolipidoses in Dogs and Cats
Globoid Cell Leukodystrophy in Dogs and Cats
Globoid cell leukodystrophy (Krabbe disease) is an inherited disease characterized by loss of galactosylceramide beta-galactosidase enzyme activity. The disease occurs mainly in Cairn Terriers 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 occurs by itself or it is combined with cerebellar disturbance. Death occurs 2–3 months after the onset of signs.
The total protein content of the CSF can be increased in cases of globoid cell leukodystrophy. Large globoid cells are distributed perivascularly throughout the white matter of the spinal cord and brain. Antemortem diagnosis can be based on genetic testing. Adeno-associated viral gene therapy has been shown to provide some amelioration of signs in dogs.
GM Gangliosidosis in Dogs and Cats
GM1 gangliosidosis (Derry disease) is a fatal, progressive disease caused by mutation in the beta-galactosidase gene (GLB1).
The disease occurs primarily in cats, particularly Asian breeds (Balinese, Javanese, Korat, Oriental Shorthair, Peterbald, Seychellois, Siamese, Thai, and Tonkinese), and in Beagles, Portuguese Water Dogs, English Springer Spaniels, Alaskan Huskies, and Shiba Inus.
Signs of cerebellar dysfunction predominate, and corneal clouding can develop.
Diagnosis is based on genetic testing.
Intraventricular cerebral injection of adeno-associated virus (AAV) gene therapy can result in partial response.
GM Gangliosidosis in Dogs and Cats
GM2 gangliosidosis (Sandhoff disease, Tay-Sachs disease) has been reported in German Shorthaired Pointers, a Japanese Spaniel, Shiba Inus, Japanese Chins, mixed-breed cats, and Korat cats.
The age of onset is 6 months, and clinical signs include behavioral changes and visual disturbances. Progressive ataxia and dementia develop later.
Clinical signs of ataxia, hypermetria, head tremor, and corneal opacity develop in kittens at approximately 3 months of age.
Tay-Sachs disease is associated with a mutation in the HEXA gene; Sandhoff disease is associated with a mutation in the HEXB gene.
A genetic test is available for antemortem diagnosis.
Niemann-Pick Disease in Cats
Niemann-Pick disease is an inherited disease in cats caused by a mutation in the NPC2 gene. It results in cerebellar dysfunction with an associated abdominal enlargement due to hepatosplenomegaly.
Neurological 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 might stabilize the disease.
Glucocerebrosidosis in Silky Terriers
Glucocerebrosidosis (Gaucher disease) is a rare disorder of Australian Silky Terriers that produces multifocal signs, with cerebellar ataxia, tremors, and hyperactivity predominating.
The age of onset is 4–6 months.
Glycoproteinoses in Small Animals
Fucosidosis of English Springer Spaniels
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 or visual deficits, and seizures.
Signs tend to progressively develop from the age of 6 months to > 24 months, and the disease is ultimately fatal.
A high proportion of peripheral lymphocytes can show cytoplasmic vacuolation. DNA testing is available.
The prognosis is poor, and the only currently available treatment in dogs, although impractical, is bone marrow transplantation. Intracisternal enzyme infusion is being investigated as a possible treatment.
Alpha-Mannosidosis in Cats and Guinea Pigs
Alpha-mannosidosis has been reported mainly in cats and cattle, and less commonly in guinea pigs.
Clinical signs include retinal and skeletal abnormalities, as well as neurological deficits. Cerebellar signs are the most consistent feature of the otherwise somewhat variable neurological 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 in Dogs
Beta-mannosidosis is more commonly identified in goats and cattle, as well as in humans, than in small animals. 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 in Dogs and Cats
Mucopolysaccharidosis is primarily a disorder of cats, but some subtypes affect dogs. The 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 have been reported: I, II, III VI, and VII. Mucopolysaccharidosis 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.
Mucopolysaccharidosis VII is associated with mutations in the beta-d-glucuronidase gene (GUSB), resulting in accumulation of glycosaminoglycans. One of the earliest signs of this type is failed initiation of secondary ossification centers in the vertebrae and long bones. The skeletal changes are nonprogressive after the age of 9 months, and decompressive surgery can improve the neurological deficits.
A genetic test is available.
Enzyme replacement therapy or adenoviral- and retroviral-based gene therapy might have some benefit in some types of mucopolysaccharidosis.
Glycogen Storage Disorders in Dogs and Cats
Glycogenosis in Dogs and Cats
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 Shepherd Dogs and Akitas), IV (Norwegian Forest Cats; autosomal recessive), and VII (English Springer Spaniels).
Clinical signs generally include generalized myopathy, weakness, exercise intolerance, muscle tremors, or dysphagia.
Mucolipidosis II in Cats
Mucolipidosis II is an autosomal recessive disease that affects domestic shorthair cats and generally causes skeletal malformations.
Clinical signs are apparent from birth and include dull mentation, failure to thrive, facial dysmorphia, and ataxia.
Radiographically, metaphyseal flaring, radial bowing, joint laxity, and vertebral fusion can be evident.
Retinal degeneration and blindness can occur by the age of 4 months.
Lafora Disease in Dogs
Lafora disease (named for Lafora bodies, which are insoluble clumps of glycogen that accumulate in neurons) occurs most commonly in miniature wirehaired Dachshunds; however, it can also affect other breeds, such as Basset Hounds, Beagles, Poodles, Chihuahuas, and mixed-breed dogs. It is best 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 of Lafora disease can include myoclonic seizures that begin late in life and, in some cases, can be triggered by visual or auditory stimuli. Other clinical examination findings are not commonly reported.
Less Common Storage Disorders in Dogs and Cats
Neuronal Ceroid Lipofuscinosis in Dogs and Cats
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 many other breeds of dogs, as well as in Siamese cats.
Clinical signs are characterized by behavioral changes, aggression, and central blindness. Some animals also exhibit ataxia, hypermetria, tremors, or seizures.
Neuronal ceroid lipofuscinosis is a late-onset disease, with clinical signs typically appearing at the age of 12–24 months and some forms occurring earlier or later. Clinical signs progress slowly, over several years.
Genetic mutations (CLN5, CLN7, CLN8, MFSD8, PPT1, and others) 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; however, gene therapy is being investigated.
Key Points
Errors of inborn metabolism in small animals most commonly present as a multifocal disorder, affecting multiple parts of the nervous system.
The hallmark of lysosomal storage disorders is accumulation of waste products from the metabolism of fat (sphingolipidoses), protein (glycoproteinoses, mucopolysaccharidoses), or carbohydrate (glycogen storage disorders) within cells.
Generalized disorders in small animals are commonly fatal, and no treatment options are currently available.
Most metabolic and lysosomal storage disorders require histological evaluation for diagnosis.
Blood and urine testing for metabolite concentrations or genetic mutations and MRI can provide an antemortem diagnosis.
For More Information
Skelly BJ, Franklin RJM. Recognition and diagnosis of lysosomal storage diseases in the cat and dog. J Vet Intern Med. 2002;16(2):133-141.
Sewell AC, Haskins ME, Giger U. Dried blood spots for the enzymatic diagnosis of lysosomal storage diseases in dogs and cats. Vet Clin Pathol. 2012;41(4):548-557.
Dewey CW, Da Costa RC, eds. Practical Guide to Canine and Feline Neurology. 3rd ed. Wiley Blackwell; 2016.
Also see pet owner content regarding brain, spinal cord, and nerve disorders of dogs and cats.
