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Shiba Inu
GM1 Gangliosidosis
Related terms: Gangliosidosis; lysosomal storage disease
VeNom term: Gangliosidosis GM1 (VeNom code: no code).
Related conditions: lysosomal storage disease
Outline: GM1 gangliosidosis is an inherited lysosomal storage disorder affecting Shiba Inu type dogs. Dogs 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 walking, loss of balance, head tremors, lethargy and weight loss. Affected dogs show signs of neurologic disease at around 5 to 6 months of age, and the condition is progressive and lethal at around 15 months of age.
Although the disease is considered rare and sporadic, there may be unreported cases due to the short lifespan of affected dogs and the difficulties in definitive diagnosis of the disease. GM1 gangliosidosis is inherited in Shiba Inu dogs in an autosomal recessive manner. This means that dogs must inherit two copies of the mutated gene (one from each parent) to develop the disease. Dogs 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
(for more information click on the links below)
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 most cells of the body, and these sacs 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 increases, 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. Salivary gland cysts and loss of vision due to corneal clouding are also associated with GM1 gangliosidosis in Shiba Inu dogs. The progressive accumulation of GM1 ganglioside in the central nervous system and cerebrospinal fluid ultimately proves fatal for dogs at a young age
2. Intensity of welfare impact
Affected dogs 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 dogs. Over time, muscles in the limbs and body become progressively stiff, heavy, difficult to move and prone to spasms. Dogs may also lose weight and become lethargic and weak.
These clinical signs progress to more severe forms, and dogs become increasingly lethargic, unable to walk and unresponsive. Eventually, at around 15 months of age, the disease proves fatal. Since the clinical signs are severe and debilitating, owners may discuss humane euthanasia of affected dogs with the veterinarian, at or before dogs have reached the end stages of the disease.
3. Duration of welfare impact
Affected dogs exhibit no signs of the disease at birth, but clinical signs of GM1 gangliosidosis start from 5 to 6 months of age and dogs are usually euthanized by 15 months of age.
4. Number of animals affected
Complete diagnosis of lysosomal storage diseases in animals is often difficult to achieve, and the true prevalence of GM1 gangliosidosis is unknown, although it is considered rare overall. In Japan, the frequency of carriers for the disease (i.e. not clinically affected) in the Shiba Inu dog population was 1.02%.
5. Diagnosis
A diagnosis of GM1 gangliosdosis 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 Shiba Inu dogs in an autosomal recessive manner. This means that the disease affects both males and females, and dogs that inherit two copies of the mutated gene - one from each of their parents - will develop the disease. Dogs 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 dog 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 dogs.
8. Methods and prospects for elimination of the problem
Dogs affected by this disease are not likely to be bred from, since the debilitating clinical signs rapidly progress before dogs reach sexual maturity. Screening for carriers is strongly recommended for all dogs 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.
For further details about this condition, please click on the following:
(these link to items down this page)
- Clinical and pathological effects
- Intensity of welfare impact
- Duration of welfare impact
- Number of animals affected
- Diagnosis
- Genetics
- How do you know if an animal is a carrier or likely to become affected?
- Methods and prospects for elimination of the problem
- Acknowledgements
- References
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 (Rodriguez et al 1982, Wang et al 2000), a glycoside hydrolase enzyme that catalyses the hydrolysis of beta-galactosides (eg carbohydrates) into monosaccharides through the breaking of a glycosidic bond. This enzyme is therefore essential and an important 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. 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 increases, 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; there is 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; Müller et al 1998, Yamato et al 2003). 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 (Brunetti-Pierri & Scaglia 2008).
Dogs 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 and clinical signs are apparent at or before 1 year 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. Other clinical signs include ataxia (weakness), reduced postural reflexes and stiffened gait. Salivary gland cysts are often associated with GM1 gangliosidosis (Rahman et al 2012). These cysts comprise of a collection of saliva that has leaked from a damaged salivary gland or duct. They most frequently collect in sublingual tissues, and the intermandibular or cranial cervical areas. Dogs with GM1 gangliosidosis may experience loss of vision, due to swelling and dysfunction of the corneal keratocytes which resulting in a clouding of the cornea of the eye (Nagayasu et al 2008). These clinical features in affected Shiba Inu dogs are similar to a late infantile/juvenile form in humans (Yamato et al 2003). The progressive accumulation of GM1 ganglioside in the central nervous system and cerebrospinal fluid ultimately proves fatal for dogs at a young age.
2. Intensity of welfare impact
Dogs which have inherited GM1 gangliosidosis are usually unaffected between birth and 5 months of age. Between the ages of 5 months and 15 months, the clinical signs of motor dysfunction start to occur and rapidly progress (Yamato et al 2003). Affected dogs experience loss of balance and mild to moderate ataxia (progressing to severe by 7-8 months), head tremors and a lack of co-ordination of limbs resulting in problems with maintaining a normal posture and overshooting the intended limb position/movement (hypermetria). Affected dogs have intermittent lameness and an inability to stand (astasia), also experience visual defects (eg 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. Affected dogs may or may not continue to eat and drink normally, but they often lose weight (Müller et al 1998).
In the final months, these clinical signs progress to more severe forms, and dogs become increasingly lethargic, unable to walk and unresponsive. Eventually, at around 15 months of age, the disease usually proves fatal. Since the clinical signs are severe and debilitating, owners may discuss humane euthanasia of affected dogs with the vet, at or before dogs have reached the end stages of the disease.
3. Duration of welfare impact
Affected dogs exhibit no signs of the disease at birth, but progressive motor dysfunctions associated with GM1 gangliosidosis start from 5 to 6 months of age. The symptoms progress in severity and dogs generally die by 15 months of age (Yamato et al 2003).
4. Number of animals affected
GM1 gangliosidosis was first reported in Shiba Inu dogs in 2000 (Yamato et al 2000). However, 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 dogs are affected by this disease.
The Shiba Inu breed is a popular traditional breed in Japan and has been imported to North America, Europe and Australia. The frequency of carrier Shiba Inu dogs (ie those which carry the mutated gene but are not clinically affected) in Japan was reported to be 1.02% on average (6 dogs of 590 studied), and was higher in specific geographical districts (eg 3 of 132 dogs in the Kinki district; 2.27%; Uddin et al 2013). Between 1997 and 2013, the number of Shiba Inu dogs diagnosed with GM1 gangliosidosis at the Japan laboratory was 23, and 19 of these were between 2006-2013, suggesting a recent increase in the prevalence (or at least awareness and diagnosis) of the disease (Uddin et al 2013). The prevalence of GM1 gangliosidosis in other countries has been insufficiently studied but it seems to be rare (Broeckx et al 2013).
5. Diagnosis
A diagnosis of GM1 gangliosidosis requires biochemical identification of the storage product and enzyme deficiency. Affected animals will have low beta-galactosidase enqyme activity in the liver and increased levels of GM-1 ganglioside in the brain. Further, GM1 gangliosidosis can be genotyped using blood samples, to identify normal, homozygous (affected) and heterozygous (carriers) animals (Chang et al 2010).
6. Genetics
GM1 gangliosidosis is inherited in Shiba Inu dogs in an autosomal recessive manner. This means that the disease affects both males and females, and dogs that inherit two copies of the mutated gene - one from each of their parents - will develop the disease. Dogs 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 dog or another carrier.
The homozygous recessive mutation causing GM1 gangliosidosis in Shiba Inu dogs has been identified as a deletion of C nucleotide 1647 in the putative coding region for the gene responsible for producing the enzyme beta-galactosidase (canine GLB1 gene; Yamato et al 2002).
7. How do you know if an animal is a carrier or likely to become affected?
Polymerase-chain reaction (PCR)-based DNA testing can be used to detect the mutation causing GM1 gangliosidosis; it can identify both carriers and affected dogs (Yamato et al 2004, 2008).
8. Methods and prospects for elimination of the problem
Dogs affected by this disease are not likely to be bred from, since the debilitating clinical signs rapidly progress in severity before dogs reach sexual maturity. To reduce the prevalence of this simple (ie affecting a single gene) recessive inherited disorder in Shiba Inu dogs, screening for carriers is strongly recommended for all dogs which may be bred from, especially if there is a history of this condition in siblings, siblings of parents or other relatives, and only dogs without the mutated gene should be bred from. The mating of two carriers together should be avoided, since a quarter of the dogs they produce will suffer from the condition and half will be carriers (Farrell et al 2015).
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.
10. References
Broeckx BJG, Coopman F, Verhoeven GEC, Van Haeringen W, van de Goor L, Bosmans T, Gielen I, Saunders JH, Soetaert SSA, Van Bree H, Van Neste C, Van Nieuwerburgh F, Van Ryssen B, Verelst E, Van Steendam K and Deforce D (2013) The prevalence of nine genetic disorders in a dog population from Belgium, the Netherlands and Germany. PloS one 8: e74811
Brunetti-Pierri N and Scaglia F (2008) GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Molecular Genetics And Metabolism 94: 391–6
Chang H-S, Arai T, Yabuki A, Hossain MA, Rahman MM, Mizukami K and Yamato O (2010) Rapid and Reliable Genotyping Technique for GM1 Gangliosidosis in Shiba Dogs by Real-Time Polymerase Chain Reaction with TaqMan Minor Groove Binder Probes. Journal of Veterinary Diagnostic Investigation 22: 234–237
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
Müller G, Baumgärtner W, Moritz A, Sewell A and Kustermann-Kuhn B (1998) Biochemical findings in a breeding colony of Alaskan Huskies suffering from GM1-gangliosidosis. Journal of Inherited Metabolic Disease 21: 430–431
Nagayasu A, Nakamura T, Yamato O, Tsuzuki K, Hosaka Y, Ueda H, Tangkawattana P and Takehana K (2008) Morphological analysis of corneal opacity in Shiba dog with GM1 gangliosidosis. The Journal Of Veterinary Medical Science 70: 881–6
Rahman MM, Kawaguchi H, Miyoshi N, Yabuki A, Nakamoto Y, Ozawa T and Yamato O (2012) Pathological Features of Salivary Gland Cysts in a Shiba Dog with GM1 Gangliosidosis: A Possible Misdiagnosis as Malignancy. Journal of Veterinary Medical Science 74: 485–489
Rodriguez M, O’Brien JS, Garrett RS and Powell HC (1982) Canine GM1 gangliosidosis. An ultrastructural and biochemical study. Journal Of Neuropathology And Experimental Neurology 41: 618–29
Uddin MM, Arata S, Takeuchi Y, Chang H-S, Mizukami K, Yabuki A, Rahman MM, Kohyama M, Hossain MA, Takayama K and Yamato O (2013) Molecular epidemiology of canine GM1 gangliosidosis in the Shiba Inu breed in Japan: relationship between regional prevalence and carrier frequency. BMC Veterinary Research 9: 132
Wang ZH, Zeng B, Shibuya H, Johnson GS, Alroy J, Pastores GM, Raghavan S and Kolodny EH (2000) Isolation and characterization of the normal canine β-galactosidase gene and its mutation in a dog model of GM1-gangliosidosis. Journal of Inherited Metabolic Disease 23: 593–606
Yamato O, Endoh D, Kobayashi A, Masuoka Y, Yonemura M, Hatakeyama A, Satoh H, Tajima M, Yamasaki M and Maede Y (2002) A novel mutation in the gene for canine acid β-galactosidase that causes GM1-gangliosidosis in Shiba dogs. Journal of Inherited Metabolic Disease 25: 525–526
Yamato O, Jo E-O, Chang H-S, Satoh H, Shoda T, Sato R, Uechi M, Kawasaki N, Naito Y, Yamasaki M, Maede Y and Arai T (2008) Molecular Screening of Canine GM1 Gangliosidosis Using Blood Smear Specimens after Prolonged Storage: Detection of Carriers among Shiba Dogs in Northern Japan. Journal of Veterinary Diagnostic Investigation 20: 68–71
Yamato O, Jo E-O, Shoda T, Yamasaki M and Maede Y (2004) Rapid and Simple Mutation Screening of GM1 Gangliosidosis in Shiba Dogs by Direct Amplification of Deoxyribonucleic Acid from Various Forms of Canine Whole-Blood Specimens. Journal of Veterinary Diagnostic Investigation 16: 469–472
Yamato O, Masuoka Y, Tajima M, Omae S, Maede Y, Ochiai K, Hayashida E, Umemura T and lijima M (2000) GM1 gangliosidosis in shiba dogs. Veterinary Record 146: 493–496
Yamato O, Masuoka Y, Yonemura M, Hatakeyama A, Satoh H, Kobayashi A, Nakayama M, Asano T, Shoda T, Yamasaki M, Ochiai K, Umeura T and Maede Y (2003) Clinical and Clinico-Pathologic Characteristics of Shiba Dogs with a Deficiency of Lysosomal Acid β-Galactosidase: A Canine Model of Human GM1 Gangliosidosis. Journal of Veterinary Medical Science 65: 213–217
© UFAW 2016
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