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Genetic Welfare Problems of Companion Animals
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American Paint Horse
Glycogen Branching Enzyme Deficiency
Related terms: GBED
Outline: Glycogen is an important energy source for tissue within the body, and is vital for maintaining normal glucose levels in the body and for growth in the developing foetus and neonate. In horses affected with glycogen branching enzyme deficiency, a genetic mutation impairs the functioning of an enzyme (glycogen branching enzyme) resulting in the faulty synthesis of glycogen. Muscles cannot store or mobilise glucose in the form of glycogen, and tissues are unable to maintain normal glucose homeostasis. Without appropriate storage of ingested glucose, the animal cannot maintain adequate levels of glucose to keep organs working effectively. Hypoglycaemic episodes, where the blood glucose level falls below normal can cause confusion, uncoordinated movement and weakness and may cause loss of consciousness, cardiac arrest and sudden death. Foals that survive to parturition become progressively weaker and most do not survive longer than a few months.
Glycogen branching enzyme deficiency is inherited in an autosomal recessive manner. This means that it can affect both males and females..
Summary of Information
(for more information click on the links below)
1. Brief description
Glycogen is the form by which glucose, an essential source of energy, is stored in the body. As such it is an important energy source for tissue within the body, and it is vital for the maintenance of the normal glucose levels in the body (homeostasis) and for growth in the developing foetus and neonate.
In glycogen branching enzyme deficiency, a genetic mutation causes reduced or impaired activity of an enzyme - glycogen branching enzyme - and this results in the faulty synthesis of glycogen. Glycogen is a multi-branched polysaccharide, formed from straight chains of glucose molecules linked together at branching points. These numerous branch points provide abundant terminals where glucose can be readily metabolised by the digestive enzyme amylase. As a result of the enzyme mutation, muscle cannot store or mobilise glucose in the form of glycogen, and individuals are unable to sustain normal glucose homeostasis. This rapidly leads to death, since without appropriate storage of ingested glucose, the animal cannot maintain adequate glucose levels to keep organs working effectively.
Foals with glycogen-branching enzyme deficiency may be stillborn, since the neonate is unable to store glucose obtained from the mother via the placenta. Foals that survive to parturition are weak, have low body temperature, and show abnormal muscle contraction, especially of the limbs, causing problems with standing and movement. Hypoglycaemic seizures are common, and are a result of blood and cerebral glucose levels falling below normal levels. These may result in loss of consciousness, cardiac arrest or sudden death.
2. Intensity of welfare impact
Affected foals, which are born alive, are weak at birth and exhibit abnormal muscle contraction and difficulty in standing and moving. Hypoglycaemic episodes, where the blood glucose level falls below normal can cause confusion, uncoordinated movement and weakness and may result in loss of consciousness, cardiac arrest and sudden death.
The condition is progressively severe and ultimately foals die or are euthanased.
3. Duration of welfare impact
Affected foals are stillborn, die suddenly or, due to the severity of the condition, are humanely euthanased by 18 weeks of age. There is no curative treatment for the condition and often, if the condition is suspected in the foetus, it may be aborted.
4. Number of animals affected
It is thought that glycogen branching enzyme deficiency may be a common cause of neonatal deaths in Paint horses. The frequency of heterozygous carriers in Paint horses (ie those horses that are unaffected by the condition but that carry a copy of the defective gene that they can pass on to their offspring) is estimated to be between 4% and 7%.
5. Diagnosis
A deficiency of glycogen can be examined histologically in muscle biopsy samples. Blood testing may show low blood glucose, low white blood cell count and elevated muscle and liver enzymes.
6. Genetic
Glycogen branching enzyme deficiency is inherited in an autosomal recessive manner. This means that it can affect both males and females, and that horses must inherit two copies of the genetic mutation responsible for the disease (ie they are homozygous), one from each parent, in order to be affected. Horses that inherit only one copy of the gene mutation, from one parent, are heterozygous carriers; these horses do not have the disease but carry the genetic mutation and have the potential to pass the mutation onto their offspring. The mating of two heterozygous horses will result in a 25% chance of the offspring being homozygous affected with glycogen branching enzyme deficiency, whilst 50% will be heterozygous carriers for the condition and a further 25% will be clear of the genetic mutation (normal).
7. How do you know if an animal is a carrier or likely to become affected?
A DNA test is available to detect the gene mutation responsible for glycogen branching enzyme deficiency. It will identify horses that are homozygous affected, heterozygous carriers or unaffected (normal.
8. Methods and prospects for elimination of the problem
Homozygous affected foals are unlikely to be bred from, since they are unlikely to reach sexual maturity. Though carriers will be unaffected, if bred together, they have a 25% chance of producing affected offspring, and a further 50% carrier offspring. Therefore, it is advisable to avoid breeding two carriers together. To reduce the prevalence of this disease in horses, it is important to use DNA screening of prospective parents.
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
Glycogen is an important energy source for tissues within the body, and is vital for the maintenance of the normal glucose levels in the body (homeostasis) and for growth in the developing foetus and neonate.
In horses affected with glycogen branching enzyme deficiency, a genetic mutation causes reduced or impaired activity of an enzyme - glycogen branching enzyme - and this results in the faulty synthesis of glycogen.
Glycogen is a multi-branched polysaccharide made by linking together molecules of glucose. It is composed of straight-chains of glucose molecules linked via alpha 1,4 glycosidic bonds, with branch points approximately every 7 to 9 glucose residues, where the glucose molecules are linked via an alpha 1,6 glycosidic bond (Figure 1). Glycogen is synthesised by glycogen synthase, which creates the straight chains, and glycogen branching enzyme, which creates the branched structure. These numerous branch points provides abundant terminal glucose residues from which glucose can be metabolised more readily by the digestive enzyme amylase than if all glucose molecules were linked together in a single chain, which would only have only two free terminal ends.
In muscle cells, glycogen acts as an immediate reserve source of available glucose and for other immediate surrounding cells. In liver cells, stored glycogen is broken down into glucose and transported into the blood stream as necessary, to meet the energy demands of other organs.
Figure 1. A 2-dimensional cross-sectional view of glycogen. A core protein of glycogenin is surrounded by branches of glucose units. The entire globular complex may contain approximately 30,000 glucose units. Image reprinted under Public Domain license (Häggström 2014).
In horses affected with glycogen branching enzyme deficiency, a genetic mutation causes a defect in the enzyme, which is important for the formation of normal branched glycogen (Valberg et al 2001). As a result, the activity of the enzyme is prevented or impaired and muscles cannot store or mobilise glucose in the form of glycogen. Affected tissues, such as cardiac and skeletal muscle, liver and brain tissues are unable to sustain normal glucose homeostasis, and this rapidly leads to death since without appropriate storage of ingested glucose, the animal cannot maintain the normal level of glucose needed to keep organs working effectively.
Foals with glycogen-branching enzyme deficiency may be stillborn, since the neonate is unable to store glucose obtained from the mother via the placenta. Foals that survive to parturition have low blood sugar (hypoglycaemia), low body temperature (hypothermia) and are weak but they gain strength when given milk. Foals may show general weakness and contracted tendons, which causes problems with standing and moving. Hypoglycaemic seizures are common, and are a result of blood and cerebral glucose levels falling below normal levels. These may result in loss of consciousness cardiac arrest, or sudden death. The condition progresses in severity since the foal cannot maintain normal activity and growth without a functional source of glucose, and affected foals become progressively weak and at risk of hypoglycaemic episodes; most do not survive longer than a few months.
2. Intensity of welfare impact
Affected foals may be stillborn. Those that are born alive, are weak, and hypothermic at birth, and may have flexural limb deformities due to hindered muscle contraction that cause difficulty in standing and moving. Hypoglycaemic episodes, where the blood glucose level falls below normal, can cause confusion, ataxia and weakness and may result in loss of consciousness, cardiac arrest and sudden death (Valberg et al 2001).
The condition causes progressive and severe weakness due to energy-starved muscles and other organ tissues, and ultimately foals die or are euthanased.
3. Duration of welfare impact
Usually, affected foals are stillborn, die suddenly or, due to the severity of the condition, are humanely euthanased by 18 weeks of age because of the extent of their muscle weakness and frequency of hypoglycaemic seizures (Valberg et al 2001). There is no curative treatment for the condition. Many affected foals are aborted, if the disease is detected in ultrasound examination of the developing foetus
4. Number of animals affected
The frequency of homozygous affected animals (ie those that have two copies of the defective gene) is difficult to determine since affected foals may be aborted, stillborn or die at an early age, and records of these with a complete diagnosis are often not readily available. It is thought that glycogen branching enzyme deficiency may be a common cause of neonatal deaths in Paint horses and their relatives, Quarter horses. Approximately 2.5% of foetal and early neonatal deaths (commonly via abortions) in Quarter horse and Paint horse -related breeds submitted to two diagnostic laboratories in the United States were homozygous affected for glycogen branching enzyme deficiency (Wagner et al 2006).
In a study of 180 American Paint horses, 7 were heterozygous carriers, giving an estimated frequency of heterozygous carriers (ie horses that are unaffected by the condition but that carry a copy of the defective gene that they can pass on to their offspring) of 3.9% (Tryon et al 2009). A similar frequency was estimated from another study, where of DNA sampling of 197 Paint horses, 14 (7.1%) were heterozygous carriers (Wagner et al 2006).
5. Diagnosis
A deficiency of glycogen can be examined histologically in muscle biopsy samples, using Periodic acid Schiffs (PAS) stains – such staining clearly shows decreased normal background staining for glycogen and an accumulation of large globular inclusions of polysaccharide in cardiac and skeletal muscle (Valberg et al 2001). Blood parameters indicative of glycogen branching enzyme deficiency include low white blood cell count, low blood glucose, elevated muscle enzymes (creatine kinase [CK] and aspartate transaminase [ALT]) and liver enzymes (elevated alkaline phosphatase).
The diagnosis of glycogen branching enzyme deficiency may be obscured by the variety in the clinical signs, which may resemble other neonatal diseases in horses. Definitive diagnosis can be made via genetic testing for the gene mutation responsible for glycogen branching enzyme deficiency.
6. Genetics
Glycogen branching enzyme deficiency is inherited in an autosomal recessive manner (Wagner et al 2006). This means that it can affect both males and females, and that horses must inherit two copies of the genetic mutation responsible for the disease (ie they are homozygous), one from each parent, in order to be affected. Horses that inherit only one copy of the gene mutation, from one parent, are heterozygous carriers; these horses do not have the disease but carry the genetic mutation and have the potential to pass the mutation onto their offspring. The mating of two heterozygous horses will result in a 25% chance of the offspring being homozygous affected with glycogen branching enzyme deficiency, whilst 50% will be heterozygous carriers for the condition and a further 25% will be clear of the genetic mutation (normal).
Glycogen branching enzyme deficiency is caused by a mutation in codon 34 of the GBE1 gene (Ward et al 2003, 2004), which prevents the synthesis of a functional glycogen branching enzyme protein, leading to severely disrupted glycogen metabolism.
Pedigree and genotype analyses suggest that the inherited trait originates from a single founder in the Paint horse breed (Wagner et al 2006).
7. How do you know if an animal is a carrier or likely to become affected?
A DNA test is available to detect the gene mutation responsible for glycogen branching enzyme deficiency. Such a test requires mane or tail hairs with roots, or foetal liver tissue. It will identify horses that are homozygous affected, heterozygous carriers or unaffected (normal).
8. Methods and prospects for elimination of the problem
Homozygous affected foals are unlikely to be bred from, since they are unlikely to reach sexual maturity. For this condition, the heterozygous carrier population should be monitored. Though carriers will be unaffected, if bred together, they have a 25% chance of producing affected offspring, and a further 50% carrier offspring. Therefore, it is advisable to avoid breeding two carriers together.
To reduce the prevalence of this disease in horses, it is important to test aborted or stillborn foals for the genetic mutation responsible for glycogen branching enzyme deficiency, and to test the parents for carrier status using DNA testing.
The American Paint horse is developed from Quarter horse and Thoroughbred bloodlines, and therefore the breed is susceptible to the same genetic health disorders of these two breeds. Glycogen branching enzyme deficiency is one of several inherited health conditions of Quarter horses, and it is important to screen prospective parents with Quarter horse lineage for all of these.
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
Häggström M (2014) Medical gallery of Mikael Häggström. Wikiversity Journal of Medicine 1 (2). DOI: 10.15347/WJM/204.008. ISSN 20018762
Tryon RC, Penedo MCT, McCue ME, Valberg SJ, Mickelson JR, Famula TR, Wagner ML, Jackson M, Hamilton MJ, Nooteboom S and Bannasch DL (2009) Evaluation of allele frequencies of inherited disease genes in subgroups of American Quarter horses.. Journal of the American Veterinary Medical Association 234: 120–5
Valberg SJSJ, Ward TLTL, Rush B, Kinde H, Hiraragi H, Nahey D, Fyfe J and Mickelson JRJR (2001) Glycogen branching enzyme deficiency in Quarter horse foals.. Journal of veterinary internal medicine / American College of Veterinary Internal Medicine 15: 572–80
Wagner ML, Valberg SJ, Ames EG, Bauer MM., Wiseman JA., Penedo MCT., Kinde H., Abbitt B. and Mickelson JR (2006) Allele Frequency and Likely Impact of the Glycogen Branching Enzyme Deficiency Gene in Quarter horse and Paint Horse Populations. Journal of veterinary internal medicine / American College of Veterinary Internal Medicine 20: 1207–1211
Ward TL, Valberg SJ, Adelson DL, Abbey C a, Binns MM and Mickelson JR (2004) Glycogen branching enzyme (GBE1) mutation causing equine glycogen storage disease IV.. Mammalian genome : official journal of the International Mammalian Genome Society 15: 570–577
Ward TL, Valberg SJ, Lear TL, Guérin G, Milenkovic D, Swinburne JE, Binns MM, Raudsepp T, Skow L, Chowdhary BP and Mickelson JR (2003) Genetic mapping of GBE1 and its association with glycogen storage disease IV in American Quarter horses. Cytogenetic and Genome Research 102: 201–206
© UFAW 2016
Credit for main photo above:
http://depositphotos.com/46267487/stock-photo-gorgeous-brown-and-white-stallion.html.
