Brody myopathy is an ultra-rare autosomal recessive inherited disorder that impairs skeletal muscle function in humans. It is caused by deficiency of the Sarco(Endo)plasmic reticulum Ca2+-ATPase isoform1 (SERCA1), arising from defects, mainly missense mutations, in the ATP2A1 gene. At present, neither specific therapy, nor mouse model exists for Brody myopathy. Bovine pseudomyotonia (PMT) is a very rare skeletal muscle disorder. As Brody myopathy, it is an autosomal recessive inherited disorder caused by missense variants in the atp2a1 gene. Most mutations generate proteins corrupted in proper folding that although catalytically active, were ubiquitinated and prematurely degraded by the ubiquitin-proteasome system, thus sharing with Cystic Fibrosis the same pathogenetic mechanism. Bovine PMT, despite unconventional, is currently the unique mammalian model of Brody disease. In this study, we show that CFTR correctors, particularly C17, successfully rescue SERCA1 mutants both in vitro and in vivo models. Our findings suggest that CFTR correctors may be a potential innovative pharmacological approach addressing Brody patients in which mutated SERCA1 retains its activity.

The zebrafish (Danio rerio) has become one of the most popular and valuable model organisms for studying rare neuromuscular diseases. Its unique characteristics, including the high number of offspring produced with each mating, transparent eggs, rapid development, and genetic similarity to humans, make this small vertebrate ideal for investigating complex and rare disorders affecting the skeletal muscle, such as Duchenne Muscular Dystrophy (DMD), Limb Girdle Muscular Dystrophies (LGMDs), and Brody Myopathy (BM). Various zebrafish models, both natural mutants and genetically engineered strains, have been developed to study these conditions. These models enable the deciphering of pathogenetic mechanisms, the real-time monitoring of disease progression, high-throughput drug screening, and the testing of novel therapeutic approaches. As research progresses, zebrafish models are likely to play an increasingly crucial role in unravelling the complexities of rare neuromuscular diseases and developing targeted therapies, offering hope for affected patients.

One of the leading thrombocytopenia occasions in childhood is immune thrombocytopenia (ITP). Small number of these patients do not respond to treatment methods known to be effective for ITP such as corticosteroids, intravenous immunoglobulin and thrombopoietin receptor agonists (eltrombopag, romiplostim, etc.) and have serious bleeding symptoms. We present a case in which a molecular genetic analysis was performed due to challenging responses to medical treatment for severe systemic bleeding symptoms which were similar to ITP. A hemizygous variant was detected in the GATA1 gene and a homozygous variant in the ATP2A1 gene for Brody myopathy. Eltrombopag, romiplostim, IVIG and corticosteroid were applied to resistant thrombocytopenia of the patient without knowing the cause. Patient had response in platelet counts in some occasions. This situation attracted our attention after the detection of this GATA variant in the etiopathogenesis of thrombocytopenia. Further investigations should be performed for much more rare causes of thrombocytopenia in patients with refractory thrombocytopenia attacks.

Brody disease (BD) is an "ultra-rare" human genetic disorder of skeletal muscle function due to defects in the atp2a1 gene causing deficiency of the SERCA protein, isoform1. The main clinical signs are exercise-induced stiffness and delayed muscular relaxation after physical exercises, even mild ones. No mouse model nor specific therapies exist for Brody myopathy, which is therefore considered an orphan disease. Bovine congenital pseudomyotonia (PMT) is a muscular disorder characterized by an impairment of muscle relaxation and is the only mammalian model of human BD. The pathogenetic mechanism underlying bovine PMT has been recently clarified. These findings prompted us to purpose a potential pharmacological approach addressing a specific population of BD patients who exhibit reduced expression but still exhibit activity of the SERCA1 pump. Preclinical research involving in vivo studies is essential and necessary before clinical trials can be pursued and SERCA protein shows a high degree of conservation among species. So far, the only animal models available to study BD in vivo are a group of zebrafish mutant lines known as accordion zebrafish (acc). In this paper, we focused on a comprehensive characterization of the "acctq206" zebrafish variant. Our aim was to use this mutant line as an experimental animal model for testing the novel therapeutic approach for BD.

Brody disease is a rare autosomal recessive myopathy, caused by pathogenic variants in the ATP2A1 gene. It is characterized by an exercise-induced delay in muscle relaxation, often reported as muscle stiffness. Children may manifest with an abnormal gait and difficulty running. Delayed relaxation is commonly undetected, resulting in a long diagnostic delay. Almost all published cases so far were adults with childhood onset and adult diagnosis. With diagnostic next-generation sequencing, an increasing number of patients are diagnosed in childhood. We describe the clinical and genetic features of 9 children from 6 families with Brody disease. All presented with exercise-induced delayed relaxation, reported as difficulty running and performing sports. Muscle strength and mass was normal, and several children even had an athletic appearance. However, the walking and running patterns were abnormal. The diagnostic delay ranged between 2 and 7 years. Uniformly, a wide range of other disorders were considered before genetic testing was performed, revealing pathogenic genetic variants in ATP2A1. To conclude, this case series is expected to improve clinical recognition and timely diagnosis of Brody disease in children. We propose that ATP2A1 should be added to gene panels for congenital myopathies, developmental and movement disorders, and muscle channelopathies.