ATP2A1 – Brody myopathy

Brody myopathy is a rare autosomal recessive skeletal muscle disorder characterized by exercise-induced impairment of muscle relaxation due to defective sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 1 (SERCA1) function. Initial linkage in two families associated biallelic ATP2A1 mutations leading to premature stop codons and loss of Ca²⁺ uptake established the gene–disease link (PMID:8841193).

Genetic evidence supports a definitive association: over 40 patients in 29 families harbor biallelic ATP2A1 variants, including missense, frameshift, splice-site, and in-frame deletions, under an autosomal recessive inheritance model (PMID:32040565) and recessive compound heterozygosity in a family with malignant hyperthermia susceptibility (PMID:25614869). A recurrent missense allele c.547G>A (p.Glu183Lys) has been reported in multiple patients (PMID:32040565).

Clinically, affected individuals present in childhood with delayed muscle relaxation manifesting as limb and eyelid stiffness, silent contractures on EMG, normal or mildly elevated creatine kinase, and preserved strength despite an athletic build. Phenotypes such as exercise-induced muscle stiffness (HP:0008967) and frequent falls are common, and a subset may exhibit malignant hyperthermia–like episodes (PMID:32040565).

Functional studies demonstrate loss of SERCA1 Ca²⁺ transport in patient muscle biopsies and recombinant assays, with reduced ATPase activity and impaired Ca²⁺ occlusion (PMID:8841193). Proteasome inhibition rescues mutant SERCA1 stability and restores Ca²⁺ handling in cellular models (PMID:25288803). Zebrafish dominant-negative atp2a1 alleles phenocopy muscle relaxation defects, corroborating haploinsufficiency mechanisms (PMID:20533403).

A clinically overlapping Brody “syndrome” without ATP2A1 mutations highlights genetic heterogeneity and cautions against overdiagnosis in the absence of molecular confirmation (PMID:22704959).

In integration, robust genetic and functional concordance classify ATP2A1 and Brody myopathy as a definitive gene–disease pair. Routine sequencing of ATP2A1 in patients with exercise-induced delayed relaxation, together with SERCA1 activity assays or western blot, guides diagnosis, genetic counseling, and management, including malignant hyperthermia precautions.

Key Take-home: Biallelic ATP2A1 mutations cause Brody myopathy via SERCA1 loss of function; ATP2A1 testing is essential for accurate diagnosis and perioperative risk mitigation.

References

• Nature Genetics • 1996 • Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. PMID:8841193
• Brain • 2020 • Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients. PMID:32040565
• Molecular Genetics & Genomic Medicine • 2014 • Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility. PMID:25614869
• The Journal of Biological Chemistry • 2014 • Inhibition of ubiquitin proteasome system rescues the defective sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1) protein causing Chianina cattle pseudomyotonia. PMID:25288803
• Neuromuscular Disorders • 2012 • Brody syndrome: a clinically heterogeneous entity distinct from Brody disease: a review of literature and a cross-sectional clinical study in 17 patients. PMID:22704959

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