Startle Disorders in Large Animals
Startle disorders (hereditary hyperekplexia) result from synaptopathy due to a genetic mutation in the glycine transporter. The functional absence of this key inhibitory neurotransmitter causes syndromes that include congenital myoclonus in Polled Hereford calves (GLRA1 mutation) and Peruvian Paso horses, and congenital muscular dystonia in Belgian Blue cattle (SLC6A5 mutation).
Clinical signs of startle disorders are stimulus induced and include muscle rigidity and tremor in response to tactile, acoustic, or visual stimulation. Standing and feeding are often impaired, and affected animals often die within days to weeks.
Shaker Calf Syndrome
Shaker calf syndrome is a neurodegenerative disorder that occurs in Hereford calves. Affected animals show a marked tremor within hours after birth, difficulty rising, a stiff gait, and loss of voice. Clinical signs progress to spastic paraplegia. There is excessive accumulation of neurofilaments within neurons of the central, peripheral, and autonomic nervous systems.
Vitamin A Deficiency in Large Animals
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 occur 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 might prevent this congenital abnormality in offspring.
Inborn Errors of Metabolism in Large Animals
Citrullinemia in Large Animals
Citrullinemia is a fatal, autosomal recessive, metabolic defect of Holstein calves (mainly in Australia and New Zealand) associated with cerebral cortical edema. It is due to increased citrulline in plasma, caused by deficiency of the urea cycle enzyme argininosuccinate synthetase.
Calves with citrullinemia appear healthy at birth but die of acute neurological disease within 1–4 days. Clinical signs are sudden in onset and consist of depression, aimless wandering, blindness, seizures, opisthotonos, and recumbency. A genetic test is available.
Maple Syrup Urine Disease in Hereford Calves
Maple syrup urine disease is an autosomal recessive disease that causes amino aciduria as a result of a deficiency of the mitochondrial enzyme branched-chain ketoacid decarboxylase (BCKDH) in Hereford calves. Affected calves are dull, become recumbent in 2–4 days, and terminally have opisthotonos. Histopathological lesions are severe and consist of generalized status spongiosus in the CNS.
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 large 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.
Generalized Glycogenosis in Large Animals
Generalized glycogenosis (Pompe disease) occurs in multiple different forms, specified as differently numbered types. In Shorthorn cattle (type II glycogenosis), Brahman cattle (type IIb), and Corriedale sheep (resembling type II), it is a lysosomal storage disease that causes ill thrift, respiratory signs, paraparesis, ataxia, and muscle weakness at the age of 3–9 months.
Several loss-of-function mutations in E1, E13, and E18 are suspected.
Neuronal Ceroid Lipofuscinosis
Neuronal ceroid lipofuscinosis (Batten disease) occurs in sheep, cattle, and goats. It is characterized by brain and retinal atrophy and deposition of lipofuscin. A number of genetic mutations in the lysosomal coding genes (CLN1, CLN5, CLN6, etc) have been identified in various species and breeds.
Clinical signs of neuronal ceroid lipofuscinosis vary among species:
Young Nubian goats show cerebellar signs.
Rambouillet sheep show blindness and decreased mentation beginning at the age of 8 months.
Hampshire lambs 9–12 months old show blindness, depression, head and thoracic limb tremor, and facial twitching, and they die by the age of 30 months.
Devon cattle become blind and weak by the age of 14 months and die by the age of 4 years.
Currently, no treatment for neuronal ceroid lipofuscinosis exists; however, gene therapies are being investigated.
Sphingolipidoses in Large Animals
Globoid Cell Leukodystrophy in Sheep
Globoid cell leukodystrophy is an inherited disease characterized by demyelination lesions in the cerebellum, pons, medulla, and spinal cord, and named for the perivascular accumulation of macrophages (globoid cells). It has been reported in polled Dorset sheep 4–18 months old.
Exaggerated tendon reflexes, ascending paralysis, and cerebellar signs can occur. Galactosylceramide beta-galactosidase enzyme activity in affected animals is < 6% of that in controls (1).
GM Gangliosidosis in Cattle
GM1 gangliosidosis occurs in inbred Friesian calves. Neuronal degeneration results from vacuolation and accumulation of cytoplasmic bodies. Clinical signs become evident during the first week of life and include depression, swaying of the hindquarters, reluctance to move, and stiffness. Death occurs after 6–8 months.
GM Gangliosidosis in Pigs
GM2 gangliosidosis causes hypermetria and weakness in Yorkshire piglets within the first 3 months of life. Death occurs within 4–6 months after onset.
Glycoproteinoses in Large Animals
Alpha-Mannosidosis in Cattle
Alpha-mannosidosis (autosomal recessive) occurs in Angus, Murray Grey, and Galloway cattle breeds. It produces ataxia, head tremor, aggression, and failure to thrive. It can also cause 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 pathological).
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 pathological).
Beta-Mannosidosis in Goats and Cattle
Beta-mannosidosis occurs in Nubian goats and Salers calves. Clinical signs can be apparent at birth and include the inability to stand, intention tremors, joint contractures, facial dysmorphisms, domed skull, and hypothyroidism.
The condition is usually fatal within hours after birth; some animals survive weeks to months with supportive care.
Mucopolysaccharidoses in Large Animals
Bovine Mucopolysaccharidosis Type IIIB
Bovine mucopolysaccharidosis type IIIB has been reported in a herd of cattle. The age of onset is typically 2 years, and clinical signs consist 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.
Key Points
Errors of inborn metabolism in large animals most commonly present as a generalized disorder, affecting multiple parts of the nervous system and sometimes other body systems as well.
Accumulation of waste products within cells is the hallmark of lysosomal storage disorders. These waste products can be from the metabolism of fat (sphingolipidoses), protein (glycoproteinoses, mucopolysaccharidoses), or carbohydrate (glycogen storage disorders).
For More Information
Gurda BL, Vite CH. Large animal models contribute to the development of therapies of central and peripheral nervous system dysfunction in patients with lysosomal storage diseases. Human Mol Genet. 2019;28(R1):R119-R131.
Jolly RD. Lysosomal storage diseases in livestock. Vet Clin North Am Food Anim Pract. 1993;9(1):41-53.
Mayhew IG, Mackay RJ. Large Animal Neurology. 3rd ed. Wiley-Blackwell; 2022.
Also see pet owner content regarding brain, spinal cord, and nerve disorders of horses.
References
Pritcard DH, Napthine DV, Sinclair AJ. Globoid cell leucodystrophy in Polled Dorset sheep. Vet Pathol. 1980;17(4):399-405. doi:10.1177/030098588001700402
