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Brody Disease is an exceptionally rare, autosomal recessive myopathy attributed to the pathogenic variants in the ATP2A1 , which encodes the sarcoplasmic/endoplasmic reticulum Ca (2+) ATPase type 1 protein SERCA1. It was first described by Brody IA in 1969. To date, only thirty-three Brody families with forty-seven patients have been reported in the literature, and the disease prevalence is considered as 1 in 10 million, demonstrating the peculiarity of the disease. Clinical characteristics of Brody Disease include muscle stiffness after exercise, myalgia, and muscle cramps. Brody Disease patients generally have disease onset in the first decade, and genetic diagnosis is delayed as a consequence of both the rareness and the mild course of the disease. Here, we report a Turkish Brody Disease patient with a homozygous c.428G>A p.Arg143Gln (NM_004320.4) missense mutation in the ATP2A1 . The male patient, whose symptoms started at the age of 14-15, is now 36 years old. His clinical manifestations are athletic appearance, exotropia, slightly elevated creatine kinase (CK), mild progressive proximal muscle weakness in the lower extremities, muscle cramps, pain and stiffness. The patient described here has a very mild progression with an onset in the second decade, expanding the Brody Disease phenotype. The study also implies that in the era of emerging genetic therapies, the routine testing of patients with myopathies is a prerequisite since not only future therapies will be designed on molecular findings, but also currently available symptomatic and palliative treatment options will be more precisely applied., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Şahin, Badakal, Kovancılar Koç, Uysal and Başak.)

Paradoxical pseudomyotonia has previously been described in the English Cocker Spaniel (ECS) and English Springer Spaniel (ESS) breeds, without the identification of potentially causative variants. This disease is characterised by episodes of exercise-induced generalised myotonic-like muscle stiffness, phenotypically similar to congenital pseudomyotonia in cattle, and paramyotonia congenita and Brody disease in people. Four additional affected ESS dogs with paradoxical pseudomyotonia are described in this report, together with the identification of the autosomal recessive c.126C>A(p.(Cys42Ter)) SLC7A10 nonsense variant as candidate disease-causing variant in both ECS and ESS. The variant has an estimated prevalence of 2.5% in both breeds in the British study samples, but was not identified in the Belgian study samples. Genetic testing-based breeding should be a useful tool to eliminate this disease in the future, although an effective treatment option is available for severely affected dogs., (© 2023 Stichting International Foundation for Animal Genetics.)

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Paramyotonia congenita and Brody disease are well-described conditions in humans, characterized by exercise-induced myotonic-like muscle stiffness. A syndrome similar to Brody disease has been reported in cattle. Reports of a similar syndrome in dogs are scarce., Objectives: To define and describe the clinical, diagnostic, and genetic features and disease course of paradoxical pseudomyotonia in Spaniel dogs., Animals: Seven client-owned dogs (4 English Springer Spaniels and 3 English Cocker Spaniels) with clinically confirmed episodes of exercise-induced generalized myotonic-like muscle stiffness., Methods: Sequential case study., Results: All dogs were <24 months of age at onset. The episodes of myotonic-like generalized muscle stiffness always occurred with exercise, and spontaneously resolved with rest in <45 seconds in all but 1 dog. Extreme outside temperatures seemed to considerably worsen episode frequency and severity in most dogs. Complete blood count, serum biochemistry including electrolytes, urinalysis, brain magnetic resonance imaging, cerebrospinal fluid analysis, electromyography, motor nerve conduction velocity, ECG, and echocardiography were unremarkable. Muscle biopsy samples showed moderate but nonspecific muscle atrophy. The episodes seemed to remain stable or decrease in severity and frequency in 6/7 dogs, and often could be decreased or prevented by avoiding the episode triggers. The underlying genetic cause is not identified yet, because no disease-causing variants could be found in the coding sequence or splice sites of the 2 major candidate genes, SCN4A and ATP2A1., Conclusions and Clinical Importance: Paradoxical pseudomyotonia is a disease affecting Spaniels. It is of variable severity but benign in most cases., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

A 56-year-old man presented with painless impairment of muscle relaxation on vigorous contraction (eg, eyelid closure, hand grip, running). There were no episodes of paralysis, symptom progression, weakness or extramuscular symptoms. Five of his fifteen siblings had similar complaints. His serum creatine kinase was normal. Electromyography showed electrical silence on muscle relaxation, without myotonic discharges. DMPK , ClCN1 and SCN4A genetic testing was normal, but he had a homozygous pathogenic variant of ATP2A1 (c.1315G>A; pGlu439Lys). Brody disease is a rare autosomal recessive myopathy due to ATP2A1 mutations that reduce sarcoplasmic reticulum calcium-ATPase1 activity, hence delaying muscle relaxation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Brody disease was first described as a benign pseudo-myotonic disorder with muscular stiffness, which increased with exercise. Biochemical and genetic studies have pointed out its close relationship to a functional defect of the fast-twitch sarcoplasmic reticulum Ca(++) ATPase pump (SERCA1) encoded by the ATP2A1 gene located on chromosome 16. The histopathological features in this form of myopathy were generally described as non-specific, i.e. moderate degree of type 2 fibre atrophy and excess of internal nuclei. We here present the clinical and histopathological features of a patient with Brody disease over a 19-year follow-up period. This patient had two heterozygous ATP2A1 mutations and complained about muscle stiffness immediately after effort. He had suffered from this since early childhood and exhibited clinical symptoms mimicking myotonia. Histological, ultrastructural and cytogenetic analyses revealed morphologically abnormal nuclei with polyploidy. In this report, we discuss the possible links between the consequences of the genetic abnormality and the peculiar aspect of the nuclei., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A missense mutation in ATP2A1 gene, encoding sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) protein, causes Chianina cattle congenital pseudomyotonia, an exercise-induced impairment of muscle relaxation. Skeletal muscles of affected cattle are characterized by a selective reduction of SERCA1 in sarcoplasmic reticulum membranes. In this study, we provide evidence that the ubiquitin proteasome system is involved in the reduced density of mutated SERCA1. The treatment with MG132, an inhibitor of ubiquitin proteasome system, rescues the expression level and membrane localization of the SERCA1 mutant in a heterologous cellular model. Cells co-transfected with the Ca(2+)-sensitive probe aequorin show that the rescued SERCA1 mutant exhibits the same ability of wild type to maintain Ca(2+) homeostasis within cells. These data have been confirmed by those obtained ex vivo on adult skeletal muscle fibers from a biopsy from a pseudomyotonia-affected subject. Our data show that the mutation generates a protein most likely corrupted in proper folding but not in catalytic activity. Rescue of mutated SERCA1 to sarcoplasmic reticulum membrane can re-establish resting cytosolic Ca(2+) concentration and prevent the appearance of pathological signs of cattle pseudomyotonia., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Brody disease is an inherited myopathy associated with a defective function of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 1 (SERCA1) protein. Mutations in the ATP2A1 gene have been reported only in some patients. Therefore it has been proposed to distinguish patients with ATP2A1 mutations, Brody disease (BD), from patients without mutations, Brody syndrome (BS). We performed a detailed study of SERCA1 protein expression in muscle of patients with BD and BS, and evaluated the alternative splicing of SERCA1 in primary cultures of normal human muscle and in infant muscle. SERCA1 reactivity was observed in type 2 muscle fibers of patients with and without ATP2A1 mutations and staining intensity was similar in patients and controls. Immunoblot analysis showed a significant reduction of SERCA1 band in muscle of BD patients. In addition we demonstrated that the wild type and mutated protein exhibits similar solubility properties and that RIPA buffer improves the recovery of the wild type and mutated SERCA1 protein. We found that SERCA1b, the SERCA1 neonatal form, is the main protein isoform expressed in cultured human muscle fibers and infant muscle. Finally, we identified two novel heterozygous mutations within exon 3 of the ATP2A1 gene from a previously described patient with BD., (© 2013 Elsevier Inc. All rights reserved.)