Introduction

Muscular dystrophies (MDs) are a heterogeneous group of genetic diseases that result in progressive muscle degeneration, cycles of regeneration and progressive weakness. Three forms of MD have been identified in cats, including feline X-linked dystrophin deficiency (Maine Coon and domestic shorthair [DSH]),^1–4 merosin (laminin alpha [α] 2) deficiency (Siamese, Maine Coon, DSH)^3–6 and sarcoglycan deficiency (DSH).^3,7

Mutations of genes coding for dystrophin or its associated proteins cause disruption of the dystrophin–glycoprotein complex (Figure 1), leading to membrane instability and leakage of intracellular contents, including creatine kinase (CK), into the extracellular fluid space, alongside skeletal and cardiac muscle fibre damage secondary to an influx of intracellular calcium and protease activation leading to myocyte death. Loss of CK prevents the formation of phosphocreatine, which is used as energy by the myocytes, leading to weakness.^3,9

Figure 1

Normal dystrophin–glycoprotein complex and its relationship with the muscle membrane and contractile units⁸

Common clinical signs of MD in cats include a stilted gait, weakness, dysphagia, regurgitation, muscle atrophy or hypertrophy and, in particular, macroglossia, which should facilitate an early diagnosis if recognised.^1–4 Although megaoesophagus has been described in dogs with MD, its presence in cats has been inconsistently reported.^2,10–13 The long-term prognosis for MD is grave. Quality of life may be improved by managing megaoesophagus with sildenafil, altering diet consistency and facilitating gravity-assisted feeding. Prednisolone therapy may assist mobility and reduce muscle pain. The cat described here displayed clinical signs from an early age with classical disease progression. It was humanely euthanased following a uraemic crisis at 2 years of age.

Case description

The kitten was acquired at 6 weeks of age, appearing normal apart from tongue protrusion. Subtle intermittent pelvic limb lameness was noted at 3 months, followed by occasional bunny hopping over subsequent months. At 5 months, pelvic radiographs, feline leukaemia virus and feline immunodeficiency virus serology, and urinalysis were unremarkable. Haematology, biochemistry, Toxoplasma IgM and IgG titres, and muscle biopsies were performed by the referring veterinarian, with marked CK elevation and other relevant clinicopathological abnormalities noted in Table 1. Biopsies of the gastrocnemius, semimembranosus and trapezius muscles were submitted to a local laboratory. The histopathological summary diagnosed lymphohistiocytic myositis with myocyte degeneration, necrosis, regeneration and protozoal cysts. Microscopically bradyzoites were identified within a thin-walled cyst multifocally within macrophages. Therapy was initiated as detailed in Table 2. Marked regurgitation, hypersalivation, intermittent coughing and mild oropharyngeal dysphagia were observed over the ensuing weeks. Thoracic radiographs with barium confirmed megaoesophagus (Figure 2).

Table 1

Abnormal results* at 5 months, 1 year and 2 years of age from haematology, biochemistry and Toxoplasma serology

Table 2

Treatment for presumed Toxoplasma myopathy

Figure 2

Oesophagram image using barium sulfate (60% w/v) with the cat in right lateral recumbency 30 mins after barium ingestion. The barium was co-administered with dry food. The radiograph also indicates a scalloped appearance of the diaphragm, which is likely due to thickening secondary to muscular dystrophy

Specialist referral at 8 months identified marked macroglossia (Figure 3a) with reduced lingual dexterity, hypertrophy of the neck and shoulder muscles (Figure 3b) with mild spinal discomfort on palpation, reduced body condition score (BCS) of 2/5, normothermia and normal cardiac auscultation. Neurological examination revealed mild ambulatory paraparesis, normal to reduced pelvic limb segmental reflexes and a reduced gag reflex. MD was suspected and cardiac troponin I, repeat CK levels and secondary histopathological review were requested. Persistent CK and marked troponin elevation (124 ng/l, reference interval [RI] 0–16) were noted. On review, the histopathologist verbally acknowledged that an error had been made, and no protozoal cysts were seen.

Figure 3

(a) Tongue size at 8 months old; (b) shoulder hypertrophy and (c) tongue size at 24 months old

Repeat muscle biopsies for specialised MD immunostains were declined. Omeprazole (1.1 mg/kg PO q24h) and upright feeding were originally initiated to manage the regurgitation and megaoesophagus with minimal clinical improvement. Sildenafil liquid (2.8 mg/kg PO q12h) was added with a moderate improvement, showing a 60–70% reduction in the frequency of regurgitation observed.

Gradual-onset diffuse hyperaesthesia, progressive muscle weakness and pain were noted, with peak signs at 11 months of age. Prednisolone was administered (1 mg/kg PO q24h) with moderate improvement in mobility and muscular pain on palpation. Prednisolone was continued at 0.5 mg/kg PO q24h thereafter as deterioration was noted when the medication was discontinued.

At 16 months of age, a fluoroscopic swallow study using iodinated contrast material (Iohexol; GE Healthcare Australia) revealed a normal pharyngeal and cricopharyngeal phase of swallowing, and the cervical oesophagus had normal tone and appropriate primary and secondary peristaltic activity; however, the thoracic oesophagus was flaccid and distended (megaoesophagus) with a lack of peristaltic activity. No conclusive evidence of oesophageal achalasia-like syndrome was detected with liquid contrast material, but the study was incomplete as the authors were unable to administer all consistencies of barium and could give only a limited number of boluses because of the cat’s demeanour. Consequently, a partial oesophageal stricture at the thoracic inlet could not be excluded but was deemed less likely. Echocardiography was recommended but declined.

At approximately 2 years of age, after slow progressive deterioration including tongue protrusion (Figure 3c) and generalised weakness, polydipsia, polyuria, abdominal pain and hyporexia developed. A physical examination confirmed abdominal pain, moderate pyrexia (39.9°C), moderate dehydration, marked muscle hypertrophy, reduced BCS of 1.5/5 and lingual calcific deposits (Figure 4). Urinalysis identified isosthenuria with a positive urine culture for a multidrug-resistant Pseudomonas aeruginosa. Marked azotaemia and hyperphosphataemia were noted (see Table 1). Abdominal ultrasound showed bilaterally reduced renal corticomedullary distinction, with increased echogenicity of the deeper cortex and mild renal pylectasia (Figure 5). The gastrointestinal tract was unremarkable and no diaphragmatic imaging was performed. Findings were suggestive of acute-on-chronic kidney disease, with presumed pyelonephritis. Despite 5 days of hospitalisation with intravenous fluid therapy, antimicrobials and supportive care, no significant improvement was observed.

Figure 4

Lingual calcium deposits, confirmed with alizarin reaction on histopathology. Calcinosis circumscripta has been a previously noted feature of cats with dystrophin-deficient MD and can be another clinical feature to prompt investigation for potential MD.¹² MD = muscular dystrophy

Figure 5

Renal ultrasound at 2 years of age: reduced corticomedullar distinction, increased cortical echogenicity

The progression of MD signs and renal disease led to euthanasia. Unfixed and fixed muscle samples collected post mortem from the biceps femoris, epaxial, triceps, tongue, neck and heart muscles were transported chilled by courier to the Comparative Neuromuscular Laboratory, San Diego, USA, for evaluation by standard histological and histochemical stains and reactions. A dystrophic phenotype was present in all muscles evaluated and included multifocal clusters of necrotic (degenerating) fibres with phagocytosis, clusters of regenerating fibres and numerous calcific deposits (Figure 6). Immunofluorescence staining of muscle cryosections using monoclonal antibodies including those against the rod and carboxy terminus of dystrophin, laminin α2, utrophin and spectrin, and against α-, beta (β)- and gamma (γ)-sarcoglycans confirmed dystrophin-deficient MD (Figure 7) with secondary reductions in dystrophin-associated proteins and glycoproteins. Spectrin staining as a control indicated good tissue quality.

Figure 6

Haematoxylin & eosin (H&E) and alizarin staining for calcific deposits

Figure 7

Immunofluorescence staining of muscle cryosections using monoclonal antibodies against dystrophin-associated proteins

Discussion

The clinical presentation at 8 months showed several distinct phenotypic features strongly associated with MD in cats, including marked lingual and shoulder muscle hypertrophy. These findings combined with marked hyperCKaemia and troponin I elevation may be considered pathognomonic for this condition.

Megaoesophagus has been described with canine MD, being noted in 34.2% of thoracic radiographs of Golden Retrievers with MD in one study.¹⁵ Regrettably, in the present case, sections of the oesophagus and diaphragm were not collected at the post-mortem examination to determine whether the MD was associated with myofibre degeneration of the thoracic and abdominal oesophageal muscles or diaphragm, as noted in a Spanish Water Spaniel.¹⁶ The use of clindamycin to treat the misdiagnosed Toxoplasma infection was considered as a possible cause of oesophageal injury; however, a classical stricture was not observed on swallow fluoroscopy and oesophagoscopy was declined.

Disease progression was observed with the development of dysphagia secondary to progressive lingual hypertrophy and megaoesophagus, leading to altered food and water intake and loss of body condition. Upright feeding was essential to reduce the risk of regurgitation and potential for aspiration pneumonia. Given the inconsistent finding of megaoesophagus in feline MD, a standing fluoroscopic swallow study was performed confirming megaoesophagus of the intrathoracic segment, with preserved cervical function.

The phosphodiesterase inhibitor sildenafil has been used in people and dogs for the management of megaoesophagus with oesophageal achalasia.^17,18 It has variable success, with some reports documenting benefit in the management of canine congenital idiopathic megaoesophagus¹⁹ and others showing no difference in oesophageal clearance time or quality-of-life scores between sildenafil and placebo.¹⁷ Clinical improvement was noted in the present cat after starting sildenafil, therefore it was presumptively beneficial. Serial radiographs may have been considered to monitor oesophageal diameter. The use of sildenafil, with concurrent upright feeding and use of omeprazole for presumed oesophagitis, may be considered in other cases of feline MD with megaoesophagus.

Uraemia, progressive regurgitation and weakness resulted in euthanasia. In human patients with MD, renal disease occurs secondarily to advanced MD due to insufficient water intake, dehydration and hyperosmolar syndrome, leading to acute renal failure.²⁰ As survival times increase, the identification of chronic kidney disease is increased in people.²⁰ The renal pathology aetiology was not elucidated in this patient; however, pyelonephritis was suspected, possibly exacerbated by prolonged prednisolone use.

Gashen et al²¹ showed male cats with MD had a higher predisposition to developing clinical cardiac disease. Although severe elevation in cardiac troponin I and abnormal cardiac histopathology were identified, testing for N-terminal pro-B-type natriuretic peptide (Cardiopet proBNP; IDEXX) was normal and clinical cardiac disease was not observed. However, all cats with suspected MD should be evaluated by echocardiogram, including siblings and female cats of the same family line, and not used for breeding.²¹

The original misdiagnosis occurred as suspected Toxoplasma bradyzoites were identified on routine paraffin histopathology. It is surmised that the pathologist may have received a truncated history, indicating the patient was Toxoplasma positive, without extensive details. This highlights the importance of a solid understanding of Toxoplasma serology interpretation, the need for further enquiry if findings do not correlate with the clinical picture and the fundamental use of immunofluorescence staining to obtain a definitive diagnosis of MD. Toxoplasmosis was discounted through failed clinical response, discussion with the pathologist and re-review, many months later. It is assumed that the positive IgG titre was due to previous exposure rather than current infection. A repeat and rising titre was not demonstrated.

Extrapolation from human medicine implies treatment with prednisolone could be beneficial in the early stages of MD.^22,23 In people, prednisone therapy is recommended to delay disease progression via slowed muscle loss and extended ambulation.^22–25 Liu et al²⁶ evaluated the use of prednisolone in Golden Retrievers that showed clinical improvement but histological decline. A recent review evaluating the effects of daily glucocorticoid therapy in boys with Duchenne MD confirmed a beneficial response.²⁴

Conclusions

This cat was diagnosed with dystrophin-deficient MD with a classical clinical disease presentation and progression including muscular and glossal hypertrophy, cardiomyopathy and dysphagia. Megaoesophagus and subsequent regurgitation were successfully managed with sildenafil, soft food and vertical feeding. Prednisolone therapy assisted ambulation with suspected reduction in muscle loss and discomfort but could have been initiated earlier with a correct diagnosis. This case highlights the importance of performing muscle biopsies in animals with hyperCKaemia and the diagnostic utility of immunohistochemical testing for the detection of many proteins that result in MD, including, but not limited to, dystrophin, sarcoglycans, laminin α2, dysferlin, α- and β- dystroglycans, utrophin and spectrin. In addition, this case highlights the the need to recognise MD as an important consideration for a cat showing marked macroglossia, lingual calcium deposits, muscular hypertrophy and marked persistent hyperCKaemia. Screening for megaoesophagus should be included for targeted therapy to optimise the patient’s quality of life.

Supplementary material

The following files are available as supplementary material:

Conflict of interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval The work described in this manuscript involved the use of non-experimental (owned or unowned) animals. Established internationally recognised high standards (‘best practice’) of veterinary clinical care for the individual patient were always followed and/or this work involved the use of cadavers. Ethical approval from a committee was therefore not specifically required for publication in JFMS Open Reports. Although not required, where ethical approval was still obtained, it is stated in the manuscript.

Informed consent Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers) for all procedure(s) undertaken (prospective or retrospective studies). For any animals or people individually identifiable within this publication, informed consent (verbal or written) for their use in the publication was obtained from the people involved.

© The Author(s) 2024

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).