Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

Korat

GM1 Gangliosidosis

Related terms: Gangliosidosis; lysosomal storage disease

VeNom term: Gangliosidosis GM1 (VeNom code: no code).

Related conditions: lysosomal storage disease; GM2 gangliosidosis

Outline: GM1 gangliosidosis is an inherited lysosomal storage disorder affecting the Korat breed. Cats with GM1 gangliosidosis have a deficiency in the activity of the enzyme beta-galactosidase, which is responsible for breaking down specific carbohydrates in the cells. This results in an accumulation of the ganglioside carbohydrate GM1 in cells, especially in the cells of the brain and nervous system, causing damage to the central nervous system.   

Clinical signs of GM1 gangliosidosis include vision loss, difficulties in walking, loss of balance, head tremors, lethargy and weight loss. Affected cats show signs of neurologic disease at around 2-3 months of age, and the condition is progressive and lethal at around one year of age.

Although the disease is considered rare and sporadic, there may be unreported cases due to the short lifespan of affected cats and the difficulties in definitive diagnosis of the disease. GM1 gangliosidosis is inherited in Korat cats in an autosomal recessive manner. This means that cats must inherit two copies of the mutated gene (one from each parent) to develop the disease. Cats that inherit a single copy of the mutated gene, from one parent, are not affected by the disease but are carriers, and may have affected offspring if bred with another carrier.


Summary of Information

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1. Brief description

GM1 gangliosidosis is an inherited metabolic disease that results from defects in lysosomal function. Lysosomes are membrane-bound, fluid filled sacs containing enzymes that are found within almost all of cells of the body, and these act as the waste disposal system of the cell breaking down large molecules, such as proteins, carbohydrates and lipids, and passing the digested fragments on to other parts of the cell for recycling. In GM1 gangliosidosis, there is a deficiency of the enzyme, acid beta-galactosidase, and this causes the accumulation of gangliosides (a type of carbohydrate found in cell membranes) which would have normally been broken down and recycled. Instead they remain intact and are stored in membrane-bound sacs (vacuoles) in the cell. As the number of vacuoles increase, there are less available space and resources for normal cell function so that neuronal cell death and degeneration occurs, damaging the central nervous system and other organs. 

Gangliosidosis is clinically characterised by discrete head and limb tremors and lack of coordination of movement (dysmetria). Other clinical signs include ataxia (weakness), reduced postural reflexes and stiffened gait. The progressive accumulation of GM1 ganglioside in the central nervous system and cerebrospinal fluid ultimately proves fatal for cats at a young age.

2. Intensity of welfare impact

Affected cats experience head tremors and become unable to coordinate movement in their limbs, so that they have difficulties standing still and moving around. Loss of vision may also occur, which may be distressing in cats. Over time, muscles in the limbs and body become progressively stiff, heavy, difficult to move and prone to spasms. Cats may also lose weight and become lethargic and weak.

These clinical signs progress to more severe forms, and cats become increasingly lethargic, unable to walk and unresponsive. Eventually, at around one year of age, the disease proves fatal. Since the clinical signs are severe and debilitating, owners may discuss humane euthanasia of affected cats with the veterinarian, at or before cats have reached the end stages of the disease..

3. Duration of welfare impact

Affected cats exhibit no signs of the disease at birth, clinical signs start to occur from 2-3 months of age and steadily progress to severe until one year of age when cats are euthanized.

4. Number of animals affected

Complete diagnosis of lysosomal storage diseases in animals are often difficult to achieve, and the true prevalence of GM1 gangliosidosis is unknown, although it is considered rare overall..

5. Diagnosis

A diagnosis of GM1 gangliosidosis requires biochemical identification of the storage product and enzyme deficiency. Further, GM1 gangliosidosis can be genotyped using blood samples, to identify normal, homozygous (affected) and heterozygous (carriers) animals.

6. Genetics

GM1 gangliosidosis is inherited in Korat cats in an autosomal recessive manner. This means that the disease affects both males and females, and cats that inherit two copies of the mutated gene - one from each of their parents - will develop the disease. Cats that inherit a single copy of the mutated gene, from only one parent, will not be clinically affected by the disease but will carry the mutation and may produce affected offspring if bred with an affected cats or another carrier.

7. How do you know if an animal is a carrier or likely to become affected?

A DNA test is available that can identify normal, carrier and affected cats.

8. Methods and prospects for elimination of the problem

Cats affected by this disease are not likely to be bred from, since the debilitating clinical signs rapidly progress before cats reach sexual maturity. Screening for carriers is strongly recommended for all cats that may be bred from, especially if there is a history of this condition in siblings, siblings of parents or other relatives. Only animals without the mutated gene should be bred from.


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1. Clinical and pathological effects

GM1 gangliosidosis is an inherited metabolic disease that results from defects in lysosomal function and which causes damage to the nervous system. Lysosomes are membrane-bound, fluid filled sacs containing enzymes that are found within almost all of the cells of the body, and these organelles act as the waste disposal system of the cell breaking down large molecules, such as proteins, carbohydrates and lipids, and passing these digested fragments on to other parts of the cell for recycling. Lysosomes can contain more than 50 different enzymes, and dysfunction occurs when one or more of the enzymes have impaired function, are present at lower than normal levels or are absent altogether, meaning that the lysosome cannot break down materials normally. Excess products, which would have normally been broken down and recycled, remain intact and are stored in the cell.

GM1 gangliosidosis is caused by a deficiency of beta-galactosidase (Brunetti-Pierri & Scaglia 2008), a glycoside hydrolase enzyme that catalyses the hydrolysis of beta-galactosides (a type of carbohydrates) into monosaccharides through the breaking of a glycosidic bond. This enzyme is an essential part of the process by which cells produce energy and the carbon building blocks of other organic molecules, through the breakdown of lactose into galactose and glucose. In clinically affected cats, there is a reduction in beta-galactosidase to approximately 18% of normal activity (De Maria et al 1998). A deficiency of beta-galactosidase results in an impaired breakdown of GM1 ganglioside and related glycoconjugates (carbohydrates linked with proteins, peptides, lipids or saccharides) and their abnormal storage in the tissues of the central and peripheral nervous systems, and particularly in nerve cells. This excess material is stored in membrane bound sacs (vacuoles) in cells, and as the number of vacuoles increase, there is less available space and resources for normal cell function. In areas where lots of vacuoles are formed, the normal functioning of the cells of nervous system is impaired with neuronal cell death, loss of the protective myelin sheath surrounding nerve cells (demyelination) and proliferation of glial cells which form myelin and maintain cell homeostasis (gliosis specifically, microgliosis and astrogliosis). The mechanisms involved in the pathogenesis of GM1 gangliosidosis are unknown, but possibilities include neuronal apoptosis (cell death), endoplasmic reticulum stress response, abnormal axoplasmic transport resulting in myelin deficiency and disturbed neuronal-oligodendroglial interactions (De Maria et al 1998, Brunetti-Pierri & Scaglia 2008).  

Cats with GM1 gangliosidosis exhibit no signs of the disease at birth, but over time, the accumulation of gangliosides in neuronal cells causes central nervous system damage. Clinical signs are apparent in cats at 2-3 months of age. Gangliosidosis is clinically characterised by discrete head and limb tremors and lack of coordination of movement (dysmetria), first appearing at an early age (De Maria et al 1998). Other clinical signs include ataxia (weakness), reduced postural reflexes and stiffened gait. Clouding of the cornea of the eye and blindness may also occur in association with GM1 gangliosidosis (Baker & Lindsey 1974). The progressive accumulation of GM1 ganglioside in the central nervous system and cerebrospinal fluid ultimately proves fatal for cats at a young age.

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2. Intensity of welfare impact

Cats which have inherited GM1 gangliosidosis are usually unaffected at birth. At 2-3 months of age, the clinical signs of motor dysfunction start to occur and will rapidly progress. Affected cats first show tremors of the head and pelvic limbs, which progresses to mild to moderate ataxia, loss of balance and co-ordination of limbs resulting in problems with maintaining a normal posture and overshooting the intended limb position/movement (hypermetria). Affected cats have intermittent lameness and an inability to stand (astasia), also experience visual impairment (e.g. due to corneal clouding) and show an exaggerated startle response to stimuli such as sound and touch. The limb muscles start to become stiff, heavy, difficult to move and prone to spasms, and this becomes generalised across the body over time and severe by 7 to 8 months of age (Baker & Lindsey 1974). Affected cat may or may not continue to eat and drink normally, but they often lose weight.

In the final months, these clinical signs progress to more severe forms, and cats become increasingly lethargic, unable to walk and unresponsive. Eventually, at around 1 year of age, the disease usually proves fatal. Since the clinical signs are severe and debilitating, owners may discuss humane euthanasia of affected cats with the vet, at or before cats have reached the end stages of the disease.

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3. Duration of welfare impact

Affected cats exhibit no signs of the disease at birth, but progressive motor dysfunctions associated with GM1 gangliosidosis start from 2-3 months of age and steadily progress to severe exaggerated motor responses, impaired vision and seizures at 1 year of age (De Maria et al 1998).

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4. Number of animals affected

The prevalence of GM1 gangliosidosis in Korat cats is not known, although it is a rare disease. It was first reported in 1998 (De Maria et al 1998) and has not yet been reported in the UK. A complete diagnosis of lysosomal storage diseases in animals is often not fully investigated, due to the difficulties of making such a diagnosis and the serious neurologic features which often result in euthanasia without definitive diagnosis. It is therefore difficult to give a true estimate of how many cats are affected by this disease.

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5. Diagnosis

A diagnosis of GM1 gangliosidosis requires biochemical identification of the storage product and enzyme deficiency. Affected animals will have low beta-galactosidase enzyme activity in the liver and increased levels of GM-1 ganglioside in the brain (Baker & Lindsey 1974, De Maria et al 1998, Martin et al 2008). Further, GM1 gangliosidosis can be genotyped using blood samples, to identify normal, homozygous (affected) and heterozygous (carriers) animals.

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6. Genetics

GM1 gangliosidosis is thought to be inherited in Korat cats in an autosomal recessive manner (Baker et al 2001, Martin et al 2008). This means that the disease affects both males and females, and cats that inherit two copies of the mutated gene - one from each of their parents - will develop the disease. Cats that inherit a single copy of the mutated gene, from only one parent, will not be clinically affected by the disease but will carry the mutation and may produce affected offspring if bred with an affected cat or another carrier.

The homozygous recessive mutation causing GM1 gangliosidosis in Korat cats has been identified as an abnormal substitution of an allele in the gene responsible for producing the enzyme beta-galactosidase (feline GLB1 gene; Baker et al 2001, Martin et al 2008).

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7. How do you know if an animal is a carrier or likely to become affected?

DNA testing can be used to detect the mutation causing GM1 gangliosidosis in Korat cats; it can identify affected cats, carriers and normal cats, without the genetic mutation.

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8. Methods and prospects for elimination of the problem

Cats affected by this disease are not likely to be bred from, since the debilitating clinical signs rapidly progress in severity before cats reach sexual maturity. To reduce the prevalence of this simple (i.e. affecting a single gene) recessive inherited disorder in Korat cats, screening for carriers is recommended for all cats which may be bred from, especially if there is a history of this condition in siblings, siblings of parents or other relatives. The mating of two carriers together should be avoided, since a quarter of the cats they produce will suffer from the condition and half will be carriers (Farrell et al 2015). Ideally, only cats without the mutated gene should be bred from, but this may not be possible where the breeding population is small or isolated. Carriers can be mated with normal cats (without the mutated gene) but there is a 50% chance offspring will be carriers and should be monitored before breeding.

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9. Acknowledgements

UFAW thanks Dr Emma Buckland (BSc PhD), Dr David Brodbelt (MA VetMB PhD DVA DipECVAA MRCVS) and Dr Dan O’Neill (MVB BSc MSc PhD MRCVS) for their work in compiling this section.

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10. References

Baker HJ and Lindsey JR (1974) Animal model: feline GM1 gangliosidosis. The American Journal of Pathology 74: 649–52

Baker HJ, Smith BF, Martin DR and Foureman P (2001) Molecular diagnosis of the feline gangliosidosis: a model for elimination of inherited disease in pure breeds. In August J (ed.) Consultations in feline internal medicine pp. 615–620, 4th edition. WB Saunders Co, Orlando, Florida

Brunetti-Pierri N and Scaglia F (2008) GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Molecular Genetics and Metabolism 94: 391–6

Farrell LL, Schoenebeck JJ, Wiener P, Clements DN and Summers KM (2015) The challenges of pedigree dog health: approaches to combating inherited disease. Canine Genetics and Epidemiology 2: 3

De Maria R, Divari S, Bo S, Sonnino S, Lotti D, Capucchio MT and Castagnaro M (1998) Galactosidase deficiency in a Korat cat: a new form of feline G M1 -gangliosidosis. Acta Neuropathologica 96: 307–314

Martin DR, Rigat BA, Foureman P, Varadarajan GS, Hwang M, Krum BK, Smith BF, Callahan JW, Mahuran DJ and Baker HJ (2008) Molecular consequences of the pathogenic mutation in feline GM1 gangliosidosis. Molecular Genetics and Metabolism 94: 212–21

© UFAW 2016


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