Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

Sphynx

Hereditary Myopathy

Related terms: Devon rex myopathy; spasticity

VeNom term:  Myopathy (muscle disorder) (VeNom code: 1371)

Outline: Hereditary myopathy in Sphynx cats is characterised by generalised muscle weakness caused by a defect in the mechanism by which signals from nerves are transmitted to the muscles. Affected cats may be unable to walk and exercise normally due to muscle weakness. They tire easily and may experience muscle tremors and collapse. These clinical signs may occur more commonly during stress or excitement, or during periods of concurrent illness. Signs of muscle weakness start to occur from three to 23 weeks of age, and usually progress slowly in severity until approximately 9 months of age when the condition often stabilises. However, some cats with megaoesophagus may experience ongoing problems swallowing and are at risk of sudden death through choking 

Hereditary myopathy is inherited as an autosomal recessive. To reduce the prevalence of this recessive inherited disorder in the Sphynx breed, screening using DNA tests is recommended for all cats that may be bred from.


Summary of Information

(for more information click on the links below)

1. Brief description

Inherited myopathy is a condition in which there is a defect 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 signals travelling down the nerve from the brain cause a release of chemicals from the nerve endings, which diffuse across the narrow synaptic gap and bind on the other side with receptors on the muscles cells. This in turn causes the muscles to contract. Cats with inherited myopathy have a deficiency in the enzyme which breaks down acetylcholine, the neurotransmitter chemical released into the synapse. This means the acetylcholine persists for longer in the synaptic gap than is normal, which results in over-stimulation of nerve activity and subsequent weak muscle contraction.

Affected cats show generalised muscle weakness, ranging from mild to severe, and are unable to raise their head properly. They may also show head bobbing and a high-stepping forelimb gait. Affected cats tire easily with exercise and the clinical signs worsen during periods of stress or excitement, and during locomotion, urination and defecation. Some cats may have difficulties vocalising, yawning and eating. Affected cats often have difficulties swallowing food, due to weakness and enlargement of the oesophagus. Small food particles can accumulate in the vicinity of the larynx, or large food pieces can become trapped in the oesophagus, and cats can experience breathing difficulties due to the obstruction of the upper airways. This can lead to asphyxiation and/or aspiration pneumonia, which can be fatal.

2. Intensity of welfare impact

Affected cats may be unable to walk and exercise normally due to muscle weakness. They tire easily and may experience muscle tremors and collapse. These clinical signs may occur more commonly during stress or excitement, or during periods of concurrent illness. There is no curative treatment for the condition but cats may be able to learn to adapt to locomotor and posture difficulties. Affected cats may have problems chewing and swallowing food, which may lead food particles obstructing the upper airways and choking, breathing difficulties (asphyxiation) and laryngospasm (spasm of the vocal chords). If severe, this may lead to coma or sudden death. Affected cats may also be prone to respiratory infections, which can be fatal.

3. Duration of welfare impact

Signs of muscle weakness start to occur from three to 23 weeks of age, and usually progress slowly in severity until approximately 9 months of age where the condition stabilises. With adequate care, cats can live a normal lifespan, although they will have periodic muscle weakness and fatigue. However, there is a risk of sudden death, for cats with megaoesophagus (an enlarged oesophagus), because of the danger of asphyxiation and laryngospasms (spasm of the vocal chords).

4. Number of animals affected

Reports of inherited myopathy in cats are rare in the scientific literature, which may indicate the condition is rare or that it is underreported due to a lack of formal diagnosis. It is known to affect Sphynx cats, although there are no specific data reported on the prevalence of the condition in cats.

5. Diagnosis

Diagnosis is challenging because the clinical signs are variable, and the response to muscle reflexes are normal. A veterinarian can collect muscle tissue samples under anaesthesia and have them assessed them for abnormalities.

6. Genetics

Hereditary myopathy is inherited as an autosomal recessive trait in Sphynx cats. This means that cats that inherit two copies of the gene mutation – one from each of their parents – will develop the condition. 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.

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

A DNA test is available which can genetically detect inherited myopathy in Sphynx and Devon rex cats.  The test can identify homozygous affected cats, heterozygous carrier cats and cats without the gene mutation (normal).

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 progress in severity and are evident before they reach sexual maturity. To reduce the prevalence of this recessive inherited disorder in the Sphynx breed, screening using DNA tests for is 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. Ideally, cats without the mutated gene should be bred from. The mating of two carriers - that each have one copy of the mutated gene - should be avoided, since a quarter of the cats they produce will suffer from the condition and half will be carriers.


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

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 between nerves and muscles 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 (an action potential) that triggers muscle contraction. Once a membrane has been activated, the membrane becomes unresponsive to any further stimulation for a period of time, known as the refractory period, and requires a much stronger response to induce the action potential.

The defect underlying the transmission disorder of hereditary myopathy in cats is a decrease in the concentration of acetylcholinesterase in the synaptic space (Abitbol et al 2015). Acetylcholinesterase is an enzyme that catalyses the breakdown of the neurotransmitter acetylcholine, and has the effect of stopping synaptic transmission by removing the signals that trigger muscle contraction. The absence of acetylcholinesterase prolongs the lifetime of acetylcholine in the synapse, and leads to an increased duration of electrical signals at the post-synaptic membrane. This activation lasts longer than the refractory period, and leads to prolonged muscle action potentials) ie prolonged electrical activity in muscle tissue (Mihaylova et al 2008). As a consequence, the muscles, especially of the head and neck, degenerate, exhibiting changes in structure due to the death and regeneration of myofibres. Regeneration can cause thickening and scarring of connective muscle tissue (fibrosis), leading to impairment in muscle function. Muscle histology in affected cats shows variability in muscle fibre size, increased growth of fibres, rounded and split fibres, individual myofibre death and regeneration (Malik et al 1993). This leads to muscle weakness and fatigue.

A mutation in the gene which encodes acetylcholinesterase-associated collagen in skeletal muscle is responsible for the deficiency of acetylcholinesterase in the synapse. The mechanism by which acetylcholinesterase is deficient could be a result of deficiency of alpha-dystroglycan (Martin et al 2008), a part of the dystroglycan protein complex, which acts to regulate agrin-induced acetylcholine receptor clustering at the neuromuscular junction. This causes a loss of acetyl-cholinesterase receptors at the synaptic neuromuscular junction.

Affected cats show generalised muscle weakness, which ranges from mild to severe (Malik et al 1993). Due to the inability of dorsal cervical muscles to support the head against gravity, affected cats have an inability to raise their head properly (Figure 1), shown ash ventroflexion of the head and neck, and protraction of the shoulder bone (scapulae). They may also show head bobbing and a high-stepping forelimb gait. The clinical signs worsen in periods of stress or excitement, and during locomotion, urination and defecation (Malik et al 1993). Cats may rest their head on the floor, wall or side of the litter tray whilst urinating or defecating. Affected cats tire easily with exercise, and eventually they collapse in sternal recumbency (on their stomachs), typically with the head coming to rest on, or to one side of, their front paws. Some cats appear to have partial spasm of the jaw muscles (trismus), with a reduced ability to fully open the mouth, and this may result in difficulties vocalising, yawning and eating (Malik et al 1993). Affected cats frequently adopt a characteristic ‘dog-begging’ or ‘Meer cat’ position (Robinson 1992), which allows them to counter-effect muscle weakness and maintain normal orientation of the head in relation to the trunk.

 

Figure 1. A Sphynx kitten with abnormal gait, with ventroflexion of the neck and dorsal protrusion of the scapulae (shoulder blades). Image is reproduced from Abitbol et al (2015) under the creative commons attribution licence (http://creativecommons.org/licenses/by/4.0/).

Megaoesophagus may also occur in affected cats (Malik et al 1993). 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 cats with myopathy these contractions of the muscle are weaker and combined with the abnormal head position, affected cats may experience difficulties swallowing food. Small food particles can accumulate in the vicinity of the larynx, or large food pieces can become trapped in the oesophagus, and cats can experience breathing difficulties due to the obstruction of the upper airways. This can lead to asphyxiation and spasm of the vocal chords (laryngospasm), which prevents the animal from breathing, and this is the most common cause of death from the disorder in affected cats. In addition, trapped food particles may cause the walls of the oesophagus to distend and enlarge. Regurgitation of the food then becomes likely, especially when the head is lowered with ventroflexion. 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 cats show fever and increased heart rate, and which often proves fatal.

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2. Intensity of welfare impact

Affected cats may be unable to walk and exercise as they normally would due to weakness in the muscles of all four limbs. They tire easily and may experience muscle tremors and collapse. These clinical signs may occur more commonly during stress or excitement, or during periods of concurrent illness.

There is no curative treatment for the condition. Cats may be able to learn to adapt to locomotor and posture difficulties, for example to compensate for neck muscle weakness they may adopt a Meer cat-like or dog-begging-like posture (periscoping). Due to the abnormal lowered head position and low muscle tone of the oesophagus and throat, affected cats may have problems chewing and swallowing food, which may lead food particles obstructing the upper airways, causing choking, breathing difficulties (asphyxiation) and laryngospasm (spasm of the vocal chords). This is severe and if the obstruction is not physically dislodged and removed, it may lead to coma or sudden death. This is the most common cause of death in cats with myopathy. Cats can be fed by hand or from a raised platform to minimise the risk of asphyxiation. Affected cats may also be prone to respiratory infection.

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3. Duration of welfare impact

Signs of muscle weakness start to occur from three to 23 weeks of age (Malik et al 1993), and usually progress slowly in severity until approximately 9 months of age where the condition stabilises. With adequate care, cats can live a normal lifespan, although periodic muscle weakness and fatigue continues to occur. However, there is a risk of sudden death for cats with megaoesophagus, because of the danger of asphyxiation and laryngospasms.

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4. Number of animals affected

Reports of inherited myopathy in cats are rare in the scientific literature, and this may indicate the condition is rare or that it is underreported due to a lack of formal diagnosis. It is known to affect Sphynx cats (Martin et al 2008, Abitbol et al 2015), although there are no specific data on the prevalence of the condition in cats. In one study of the expression of the gene mutation associated with inherited myopathy, there were 2 affected Sphynx cats versus 14 Sphynx cats that were carriers of the condition (unaffected but able to pass on the genetic mutation) and 9 Sphynx cats without the mutation (Abitbol et al 2015), although bias in the way the sample was collected mean that this does not reflect the prevalence of the mutation in the wider population.

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5. Diagnosis

Diagnosis is challenging because the clinical signs are variable, and the responses to muscle reflex testing are normal. A veterinarian can collect muscle tissue samples under anaesthesia and have them assessed for abnormalities. Typical abnormalities of muscle tissue include round and atrophic or hypertrophic myofibres, especially in cervical muscle. At the neuromuscular junction of myofibres, affected cats have an abnormal, dispersed activity of synaptic acetylcholine esterase whereas post-synaptic acetylcholine receptor activity is normal.

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6. Genetics

Hereditary myopathy is inherited as an autosomal recessive trait in Sphynx cats (Robinson 1992, Abitbol et al 2015). This means that cats that inherit two copies of the gene mutation – one from each of their parents – will develop the condition. 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 condition is caused by a mutation in the feline COLQ gene (collagen-like tail subunit of asymmetric acetylcholinesterase gene), which causes a deficiency of acetylcholinesterase in the synapse at neuromuscular junctions in skeletal muscle (Abitbol et al 2015).

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

Since inherited myopathy in Sphynx cats is a recessive condition, if a cat only has one copy of the mutation, it will not be clinically affected and will show no external signs of the disease, but will be a carrier capable of passing on the mutated gene to some of its offspring. If two carriers mate, each carrying one copy of the mutated gene, 25% of their offspring are likely be affected and a further 50% will be carriers of the condition, therefore spreading the incidence of affected offspring in the future.

A DNA test is available which can genetically detect inherited myopathy in Sphynx and Devon rex cats.  The test can identify homozygous affected cats, heterozygous carrier cats and cats without the gene mutation (normal).

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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 progress in severity before they reach sexual maturity. To reduce the prevalence of this recessive inherited disorder in the Sphynx breed, screening using DNA tests for is recommended for all cats that may be bred from (Farrell et al 2015), especially if there is a history of this condition in siblings, siblings of parents or other relatives. Ideally, only cats without the mutated gene should be bred. The mating of two carriers – each of which have one copy of the mutated gene -should be avoided, since a quarter of the cats they produce will suffer from the condition and half will be carriers. 

Sphynx and Devon rex breeds are genetically very close, because of the repeated use of Devon rex cats in Sphynx breeding programs and therefore both cat breeds should be tested for this 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

Abitbol M, Hitte C, Bossé P, Blanchard-Gutton N, Thomas A, Martignat L, Blot S and Tiret L (2015) A COLQ Missense Mutation in Sphynx and Devon Rex Cats with Congenital Myasthenic Syndrome. PloS One 10: e0137019

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

Malik R, Mepstead K, Yang F and Harper C (1993) Hereditary myopathy of Devon rex cats. Journal of Small Animal Practice 34: 539–545

Martin PT, Shelton GD, Dickinson PJ, Sturges BK, Xu R, LeCouteur RA, Guo LT, Grahn RA, Lo HP, North KN, Malik R, Engvall E and Lyons LA (2008) Muscular dystrophy associated with alpha-dystroglycan deficiency in Sphynx and Devon Rex cats.. Neuromuscular Disorders 18: 942–52

Mihaylova V, Müller JS, Vilchez JJ, Salih MA, Kabiraj MM, D’Amico A, Bertini E, Wölfle J, Schreiner F, Kurlemann G, Rasic VM, Siskova D, Colomer J, Herczegfalvi A, Fabriciova K, Weschke B, Scola R, Hoellen F, Schara U, Abicht A and Lochmüller H (2008) Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes. Brain: A Journal of Neurology 131: 747–59

Robinson R (1992) ‘Spasticity’ in the Devon rex cat. The Veterinary Record 130: 302

© UFAW 2016


Credit for main photo above:

http://depositphotos.com/57601283/stock-photo-beautiful-sphynx-cat-portrait.html

©Depositphotos.com/sorokopud