Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

French BulldogFox Terrier (smooth)

Congenital Myasthenia Gravis

Related terms: VeNom term: Myasthenia gravis (VeNom code: 1355). 

Related conditions: acquired myasthenia gravis, megaoesophagus, aspiration pneumonia

Outline: Myasthenia gravis – meaning grave muscle weakness - is a group of syndromes characterised by a defect in the transmission of signals from nerves to muscles Muscular weakness and excessive fatigue are characteristic of myasthenia gravis, and affected dogs suffer rapid exhaustion of strength in skeletal muscles during exercises but recover after a period of rest. However, the muscle weakness is progressive, and in time it leads to general severe weakness and inability to move. Congenital myasthenia gravis occurs in young dogs, and abnormal muscle weakness is usually evident by 9 weeks of age. Physical and neurological examinations are required to diagnose congenital myasthenia gravis. Enlargement of the oesophagus or gullet, (termed-megaoesophagus), can also occur, predisposing affected individuals to regurgitate swallowed food and liquid. Aspiration pneumonia, as a result of bacterial infection, may develop if food inhalation into the lungs occurs during regurgitation.

Congenital myasthenia gravis is considered a fatal trait, and affected puppies do not usually reach sexual maturity (at around 9 months). It is not known how many dogs suffer from myasthenia gravis but the condition is known to be inherited in Smooth fox terriers. It is inherited as an autosomal recessive trait, which means that affected dogs need to inherit a copy of the defective gene from each of their parents, both who will be carriers of the condition.


Summary of Information

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1. Brief description

Congenital myasthenia gravis is an inherited disorder in which there are one or more defects in the mechanism by which signals from nerves are transmitted to the muscles. At the junction between the nerve and muscle (the synapse) the electrical signal from the nerve causes a release of chemicals from the nerve endings, which diffuse across the narrow gap and bind with receptors on the muscles cells. This in turn causes the muscles to contract. Dogs with congenital myasthenia gravis have a defect in the muscle cells’ receptors, which reduces the cells’ ability to bind with acetylcholine, the chemical released into the synapse. This results in weakened response to nerve activity and subsequent abnormally weak muscle contraction.

Myasthenia gravis primarily affects the limbs, face and throat, but there is widespread skeletal muscle weakness. During exercise, puppies progress from initially walking normally to increasingly shortened strides, stiffening limbs, and to stumbling, ‘bunny hoping’ and intermittent collapse. Such signs become after prolonged and intense periods of exercise. Following a period of rest, affected dogs return to a normal gait but congenital myasthenia gravis is a progressive condition and with time the periods of fatigue and muscle weakness become longer and more exaggerated. Ultimately dogs with the condition exhibit generalised weakness, muscle wastage and an inability to walk. In Smooth fox terriers, enlargement of the oesophagus (a condition called megaoesophagus) can also occur. This is because the muscles of the oesophagus that connect the throat to the stomach are not strong enough to push swallowed food through into the stomach and instead it becomes trapped. Affected individuals are predisposed to regurgitate this retained, swallowed food, especially when the head is lowered. If some of this regurgitated food is inhaled into the lungs, as is common, bacterial infection of the lung is likely and this leads to a life threatening condition called ‘aspiration pneumonia’.

2. Intensity of welfare impact

The quality of life of affected dogs is likely to be severely compromised due to excessive weakness and fatigue, which hinders their ability to behave normally. Over time, dogs become increasingly weak and unable to walk. Affected dogs with megaoesophagus may also have difficulties breathing, regurgitation of their stomach content and swallowing difficulties. There is no treatment for the congenital form of myasthenia gravis and the condition is considered fatal; the major cause of death in dogs with this condition is aspiration pneumonia.

3. Duration of welfare impact

The strength and bodyweight of affected dogs appear normal at birth but the first signs of congenital myasthenia gravis are usually observed in young dogs, between 6 to 9 weeks of age. Long-acting cholinesterase inhibitors (eg Pyridostigmine), which prolong the activity of neurochemical acetylcholine in the synapse, are used for temporary management of the disease. However, the long-term outlook for congenitally affected dogs is poor and it is common for affected dogs to die before they reach sexual maturity, regardless of whether they are treated or not.

4. Number of animals affected

It is not known how many dogs are affected by congenital myasthenia gravis, although we do know that Smooth fox terriers are predisposed to the condition (Miller et al 1984). Males and females are both equally affected by the condition.

5. Diagnosis

Physical and neurological examinations are required to diagnose congenital myasthenia gravis. An exercise test can be conducted to observe the exercise-induced weakness and fatigue, and the recovery post-rest, and this should be a good indicator of myasthenia gravis in young puppies. A Tensilon test can also be conducted, which looks at recovery of exercise induced weakness after administration of acetylcholine blocking drugs (Edrophonium). In addition, repetitive nerve stimulation or single fibre electromyography tests can be conducted to identify abnormalities in muscle contraction responses.

6. Genetics

Myasthenia gravis in Smooth fox terriers is inherited in a simple autosomal recessive manner. Dogs that inherit one copy of the defective gene from each of their parents will be affected by the condition, whilst dogs that only inherited one copy from one parent will be carriers and pass produce affected offspring, if mated to affected or carrier dogs.

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

To our knowledge, there is currently no test for carriers of this disease. We do know that Smooth fox terriers are more commonly affected by myasthenia gravis than dogs of other breeds.

8. Methods and prospects for elimination of the problem

Since puppies with myasthenia gravis often do not reach sexual maturity, dogs affected with this condition are unlikely to be bred from. However, once a dog has shown signs of this condition, littermates and parents of affected dogs should not be bred from since they are very likely to be affected by, or carriers of the condition. 

 

For further details about this condition, please click on the following:
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1. Clinical and pathological effects

Congenital myasthenia gravis is an inherited disorder in which the transmission of nerve signals across the neuromuscular junction is compromised by one or more defects (Hopkins 1992). The neuromuscular system is comprised of peripheral nerves, muscles and the junctions between muscle and the nerve – the synapse - and is the means by which the contraction of the muscles is controlled. At the junction, there is a gap, called the synaptic cleft, where the motor nerve axons that carry nerve signals from the brain are at their closest point to the cells of the muscle. This junction effectively serves as a transducer, converting electrical signals (nerve impulses) into chemical signals and then back to electrical signals (muscle action potentials) to induce muscle contraction. At the synapse, electrical signals from the brain cause the release of a chemical neurotransmitter – acetylcholine- from where it is stored in membrane bound vesicles at the end of the axon (the pre-synaptic membrane). The acetylcholine diffuses across the synaptic cleft binding to receptors on the membrane of the muscles cells on the other side (the post-synaptic membrane). This in turn triggers an electrical signal that triggers muscle contraction.

The defect underlying the transmission disorder in congenital myasthenia gravis in dogs is a decrease in the number of functional receptors on the post-synaptic membrane of the muscle cells; the density of acetylcholine receptors on the post-synaptic membrane is approximately 75% lower than for normal dogs (Oda et al 1984). The degree of clinical weakness that affected dogs show is closely correlated to the magnitude of receptor loss. The decreased number of receptors on the post-synaptic membrane reduces the probability of acetylcholine binding to these and therefore reduces the chances of muscle fibre contraction, especially after repeated or prolonged nerve fibre activity. This is why muscle weakness in dogs with this condition is more pronounced after a bout of exercise.

Myasthenia gravis affects skeletal muscles, and affects the limbs, face and throat. In the congenital form, there is widespread skeletal muscle weakness that is brought on by exercise. During bouts of prolonged or intense exercise,  even of a short duration (eg 5 minutes), affected puppies progress from initially walking normally to increasingly shortened strides, stiffening limbs, and to stumbling, ‘bunny hoping’ and intermittent collapse. At this point, postural reflex testing, in which the dog’s ability to right itself and keeping moving is assessed, gives a very abnormal response because of the weakness (Hopkins 1992). A low head carriage may also be seen following exercise, suggesting muscle weakness of the neck. Dogs return to normal gait following a rest period of approximately 10 minutes. However, congenital myasthenia gravis, is a progressive condition in which the weakness gets worse and, with time, the periods of fatigue and muscle weakness become longer and more exaggerated, ultimately leading to generalised weakness, muscle wastage and inability to walk.

In Smooth fox terriers, megaoesophagus may also occur (Miller et al 1983). The oesophagus, is a muscular tube connecting the throat to the stomach. When food is swallowed the muscles of the oesophagus normally help to push it down into the stomach, but in dogs with myasthenia gravis these contractions are weaker and rather than passing into the stomach the food may become trapped and the walls of the oesophagus may distend and enlarge. Regurgitation of this food then becomes likely, especially when the head is lowered. Regurgitation differs from vomiting in that it is done with ease, and requires little muscular contraction. Regurgitation may cause narrowing or tightening of the oesophagus, which may cause difficulties swallowing. If regurgitated food particles are inhaled into the lungs, bacterial infection of the lung is likely, which causes breathing difficulties and coughing. This in turn can lead to a condition called ‘aspiration pneumonia’, in which dogs show fever and increased heart rate, and which often proves fatal (Hopkins et al 1992)..

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2. Intensity of welfare impact

At rest, affected dogs may be mildly affected by some muscle weakness but show abnormal muscle weakness and fatigue after exercise of even a short duration eg 5 minutes (Platt & Olby 2004). During exercise, dogs may stumble and eventually collapse. This inability to undertake intense and prolonged exercise leads to likely consequences for the dog’s wellbeing, since it will be unable to carry out normal behaviours, especially the high-energy activity and play of a normal puppy. There is, however, no pain associated with the muscle weakness. The disorder is progressive, and over time the periods of fatigue and muscle weakness become longer and more exaggerated, and the dog will become generally weak and unable to walk. Whilst there are several treatment options available for the acquired (auto-immune) form of myasthenia gravis, there is no long-term treatment for the congenital form and the trait is considered fatal, though treatment with cholinesterase inhibitors, which prolong the activity of neurochemical acetylcholine in the synapse, may help temporarily. Affected dogs with megaoesophagus may also have breathing difficulties, regurgitation of their stomach content and oesophageal narrowing/tightening causing swallowing difficulties, all of which may cause some distress in the affected animal. There is no treatment for the congenital form of myasthenia gravis and the condition is considered fatal; the major cause of death in dogs with this condition is aspiration pneumonia.

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3. Duration of welfare impact

The strength and bodyweight of affected dogs appear normal at birth but the first presenting signs of congenital myasthenia gravis are usually observed in young dogs, between 6 to 9 weeks of age. The muscle weakness and fatigue are progressive and the dog will become generally weak and unable to move over a period of weeks or possibly months. Temporary management of the condition is by the use of long-acting cholinesterase inhibitors (eg Pyridostigmine bromide), which prolong the activity of neurochemical acetylcholine in the synapse (Khorzad et al 2011). However, the long-term outlook for congenitally affected dogs is generally poor since muscle use deteriorates over time. Since there is no effective treatment, veterinary surgeons may discuss whether euthanasia is appropriate for dogs diagnosed with myasthenia gravis or when there has been severe progression of the disease.

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4. Number of animals affected

It is not known how many dogs are affected by congenital myasthenia gravis, although we do know that Smooth fox terriers are predisposed to the condition (Miller et al 1984). Males and females are both equally affected by the condition.

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5. Diagnosis

Physical and neurological examinations are required to diagnose congenital myasthenia gravis.

An exercise test can be conducted to observe the exercise-induced weakness and fatigue, and recovery post-rest, and this should be a good indicator of myasthenia gravis in young puppies (Miller et al 1983). Cholinesterase inhibitors (eg edrophonium) can be administered, as, as a further diagnostic tool (a Tensilon test). Administration results in prolonged and higher concentrations of acetylcholine in the synaptic cleft, enhancing transmission, and therefore the dog shows a dramatic (but temporary) amelioration of the signs of muscle weakness.

Repetitive nerve stimulation or single fibre electromyography tests can be conducted to record muscle action potentials. In dogs with myasthenia, the amplitude and area of the action potentials often decrease over repeated stimulation, and the latency between successive reflexes is increased, indicating instability of neuromuscular transmission.

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6. Genetics

In a phenotypic study of Smooth fox terriers (Miller et al 1984), congenital myasthenia gravis was found to be a simple inherited condition of an autosomal, recessive manner with complete penetrance, meaning that it affected both males and females and that all affected animals that had inherited two copies of the recessive gene from both parents exhibit clinical symptoms The underlying defect is unknown and may be caused by a gene that causes a defect in structure of the acetylcholine receptor molecule itself, or a defect in the membrane insertion of the acetylcholine receptor molecule.

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

Since congenital myasthenia gravis in Smooth fox terriers is a recessive condition, if a dog only has one copy of the mutation, it will not be affected and will show no sign of the disease, but will be a carrier passing on the mutated gene to some of its offspring. If two dogs, each carrying one copy of the mutated gene are mated together, 25% of their offspring are likely be affected and a further 50% will be carriers of the condition.

To our knowledge, there is no DNA test to detect congenital myasthenia gravis.

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8. Methods and prospects for elimination of the problem

Since puppies with myasthenia gravis often do not reach sexual maturity, dogs affected with this condition are unlikely to be bred from. However, once a dog has shown signs of this condition, littermates and parents of affected dogs should not be bred from since they will almost certainly be carriers of the condition.

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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

Hopkins AL (1992) Canine myasthenia gravis. Journal of Small Animal Practice 33: 477–484. doi:10.1111/j.1748-5827.1992.tb01028.x

Khorzad R, Whelan M, Sisson A and Shelton GD (2011) Myasthenia gravis in dogs with an emphasis on treatment and critical care management. Journal of Veterinary Emergency and Critical Care 21: 193–208

Miller LM, Hegreberg GA, Prieur DJ and Hamilton MJ (1984) Inheritance of congenital myasthenia gravis in smooth fox terrier dogs. The Journal of Heredity 75: 163–6

Miller LM, Lennon VA, Lambert EH, Reed SM, Hegreberg GA, Miller JB and Ott RL (1983) Congenital myasthenia gravis in 13 Smooth Fox terriers. Journal of the American Veterinary Medical Association 182: 694–7

Oda K, Lambert EH, Lennon VA and Palmer AC (1984) Congenital canine myasthenia gravis: I. Deficient junctional acetylcholine receptors. Muscle & Nerve 7: 705–716. doi:10.1002/mus.880070904

Platt SR and Olby NJ (2004) BSAVA Manual of Canine and Feline Neurology 287: 3rd ed. British Small Animal Veterinary Association; Gloucester, UK

© UFAW 2016


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