Genetic Welfare Problems of Companion Animals

An information resource for prospective pet owners

Labrador Retriever Labrador Retriever

Centronuclear Myopathy

Related terms: CM; myotubular myopathy; Labrador retriever myopathy; hereditary myopathy; inherited myopathy; muscular dystrophy; spasticity

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

Outline: Centronuclear myopathy in Labrador retrievers is characterised by generalised muscle weakness caused by a defect in the mechanism by which muscle fibers are formed. Affected dogs may be unable to walk and exercise normally due to muscle weakness. They tire easily and may experience muscle tremors and collapse. Signs of muscle weakness can start to occur from 6 weeks up to 7 months of age, and usually progress in severity until approximately 1 year of age when the condition stabilises. However, some dogs may experience problems swallowing and are at risk of sudden death through choking or respiratory infection.  

Hereditary myopathy is inherited as an autosomal recessive trait. To reduce the prevalence of this inherited disorder in the Labrador retriever, screening using DNA tests is recommended for all dogs that may be used for breeding.


Summary of Information

(for more information click on the links below)

1. Brief description

Inherited myopathy is a condition thought to be caused by a defect in the formation of muscle tissue, especially during embryonic development. It causes abnormal muscle fibre structure, organisation and content, with a deficiency of type 2 fibre’s important for anaerobic muscle contraction.

Affected dogs show generalised muscle weakness, ranging from mild to severe. Affected dogs are unable to raise their head properly and tire easily with exercise. The clinical signs worsen during periods of stress or excitement, and during locomotion, urination and defecation. Some dogs may have difficulties vocalising, yawning and eating. Affected dogs 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 dogs 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 dogs 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 dogs learn to adapt to locomotor and posture difficulties. Severely affected dogs may have problems chewing and swallowing food, which may lead food particles obstructing the upper airways and causing choking, breathing difficulties (asphyxiation) and laryngospasm (spasm of the vocal chords). This may lead to coma or sudden death. Affected dogs may also be prone to respiratory infections, which can be fatal.

3. Duration of welfare impact

Signs of muscle weakness start to occur from 6 weeks up to 7 months of age, and usually progress slowly in severity until approximately 1 year of age when the condition stabilises. With adequate care, dogs can live a normal lifespan, although they will have periodic muscle weakness and fatigue. However, there is a risk of sudden death for dogs with megaoesophagus (an enlarged oesophagus), because of the danger of asphyxiation and laryngospasm (spasm of the vocal chords).

4. Number of animals affected

Inherited myopathy has been most commonly described in Labrador retrievers, although there are no specific data reported on the prevalence of the condition in dogs. Reports 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.

5. Diagnosis

Diagnosis is challenging because the clinical signs are variable, and the response to muscle reflexes may be normal, although there may be weak or absent tricep or patellar reflexes. A veterinarian can collect muscle tissue samples under anaesthesia and have them assessed for abnormalities. A DNA test can genetically detect inherited myopathy in Labrador retrievers.

6. Genetics

Hereditary myopathy is inherited as an autosomal recessive trait in Labrador retrievers. This means that dogs which inherit two copies of the gene mutation – one from each of their parents – will develop the condition. 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 which can genetically detect inherited myopathy in Labrador retriever.  The test can identify homozygous affected cats, heterozygous carrier dogs and dogs without the gene mutation (normal).

8. Methods and prospects for elimination of the problem

Dogs affected by this disease are less likely to be bred from, since the clinical signs progress in severity and are evident before they reach sexual maturity. To reduce the prevalence of this recessive inherited disorder in the Labrador retriever, screening for heterozygous carriers, using DNA tests, is recommended for all dogs that may be used for breeding, especially if there is a history of this condition within the family. Ideally, only dogs 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 where possible, since a quarter of the puppies 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

Skeletal muscle is one of three major muscle types (along with cardiac muscle and smooth muscle). It is a form of striated muscle tissue and a skeletal muscle refers to multiple bundles of cells called muscle fibres. A muscle fibres is a single cell with hundreds to thousands of individual nuclei, each of which influences a domain within the muscle fibre. Muscle fibres are grouped in bundles (fascicles) and are surrounded by connective tissue layers (fasciae). Muscle fibres contain myofibrils, a basic rod-like unit composed of long proteins including actin and myosin. These proteins are organised into thick (myosin) and thin (actin) filaments which repeat along the length of the myofibril in sections called sarcomeres. The sarcomere is responsible for muscle contraction; muscles contract by sliding the thick (myosin) and thin (actin) filaments along each other.  Within skeletal muscle there are two types of fibre; type I and type II. Type I fibres have a high presence of myoglobin - the oxygen-binding protein - (causing them to be red in colour) and are therefore resistant to fatigue and able to repeat low-level contractions by producing large amounts of ATP through aerobic metabolism. Type I fibres are therefore often found in postural muscles such as those in the neck and spine. Type II fibres produce ATP at a slow rate through anaerobic metabolism, since they contain few myoglobin and mitochondria and this results in short, fast bursts of muscle contraction and rapid fatigue.

In dogs affected with inherited myopathy, a genetic mutation results in the loss of function of the protein tyrosine phosphatase-like A (PTPLA; Maurer et al 2012), which is thought to result in impaired differentiation of muscle fibre components during myogenesis, the formation of muscle tissue, especially during embryonic development. However, the full pathogenesis of this condition is currently unclear (McKerrell & Braund 1987).

Pathological changes in the muscle tissue of affected dogs include an increased number of muscle fibres with central nuclei (Olby et al 2001), and this is considered abnormal since central nuclei are present in less than 3% of normal skeletal muscle. There is a predominance of type 1 fibres with a deficiency of type 2 fibres. There is marked variation in muscle fibre size with both enlarged (hypertrophic) and decreased (atrophic) fibres, and an abnormal arrangement of fibres resulting in architectural changes in intermyofibrillar network. Muscle fiber necrosis and regeneration is also present in many cases (McKerrell & Braund 1987). The concentration of dystrophin and associated proteins in the muscle tissue (eg sarcoglycans, α-actinin, dysferlin and calpain 3) are not affected in this condition  (Olby et al 2001).

Affected dogs show generalised and intermittent muscle weakness and ataxia (loss of body movement control), which ranges from mild to severe (McKerrell & Braund 1987). There is commonly an absence or reduction of triceps and patellar reflexes. Affected dogs may have a stiff gait, and sometimes demonstrate “bunny hoping”. There may be an inability of the dorsal cervical muscles to support the head against gravity, leading to ventroflexion of the head and neck with abnormally low head and neck posture (Figure 1). Affected dogs tire easily with exercise, and eventually they may collapse in sternal recumbency (on their stomach), typically with the head coming to rest on, or to one side of, their front paws.

Figure 1 Young Labrador Retriever with clinical presentation and histopathological features consistent with hereditary myopathy of Labrador Retrievers. This dog shows a typical abnormal posture with low carriage of the neck. (Courtesy of Michael Podel, MSc, DVM, The Ohio State University, Columbus, OH). Reprinted from Veterinary Clinics of North America: Small Animal Practice, Volume 32, Shelton & Engvall, Muscular dystrophies and other inherited myopathies pp. 103–124, Copyright (2002), with permission from Elsevier.

Severely affected Labradors may have megaoesophagus (Green et al 2005).  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 myopathy, these contractions of the muscle are weaker and, combined with the abnormal head position, affected dogs 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 dogs can experience breathing difficulties due to the obstruction of the upper airways. This can lead to asphyxiation and spasm of the vocal chords (laryngospasm) that prevents the animal from breathing, and this is the most common cause of death from the disorder in affected dogs. 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 dogs show fever and increased heart rate, and which often proves fatal.

The clinical signs worsen in periods of stress or excitement, and during locomotion, urination and defecation (Green et al 2005). Dogs may rest their head on the floor or wall.

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2. Intensity of welfare impact

Affected dogs may be unable to walk and exercise normally due to weakness in the muscles of their back, shoulders and neck. They tire easily and may show muscle tremors and collapse. These clinical signs may occur more commonly during stress or excitement, or during periods of concurrent illness (Green et al 2005).

There is no curative treatment for the condition, but the clinical signs tend to stabilise at 1 year of age, and thereafter dogs may learn to adapt to locomotor and posture difficulties. For example to compensate for neck muscle weakness, they may adopt a low head carriage. Due to the abnormal lowered head position and low muscle tone of the oesophagus and throat, affected dogs 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 dogs with myopathy. Dogs can be fed by hand or from a raised platform to minimise the risk of asphyxiation. Affected dogs may also be prone to respiratory infection.

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3. Duration of welfare impact

Signs of muscle weakness start to occur from 6 weeks to 7 months, and usually progress slowly in severity until approximately 1 year of age when the condition tends to stabilise (Green et al 2005). With adequate care, dogs can live a normal lifespan, although they will not be able to exercise or “work”, and periodic muscle weakness and fatigue continues to occur. However, there is a risk of sudden death for dogs with megaoesophagus, because of the danger of asphyxiation and laryngospasms.

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4. Number of animals affected

There are few specific data on the prevalence of the condition in Labrador retrievers. We do know that the condition in inherited in Labrador retrievers, and that it affects both males and females regardless of coat colour.

In a world-wide study of 7426 Labrador retrievers, it was found that 80 dogs (1.08%) were homozygous for the gene mutation responsible for hereditary myopathy in Labrador retrievers and all of these dogs showed clinical signs of the condition (Maurer et al 2012). A further 1172 dogs (15.8%) were heterozygous, carrying only one copy of the gene mutation, from one parent, and remained unaffected by the condition. A decrease in the prevalence of homozygous affected and heterozygous carrier dogs was observed over the 7 year study period, likely as a result of the availability of a genetic test. Over two years (2010 to 2012), it was estimated that 1 in 7 Labrador retrievers was a carrier for the genetic mutation (245 of 1757 dogs; 13.9%). The genetic mutation was identified in Labrador retrievers within 13 different countries. The highest prevalence of carriers was found in the UK and Ireland (19% in 2010-2012), the USA (13%) and Canada (11.5%)..

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5. Diagnosis

Diagnosis is challenging because the clinical signs are variable, and the response to muscle reflexes may be normal, although there may be weak or absent tricep or patellar reflexes. A veterinarian can collect muscle tissue samples under anaesthesia and have them assessed for abnormalities. The histopathological changes in muscle may be variable. Typical abnormalities of affected muscle tissue include an increased number of fibres with central nuclei and changes in the size of fibres, with some enlarged (hypertropic) and some decreased (atrophic) in size. 

A definitive diagnosis can be made using the test for the genetic mutation responsible for the condition (ie DNA testing).

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6. Genetics

Hereditary myopathy is inherited as an autosomal recessive trait in Labrador retriever (Bley et al 2002). This means that dogs that inherit two copies of the gene mutation – one from each of their parents – will develop the condition. 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 condition is caused by a mutation in the canine PTPLA gene (protein tyrosine phosphatase-like A; Maurer et al 2012). The PTPLA gene is required for myoblast growth and differentiation, and therefore a mutation in this gene causing loss of function is suggested to cause impaired myoblast differentiation, impeded cell growth (Lin et al 2012), although the underlying mechanism/s are not yet fully understood, and there are several centronuclear myopathy-causing genes.

The occurrence of the genetic mutation was estimated to have arisen approximately 50 years ago, and from a single founder within the pedigree of a prolific stud dog (Maurer et al 2012), where it rapidly disseminated in the breed through the extensive use of popular sires.

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

Since inherited myopathy in Labrador retriever is a recessive condition, if a dog 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 are mated, each carrying one copy of the mutated gene, then 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 Labrador retrievers.  The test can identify homozygous affected cats, heterozygous carrier dogs and dogs without the gene mutation (referred to as normal or wild-type).

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8. Methods and prospects for elimination of the problem

Dogs affected by this disease are less 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 Labrador retriever, screening using DNA tests for is recommended for all dogs which 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 dogs 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 where possible, since a quarter of the dogs they produce will suffer from the condition and half will be carriers.

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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

 

Bley T, Gaillard C, Bilzer T, Braund K., Faissler D, Steffen F, Cizinauskas S, Neumann J, Vögtli T, Equey R and Jaggy A (2002) Genetic aspects of labrador retriever myopathy. Research in Veterinary Science 73: 231–236

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

Green SL, Tolwani RJ, Varma S and Shelton GD (2005) Absence of mutations in the survival motor neuron cDNA from labrador retrievers with an inherited myopathy. Veterinary Record 157: 250–254

Lin X, Yang X, Li Q, Ma Y, Cui S, He D, Lin X, Schwartz RJ and Chang J (2012) Protein tyrosine phosphatase-like A regulates myoblast proliferation and differentiation through MyoG and the cell cycling signaling pathway. Molecular and Cellular Biology 32: 297–308

Maurer M, Mary J, Guillaud L, Fender M, Pelé M, Bilzer T, Olby N, Penderis J, Shelton GD, Panthier J-J, Thibaud J-L, Barthélémy I, Aubin-Houzelstein G, Blot S, Hitte C and Tiret L (2012) Centronuclear myopathy in Labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide. PloS one 7: e46408

McKerrell RE and Braund KG (1987) Hereditary myopathy in Labrador Retrievers: clinical variations. Journal of Small Animal Practice 28: 479–489

Olby NJ, Sharp NJH, Anderson LVB, Kunkel LM and Bönnemann CG (2001) Evaluation of the dystrophin–glycoprotein complex, α-actinin, dysferlin and calpain 3 in an autosomal recessive muscular dystrophy in Labrador retrievers. Neuromuscular Disorders 11: 41–49

Shelton GD, and Engvall E (2002) Muscular dystrophies and other inherited myopathies. Veterinary Clinics of North America: Small Animal Practice 32: 103–124. doi:10.1016/S0195-5616(03)00081-0

© UFAW 2016


Credit for main photo above:

By Erikeltic at English Wikipedia [CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons