Brody Myopathy — Comprehensive Disease Research Report

Prepared: 2026-08-16 · Target entity: Brody myopathy / Brody disease · MONDO:0010977 (verified via OLS4)

How to read the citations here. Quotes marked [verbatim] were pulled character-for-character from the PubMed abstract record via NCBI E-utilities and are safe to use as evidence snippet: values. Anything marked [full-text derived] came from reading article body text through a summarizing fetch — those numbers are leads, and need re-verification against the source before they get curated with a snippet. Ontology IDs marked [OAK-verified] were checked against local sqlite:obo:* adapters in this session; everything else is a suggestion to check.

1. Disease Information

What it is

Brody myopathy is an ultra-rare, autosomal recessive skeletal muscle disorder in which the calcium pump that resets fast-twitch muscle after a contraction is broken. Think of a sink with a slow drain: the contraction fills the cytoplasm with calcium just fine, but emptying it back into the sarcoplasmic reticulum takes far too long. Clinically that reads as exercise-induced stiffness and delayed relaxation — a cramp-like tightening that looks exactly like myotonia but is electrically silent on needle EMG. That silence is the diagnostic tell.

It is caused by biallelic pathogenic variants in ATP2A1, encoding SERCA1 (sarco/endoplasmic reticulum Ca²⁺-ATPase, isoform 1), the pump that dominates type II (fast-twitch) fibers.

[verbatim] "Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene." — Molenaar et al., Brain 2020 (PMID:32040565)

[verbatim] "Brody disease is a rare inherited disorder of skeletal muscle function. Symptoms include exercise-induced impairment of skeletal muscle relaxation, stiffness and cramps. Ca2+ uptake and Ca2+ ATPase activities are reduced in the sarcoplasmic reticulum…" — Odermatt et al., Nature Genetics 1996 (PMID:8841193)

First description

Irwin A. Brody, NEJM 1969;281(4):187–192, "Muscle contracture induced by exercise. A syndrome attributable to decreased relaxing factor" (PMID:4239835). No structured abstract exists on this record — do not attempt to snippet-validate against it. The gene link followed 27 years later (Odermatt 1996).

Key identifiers

Synonyms and naming

• Brody disease (BROD)
• Brody myopathy
• SERCA1 deficiency
• Sarcoplasmic reticulum Ca²⁺-ATPase deficiency
• ATP2A1-related myopathy

One naming distinction really matters for curation. The literature separates:

• Brody disease — reduced SERCA activity with identified biallelic ATP2A1 variants.
• Brody syndrome — the same clinical/biochemical picture without ATP2A1 variants; genetically unsolved.

[verbatim, partial] "Brody disease is a rare inherited myopathy due to reduced sarcoplasmic reticulum Ca(2+) ATPase (SERCA)1 activity." … "Brody disease presents with an onset in the 1st decade, a generalized pattern of muscle stiffness" … "Patients with Brody syndrome more often report myalgia and experience a considerable impact on daily life." — Voermans et al., Neuromuscul Disord 2012 (PMID:22704959), cross-sectional study of 17 Brody syndrome patients

MONDO folds "Brody disease" in as a synonym of MONDO:0010977. If you want the syndrome/disease split represented, do it with a subtype or a lump/split note rather than a second MONDO term.

Data provenance

Everything below is disease-level aggregated knowledge — case reports, one 40-patient international cohort, and one 17-patient cross-sectional study. There is no registry, no EHR-derived cohort, and no natural-history study with structured longitudinal data. Curate accordingly: frequencies come from n≈40, not from a population.

2. Etiology

Primary cause

Biallelic (homozygous or compound heterozygous) loss-of-function variants in ATP2A1 (16p11.2; older literature maps it to 16p12.1-12.2). Purely Mendelian — no infectious, environmental, or autoimmune contribution to causation.

Two mechanistic flavors of "loss of function," and they matter therapeutically:

1. Quantitative loss — nonsense, frameshift, splice, large deletion → little or no SERCA1 protein made.
2. Qualitative/folding loss — missense → protein is often catalytically competent but misfolded, recognized by ER quality control, ubiquitinated, and destroyed before it reaches the SR membrane. This is the CFTR-ΔF508 playbook running in a different gene, and it's the entire basis for the corrector-drug strategy in §12.

[verbatim] "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." — Sacchetto group, Hum Mol Genet 2025 (PMID:41206505)

Genetic risk factors

• Causal: biallelic ATP2A1 variants. Heterozygous carriers are clinically unaffected.
• Not causal: heterozygous ATP2A1 variants alone. Odermatt 2000 explicitly disproved one candidate this way.

[verbatim] "In a fourth family, the heterozygous substitution of T for C2455, mutating Arg819 to Cys, was identified. This mutation was also readily expressed in HEK-293 cells and shown to have near normal Ca2+ transport activity, indicating that it is not causal for Brody disease." — Odermatt et al., Hum Genet 2000 (PMID:10914677)

• Consanguinity raises risk, as for any AR disorder; the 2023 Turkish case was homozygous, consistent with that.
• No modifier genes have been identified. Genotype–phenotype correlation is reported as absent (see §4).

Environmental risk / trigger factors

There is a clean distinction here that a knowledge base should preserve: nothing environmental causes Brody myopathy, but several things unmask or worsen it. Triggers, not etiology:

Suggested ECTO grounding: exposure to cold temperature and exposure to anesthetic agent concepts — verify CURIEs with OAK before binding; I did not verify ECTO terms this session.

Protective factors

• None documented. No protective allele, dietary factor, or lifestyle exposure has been reported.
• Pacing, warm environments, and avoidance of maximal exertion are symptom-avoidance strategies, not protective factors in the epidemiological sense.
• There is no "second wind" phenomenon (that's McArdle disease) — a useful negative for differential diagnosis.

Gene–environment interaction

One real, clinically consequential interaction: genotype (biallelic ATP2A1 LoF) × anesthetic exposure → MH-like crisis. The proposed convergence is shared elevated myoplasmic calcium.

[verbatim, partial] Sambuughin et al. note that "elevated myoplasmic Ca(2+) content" is common to both conditions, explaining the secondary malignant hyperthermia diagnosis alongside the primary Brody myopathy. — Mol Genet Genomic Med 2014 (PMID:25614869)

3. Phenotypes

HPO annotations currently attached to OMIM:601003

Retrieved live from the HPO annotation service. Note the many 0/N entries — these are curated exclusions, and they're arguably the most diagnostically valuable part of the profile:

All HP IDs above independently [OAK-verified] against sqlite:obo:hp except where the HPO service supplied them directly.

Clinical features with cohort frequencies

From the 40-patient international cohort (Molenaar 2020, PMID:32040565). [full-text derived — re-verify before snippet-curation]

The abstract-level statements are safely quotable:

[verbatim] "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." — PMID:32040565

The eyelid involvement isn't a curiosity — it's mechanistically informative. Orbicularis oculi (UBERON:0001578 [OAK-verified]) is a fast-twitch-rich muscle, so it's exactly where a SERCA1-specific defect should show up first.

Phenotype characteristics

• Age of onset: first decade in the large majority. Mean reported symptom onset 19.2 ± 15.0 yr with 38/40 in childhood [full-text derived] — the mean is skewed by late-recognized cases; the modal onset is childhood. The 2023 Turkish case pushed onset into the second decade (age 14–15).
• Severity: mild to moderate. Strength preserved. Most patients function independently.
• Progression: essentially non-progressive or minimally progressive. This is a load-bearing fact for prognosis.
• Course: episodic/exertional — stiffness appears with activity and resolves with a few minutes of rest.
• Duration: lifelong.

Laboratory phenotype

• Creatine kinase (HP:0003236 [OAK-verified]): normal or mildly elevated. Range 50–1,300 IU/L, roughly half normal and half mildly-to-moderately raised [full-text derived].
• SERCA activity in muscle homogenate: markedly reduced — now with proper reference values, see §10.
• Rhabdomyolysis (HP:0003201 [OAK-verified]): rare. A 2026 case presented with exercise-induced rhabdomyolysis as the index event (PMID:41926432) — this genuinely expands the recognized presentation.

Quality-of-life impact

Thin evidence, honestly. The 2020 cohort used a Modified Rankin Scale, with 13/23 (57%) at "slight disability but able to look after own affairs" [full-text derived]. No EQ-5D, SF-36, or PROMIS data exist for this disease. Notably, Voermans 2012 reports that Brody syndrome patients (the gene-negative group) report more myalgia and greater daily-life impact than Brody disease patients — a genuine, quotable contrast.

4. Genetic / Molecular Information

Causal gene

ATP2A1 — ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 1

• HGNC: hgnc:811 [OAK-verified] (note repo convention: lowercase hgnc:)
• OMIM gene: 108730
• Locus: 16p11.2
• Reference transcript commonly used in reports: NM_004320.4
• Protein: SERCA1a, ~994 aa, ~110 kDa P-type ATPase
• UniProt: O14983 (SERCA1 human) — verify before binding

Splice isoforms. ATP2A1 makes two developmentally regulated isoforms by alternative splicing at the 3′ end: SERCA1a (adult; stop codon in exon 22) and SERCA1b (neonatal; skips exon 22, stop in exon 23). SERCA1a is >99% of SERCA1 in adult skeletal muscle. This matters for in-vitro work — Guglielmi 2013 found the neonatal SERCA1b isoform predominates in cultured human myotubes and in infant muscle, which limits how well cultured fibers model the adult defect.

Pathogenic variant landscape

Variant classes seen in Brody disease (all reported): nonsense, frameshift (deletions and insertions/duplications), canonical splice-site, in-frame single-codon deletions, missense, and large rearrangements including whole-gene deletion.

From the 40-patient cohort, 33 distinct mutations [full-text derived]:

Recurrent variants noted across unrelated families [full-text derived]: p.Leu67del, c.2464dup, exon 9 deletion, p.Arg560Cys. None constitutes an established founder allele.

Individually characterized variants worth curating:

[verbatim] "Here, we report a Turkish Brody Disease patient with a homozygous c.428G>A p.Arg143Gln (NM_004320.4) missense mutation in the ATP2A1." — PMID:38125752

Variant classification / population frequency — honest gaps:

• ClinVar: a query on ATP2A1[gene] returns 1,113 variation records total; restricting to pathogenic/likely-pathogenic returns 268. That P/LP number is almost certainly inflated by multi-gene CNV records, because ATP2A1 sits inside the recurrent distal 16p11.2 BP2–BP3 ~220 kb deletion (chr16:28.73–28.95 Mb, ~9 genes including SH2B1; OMIM 613444), which is curated as pathogenic for obesity/developmental delay. Do not curate 268 as "268 pathogenic ATP2A1 variants." Re-derive with an explicit single-gene filter.
• gnomAD constraint (pLI, LOEUF, o/e): I was unable to retrieve these — the gnomAD browser is a JS app and its API needs POST. Flagging as not-retrieved rather than guessing. What is clinically established: heterozygous carriers are asymptomatic, so ATP2A1 is not haploinsufficient in the disease-causing sense.
• Carrier frequency: not established anywhere I could find. Given ~47 patients ever reported, it has never been measured directly.

Somatic vs germline

Entirely germline. No somatic ATP2A1 disease has been described. (Incidental note: ATP2A1 shows up in cancer expression literature, but that's not a somatic disease mechanism relevant here.)

Functional consequences

• Loss of function in all pathogenic cases. Two sub-mechanisms: reduced protein quantity (truncating) and reduced protein stability/trafficking despite retained catalysis (missense; see §6).
• No gain-of-function or dominant-negative mechanism reported.

Modifier genes, epigenetics, chromosomal abnormalities

• Modifier genes: none identified.
• Genotype–phenotype: explicitly reported as absent — "No gradation in severity could be demonstrated in clinical presentation… leading to no particular phenotype-to-genotype correlations." [full-text derived, PMID:32040565]
• Epigenetics: no DNA methylation, histone, or chromatin studies exist for Brody myopathy. Genuine blank.
• Chromosomal abnormalities: whole-gene ATP2A1 deletion has been reported as one allele. The distal 16p11.2 BP2–BP3 deletion removes one ATP2A1 copy but is not reported to cause Brody myopathy on its own — it would need a second-hit point variant in trans. This is a plausible-but-unreported compound-heterozygous mechanism worth flagging as a knowledge gap.

5. Environmental Information

Short section, and it should be. Brody myopathy is Mendelian, full stop.

• Environmental factors: no toxin, radiation, pollutant, or occupational exposure contributes to causation. Cold and exertion are symptom triggers, not causes.
• Lifestyle factors: no dietary, smoking, or alcohol association. Athletic training is neither causal nor protective; several patients are notably athletic despite the disease.
• Infectious agents: none. Not applicable.
• Iatrogenic exposure worth modeling: volatile anesthetics and depolarizing muscle relaxants (succinylcholine, CHEBI:45652 [OAK-verified]) as MH-crisis triggers. This is the one exposure that belongs in an environmental: block with influences_mechanisms.

6. Mechanism / Pathophysiology

Here's the causal chain, laid out for a pathograph.

The normal biology it breaks

SERCA1 is a P-type ATPase with three cytoplasmic domains (A/actuator, N/nucleotide-binding, P/phosphorylation) and ten transmembrane helices carrying two Ca²⁺-binding sites. It runs a Post-Albers E1/E2 cycle, pumping 2 Ca²⁺ into the SR lumen per ATP hydrolyzed against a countertransport of protons. In fast-twitch fibers it is the overwhelmingly dominant route by which cytosolic calcium is cleared after a contraction — i.e., it is the relaxation machinery. It is tonically restrained by small regulatory peptides (sarcolipin, myoregulin); phospholamban does the equivalent job for the SERCA2a isoform in heart and slow muscle. Structural reference: Toyoshima's rabbit SERCA1a structure (PDB 1SU4) — verify PDB before binding.

Causal chain, upstream → downstream

Step 1 (MOLECULAR). Biallelic ATP2A1 LoF variants. → Two routes: - 1a. Truncating/splice/deletion → little or no SERCA1 protein synthesized. - 1b. Missense → protein folds badly, is ubiquitinated, and is stripped out by the ubiquitin–proteasome system before reaching the SR membrane, despite retaining catalytic activity.

[verbatim, partial] Bianchini et al. showed the mutation "impairs protein folding rather than catalytic function," and that proteasome inhibition restores "the same ability of wild type to maintain Ca(2+) homeostasis within cells." — J Biol Chem 2014 (PMID:25288803)

Step 2 (MOLECULAR). Reduced SERCA1 protein at the SR membrane → reduced SR Ca²⁺-ATPase activity. Measured reduction: 50–80% of control activity [full-text derived], and now quantified against proper reference values:

[verbatim] "With the optimized assay, SERCA activity was assessed in muscle samples from healthy controls (n = 28) and patients with Brody disease (n = 4)… demonstrate marked decreased SERCA activity in Brody disease muscle samples (30.0 ± 4.2 mU/mg protein) compared to controls (86.7 ± 25.1 mU/mg protein)." — Biochem Biophys Rep 2026 (PMID:41938373)

Step 3 (CELLULAR). Impaired Ca²⁺ re-uptake into the SR → prolonged elevation of cytosolic free Ca²⁺ after each contraction, i.e. a slow calcium-transient decay. Directly imaged in the zebrafish model:

[verbatim] "In vivo imaging of muscle Ca2+ transients revealed that cytosolic Ca2+ decay was significantly slower in acc muscle. Thus, it appears that the mutant behavior is caused by a muscle relaxation defect due to the impairment of Ca2+ re-uptake." — Hirata et al., Development 2004 (PMID:15469975)

Step 4 (CELLULAR/TISSUE). Sustained cytosolic Ca²⁺ keeps troponin C saturated and cross-bridges cycling → electrically silent contracture. The key word is silent: the sarcolemma isn't misbehaving, so needle EMG records nothing during the stiffness. That's what separates it from every myotonia on the differential.

Step 5 (TISSUE). Selective type II (fast-twitch) fiber involvement, because SERCA1 is the fast-fiber isoform and slow fibers run SERCA2a instead. Explains the muscle distribution (limbs, eyelids), the exertion dependence, and the biopsy finding of type II fiber atrophy.

Step 6 (ORGANISM). Exercise-induced stiffness, delayed relaxation, cramps, myalgia; cold exacerbation (SERCA kinetics slow further at low temperature); MH-like susceptibility on anesthetic exposure via shared myoplasmic Ca²⁺ overload; rarely, exertional rhabdomyolysis.

The compensation branch — why this disease is mild

Here's the biologically interesting bit. A complete SERCA1 knockout is lethal in mice, yet humans with essentially absent SERCA1 walk around with an athletic build and stiff eyelids. Something is picking up the slack.

[verbatim] "…raising the intriguing question: how have these Brody patients partially compensated for the functional knockout of a gene product believed to be essential for fast-twitch skeletal muscle relaxation?" — PMID:8841193

Candidate compensators (all still contested): - SERCA2 upregulation — supported in the MH family (PMID:25614869: "Muscle analysis revealed absent SERCA1 but elevated SERCA2, suggesting compensatory mechanisms partially restoring calcium transport"), but the 2020 cohort found SERCA2 expression normal in 7/8 tested [full-text derived]. Genuinely conflicting. - Plasma membrane Ca²⁺-ATPase (PMCA) upregulation — the bovine model supports this over SERCA2 [full-text derived]. - Na⁺/Ca²⁺ exchanger activation. - Mitochondrial Ca²⁺ uptake. - Reduced myoregulin/sarcolipin inhibition of residual pump.

This unresolved compensation question is an excellent KNOWLEDGE_GAP discussion for a dismech entry — and the SERCA2 contradiction is a textbook case for curating two competing mechanistic_hypotheses rather than one settled chain.

Ontology term suggestions for the mechanism

GO biological process / molecular function / cellular component — all [OAK-verified]:

Cell types — [OAK-verified]; note the numbering is easy to flip:

Pathways. KEGG hsa04020 (calcium signaling pathway) and hsa04260/04261; Reactome "Ion homeostasis" (R-HSA-5578775) and "Reduction of cytosolic Ca++ levels" (R-HSA-418359) — verify Reactome IDs before use.

Immune system, metabolism, fibrosis

• Immune involvement: none. Not an inflammatory or autoimmune myopathy. (Contrast: rippling muscle disease has an immune-mediated form; Brody does not.)
• Metabolic changes: no primary metabolic defect. Indirect consequence — SERCA pumping is a major consumer of muscle ATP, so a broken pump alters the energy economy of contraction, but there is no documented glycogen, lipid, or amino-acid abnormality. Explicitly not a metabolic myopathy in the McArdle sense.
• Tissue damage: mild. Type II fiber atrophy, fiber-size variability, internal nuclei. Myonecrosis essentially absent (one exception in the 40-patient cohort) [full-text derived]. No fibrosis, no ischemia, no oxidative-stress mechanism established.

Molecular profiling — a candid inventory

• Transcriptomics: no Brody-specific human muscle RNA-seq dataset published.
• Proteomics: no dedicated proteomic study. The protein-level work is targeted western blot and 2D gel (PMID:20142766 used high-resolution 2D electrophoresis).
• Metabolomics / lipidomics: none.
• Single-cell / spatial transcriptomics: none. Given the fiber-type-selective mechanism, single-nucleus RNA-seq of Brody muscle is an obvious unexploited experiment — worth curating as a proposed_experiments entry.
• Functional genomics screens: none disease-specific.
• Ultrastructure (the one thing that is characterized):

[verbatim] "Ultrastructural examination revealed dilatation of lateral cisternae and proliferation of tubular elements of the sarcoplasmic reticulum." — PMID:20142766

7. Anatomical Structures Affected

Organ level

• Primary: skeletal muscle — UBERON:0001134 skeletal muscle tissue [OAK-verified]; UBERON:0014892 skeletal muscle organ, vertebrate [OAK-verified].
• Body system: musculoskeletal only. No cardiac involvement (heart runs SERCA2a from ATP2A2), no CNS/PNS involvement, no respiratory involvement in humans.
• Secondary organ involvement: essentially none. The exceptions are crisis-related — MH-like hypermetabolic episodes and, rarely, rhabdomyolysis with its downstream renal risk.

Note the striking species contrast: the mouse Atp2a1-null dies of diaphragm failure (UBERON:0001103 [OAK-verified]), a compartment humans with the same defect do not clinically manifest. See §15 — this is a genuine HUMAN_MODEL_MISMATCH.

Regional distribution

Lateralization: bilateral and symmetric. No asymmetric or focal presentation reported.

Tissue and cell level

• Tissue type: striated skeletal muscle.
• Target cell population: type II / fast-twitch muscle fibers (CL:0002212), with type I fibers spared. Biopsies show a shifted fiber composition — mean type II fiber fraction in quadriceps ~75% vs. a 50–65% normal range [full-text derived] — alongside selective type II atrophy.

Subcellular level

• Sarcoplasmic reticulum (GO:0016529), specifically the SR membrane (GO:0033017) and the longitudinal/free SR where SERCA1 concentrates.
• Terminal cisternae / lateral cisternae — dilated on EM.
• Cytosol/myoplasm — the compartment where calcium wrongly lingers.
• For missense alleles: endoplasmic reticulum quality-control compartment and the proteasome (GO:0043161) are where the protein is lost.

8. Temporal Development

Onset

• Typical: first decade of life. HPO annotates HP:0011463 (Childhood onset) at 5/5. The 2020 cohort had 38/40 with childhood onset [full-text derived].
• Range: one neonatal-onset annotation exists (HP:0003623, 1/1); at the other end, the 2023 Turkish case began at 14–15.
• Pattern: insidious and chronic, punctuated by discrete exertional episodes. Not acute.
• Diagnostic delay is the norm — mean age at diagnosis 27.3 ± 14.6 yr, mean delay 9.9 ± 13.7 yr [full-text derived]. Nearly a decade. That's the headline number for any "under-recognition" argument.

[verbatim] "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." — PMID:32040565

Progression

• Rate: none to minimal. This is the single most reassuring fact about the disease.

[verbatim] "Onset begins in childhood and there was no or only mild progression of symptoms over time." — PMID:32040565

• Stages: no staging system exists, and none is warranted for a non-progressive condition.
• Course: episodic/exertional on a stable chronic baseline. Symptoms appear with activity and remit within minutes of rest.
• Duration: lifelong.

The mild-progression rule has at least one documented exception at the individual level — the 2023 Turkish patient showed "mild progressive proximal muscle weakness in the lower extremities" [verbatim, PMID:38125752]. Curate that as an individual observation, not a general course.

Patterns

• Remission: none spontaneous; symptom relief is rest-dependent and immediate rather than a true remission.
• Critical periods: the actionable ones are perioperative windows (anesthetic exposure) and any planned high-intensity exertion. There is no developmental critical window for intervention.

9. Inheritance and Population

Epidemiology

• Prevalence: approximately 1 in 10,000,000. Orphanet classes it as <1/1,000,000 (point prevalence, worldwide).

[verbatim] "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." — PMID:38125752

For a dismech prevalence block: measure_type: POINT_PREVALENCE, prevalence_class: BELOW_1_IN_1000000, rate_per_100000: 0.01, population: Worldwide, with the verbatim sentence above as the snippet. A parallel CASES_IN_LITERATURE record (47 patients / 33 families as of 2023; the 2020 cohort itself totaled 40 patients from 28 families) captures the other framing.

• Incidence: never measured.
• Almost certainly under-diagnosed — the ~10-year diagnostic delay plus the "incomplete recognition" statement above both argue the true figure is higher than the counted figure.

Genetic epidemiology

• Inheritance: autosomal recessive (HP:0000007). Confirmed repeatedly since 1996.
• Penetrance: appears complete in biallelic individuals; no unaffected homozygotes reported. But with n≈47 total, "complete penetrance" is an observation, not a measurement.
• Expressivity: variable — from the very mild second-decade Turkish case to patients with MH crises. Notably, that variability does not track genotype.
• Genetic anticipation: not applicable (no repeat expansion).
• Germline mosaicism: not reported.
• Founder effects: none established. Several recurrent alleles (p.Leu67del, c.2464dup, exon 9 del, p.Arg560Cys) appear in >1 family but haven't been shown to share haplotypes.
• Consanguinity: contributory, as expected for AR; homozygous cases in consanguineous populations are described.
• Carrier frequency: not established.

Population demographics

• Sex ratio: approximately 1:1 — consistent with autosomal inheritance, and reported as roughly equal in the 40-patient cohort [full-text derived].
• Geographic distribution: no endemic focus. The 2020 cohort drew from France, Netherlands, Canada, UK, Germany, Spain, Italy, Switzerland, and USA [full-text derived]; additional reports from Turkey (2023) and Italy (2023). Ascertainment follows neuromuscular-center density, not biology.
• Ethnic predisposition: none identified.
• Age distribution of affected individuals: all ages, since the disease neither kills nor progresses; the reported population skews toward young adults simply because that's when the decade-long diagnostic delay finally resolves.

10. Diagnostics

Diagnostic reasoning in one sentence

Exercise-induced stiffness + delayed relaxation on repetitive contraction + electrically silent EMG during the stiffness → sequence ATP2A1.

[verbatim] "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." — PMID:32040565

Clinical / bedside tests

• Repetitive contraction provocation — repeated forceful eye closure or hand grip, watching for progressively delayed relaxation. The cardinal sign.
• Percussion myotonia: absent (HP:0010548, 0/10) — this negative is diagnostically load-bearing.
• No warm-up phenomenon (unlike myotonia congenita); no second wind (unlike McArdle).

Laboratory tests

Electrophysiology — the discriminating test

• Needle EMG: no myotonic discharges (HP:0100284, 0/5 excluded). Instead, silent contractures in roughly 64% of tested patients [full-text derived], defined as "prolonged involuntary muscle contractions following voluntary phasic contractions without electrical activity."
• The 2020 authors argue for the term "silent contractures" over the older "silent cramps," since the strict electromyographic definition of cramp doesn't apply [full-text derived].
• Nerve conduction studies: normal.
• ECG/EEG: normal; not diagnostically relevant.

Muscle biopsy and histopathology

Mild, nonspecific, and supportive rather than diagnostic:

[verbatim] "…muscle biopsy showed mild myopathic changes with selective type II atrophy." — PMID:32040565

(Frequencies [full-text derived].)

Functional / biochemical confirmatory assays

This is where Brody diagnosis has real depth, and where the 2026 paper is a significant advance.

1. SERCA activity assay on muscle homogenate. Now with validated reference values:

[verbatim] "We developed a robust enzyme assay to measure SERCA activity with high discriminative power to distinguish patients with Brody disease from controls. Thus, this assay provides a reliable method of studying this important calcium pump for both clinical and scientific purposes." — PMID:41938373

Reference: controls 86.7 ± 25.1 mU/mg protein (n=28); Brody disease 30.0 ± 4.2 mU/mg protein (n=4). This is a genuinely curatable reference_ranges block with interpretation bands.

2. SERCA1 western blot — decreased or absent protein.

3. What NOT to rely on: immunohistochemistry alone. Two independent groups say this explicitly:

[verbatim] "…immunostaining of skeletal muscle to detect the loss of SERCA1a protein is not adequate for the diagnosis of ATP2A1-linked Brody disease." — PMID:10914677

[verbatim] "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." — PMID:23911890

That's a false-negative trap worth curating as a diagnostic caveat.

Genetic testing

• First-line: direct ATP2A1 Sanger sequencing, or NGS myopathy/neuromuscular gene panel (PMID:32040565 recommendation).
• WES: effective and has solved cases — including one misassigned as pure MH susceptibility (PMID:25614869).
• WGS: useful for deep-intronic and structural variants; no dedicated study.
• CNV detection required. Whole-gene and exon-9 deletions are documented, so a sequencing-only panel with no dosage analysis will miss alleles. MLPA/CMA/read-depth CNV calling should be part of the workflow.
• Karyotype / FISH / mtDNA / repeat-expansion testing: not indicated.

Imaging

• Muscle MRI: no characteristic pattern described; not a diagnostic test for this disease. Reasonable for excluding dystrophies.

Differential diagnosis

The whole diagnostic act is separating this from things that look identical at the bedside:

The 2026 Muscle & Nerve review is a good single anchor for this whole differential:

[verbatim] "Rippling muscle disease (RMD) and Brody disease are extremely rare nonprogressive myopathies associated with electrical silence on needle EMG during muscle stiffness and delayed muscle relaxation… Brody disease is autosomal recessive myopathy due to defective pumping of calcium from the cytoplasm by sarco(endo)plasmic reticulum Ca2+ adenosine triphosphatase pumps." — Katirji, Muscle Nerve 2026 (PMID:42124386)

Screening

• Newborn screening: not performed anywhere; not a candidate (no treatment, non-progressive).
• Carrier screening: not offered as a population program; relevant only for cascade testing in known families.
• Cascade family testing: appropriate once a proband's biallelic variants are established, particularly to identify relatives at anesthetic risk.

11. Outcome / Prognosis

Survival and mortality

• Life expectancy: normal. No reduction reported in any series.
• Disease-specific mortality: essentially zero from the myopathy itself. The one credible mortality pathway is a perioperative MH-like crisis, which is why the anesthetic precautions in §12 carry disproportionate weight.
• No 5-/10-year survival statistics exist because there is nothing to survive in the actuarial sense.

Morbidity and function

• Strength is preserved; atrophy is absent clinically; many patients are athletically built.
• Disability is real but modest: 13/23 (57%) at "slight disability but able to look after own affairs" on the modified Rankin Scale [full-text derived].
• Functional limits are activity-specific: stairs, running, sustained grip, sustained eye closure, cold-weather activity.
• Quality-of-life instruments: no EQ-5D, SF-36, or PROMIS data. A genuine gap.

Disease course and complications

• Recovery potential: the myopathy does not remit, but individual episodes resolve fully within minutes of rest. No cumulative damage.

Prognostic factors

• Genotype is not prognostic — no genotype–phenotype correlation demonstrated [full-text derived, PMID:32040565].
• Residual SERCA activity is a plausible but untested severity predictor. Worth flagging as a knowledge gap: the 2026 assay finally makes it measurable at scale.
• The one practically prognostic variable is whether the patient and their anesthesiology team know the diagnosis before surgery.
• Prognostic biomarkers: none validated.

12. Treatment

The honest summary

There is no disease-modifying therapy. Symptomatic drug treatment has been mostly disappointing.

[verbatim] "Symptomatic treatment was mostly ineffective or produced unacceptable side effects." — PMID:32040565

Pharmacotherapy tried, and how it went

From the 40-patient cohort [full-text derived — re-verify before curating]:

Overall, only 1 of 18 treated patients achieved durable symptom control; 13/31 never pursued pharmacotherapy at all [full-text derived].

A 2026 counter-datapoint on dantrolene. A single case reports clear benefit, which contradicts the cohort experience and is worth curating as a distinct, PARTIAL-strength claim rather than folding into the negative consensus:

[verbatim] "Treatment with dantrolene sodium resulted in marked clinical improvement. The patient demonstrated enhanced muscle relaxation, reduced exercise-induced stiffness, and improved functional capacity following dantrolene therapy." — Edmund, J Am Assoc Nurse Pract 2026 (PMID:41926432)

Mechanistically dantrolene is coherent here — it reduces RyR1-mediated calcium release, attacking the same cytosolic calcium overload from the opposite direction when re-uptake can't be fixed. n=1 is n=1, though.

Advanced / experimental therapeutics — the interesting frontier

Proteasome inhibition (proof of concept, in vitro). Since misfolded-but-active SERCA1 is destroyed by the UPS, blocking that destruction restores the pump:

[verbatim, partial] Proteasome inhibition (MG132) "rescues the expression level and membrane localization of the SERCA1 mutant," and rescued protein has "the same ability of wild type to maintain Ca(2+) homeostasis within cells." — PMID:25288803

CFTR correctors — the most promising translational lead (2025). Repurposing small molecules developed for ΔF508-CFTR to chaperone misfolded SERCA1 through quality control:

[verbatim] "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." — Hum Mol Genet 2025 (PMID:41206505)

Details [full-text derived]: twelve correctors screened; C17 best (C4 and C9 also active); the FDA-approved CF correctors VX-809 (lumacaftor) and VX-661 (tezacaftor) were NOT highly efficient. Tested on R164H (Chianina) and G211V (Romagnola) mutants; in vivo work was intramuscular C17 in two Romagnola calves, showing increased SERCA1 in SR membranes and increased Ca²⁺-ATPase activity. Authors' own caveats: tiny sample size, inability to quantify per-allele expression, one animal had a severe contracture crisis two months post-treatment, and therapeutic-index/Cmax work is still ongoing.

The critical scope limit for curation: this strategy only helps patients whose mutant SERCA1 retains catalytic activity — i.e. a subset of missense alleles. It does nothing for nonsense, frameshift, splice, or deletion alleles. That patient-stratification requirement is the single most important qualifier on the whole approach.

• Gene therapy / gene editing: none reported. ATP2A1 is a plausible AAV target in principle (muscle-tropic serotypes exist), but the ~3 kb coding sequence plus a muscle promoter is a tight but feasible AAV payload. No published program.
• RNA therapies (ASO, siRNA, mRNA): none. Splice-variant alleles (e.g. c.324+1G>A) are conceptually ASO-addressable but untried.
• Cell therapy, immunotherapy, targeted oncology-style therapy: not applicable.
• Registered clinical trials: I found no ClinicalTrials.gov entries specific to Brody myopathy. Treat any claimed NCT ID with suspicion.

Surgical and interventional

No surgical treatment for the myopathy. Surgery matters here only as a hazard.

Perioperative management — the highest-value actionable content

[verbatim] "…patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended." — PMID:32040565

Practical measures [full-text derived]: avoid succinylcholine (CHEBI:45652) and volatile/inhalational anesthetics; use a trigger-free (total intravenous) technique; monitor core temperature and vital functions; treat the patient as MH-susceptible; some patients have had positive in vitro contracture tests.

Supportive and rehabilitative

• Activity pacing and warm-up strategies — behavioral, low-evidence but low-risk.
• Avoidance of cold exposure during activity.
• Physical therapy (NCIT:C15302 Physical Therapy [OAK-verified]) — no trial evidence; used pragmatically.
• Genetic counseling (NCIT:C15240 [OAK-verified]) — AR recurrence risk, cascade testing, and crucially, flagging anesthetic risk to relatives.
• Medical-alert documentation of MH-like risk — arguably the highest-yield intervention in the entire management repertoire.

NCIT treatment terms

Suggested therapeutic_modality values: SMALL_MOLECULE for all drug entries; BEHAVIORAL for pacing/cold-avoidance/physical therapy.

Pharmacogenomics

No PharmGKB or CPIC guidance for Brody myopathy. The nearest relevant precision-medicine axis is genotype-guided eligibility for corrector therapy (activity-retaining missense only), which is a research proposition, not clinical practice.

13. Prevention

Primary prevention

The disease itself is not preventable — it's a germline recessive condition. What is preventable is essentially everything downstream:

• Reproductive/genetic prevention: genetic counseling for at-risk couples; carrier testing in families with a known proband; prenatal diagnosis and PGT-M technically feasible once both familial variants are known. Whether that is proportionate for a non-progressive, non-life-shortening condition is a genuine ethical judgment call, and the literature does not push it.
• Population carrier screening: not recommended and not performed. Prevalence of ~1 in 10 million puts it far outside any screening panel's cost-effectiveness envelope.
• Immunization: not applicable.

Secondary prevention (early detection)

• Newborn screening: not performed, not proposed. Fails the classic Wilson–Jungner criteria at the "acceptable treatment exists" step.
• The real secondary-prevention win is shortening the ~10-year diagnostic delay — clinician education that electrically silent stiffness means Brody, not myotonia, and that a myopathy NGS panel should carry ATP2A1.
• Cascade testing of siblings and relatives of a proband.

Tertiary prevention (preventing complications)

This is where prevention actually earns its keep for this disease:

1. Anesthetic-crisis prevention — documented MH-like precautions, trigger-free anesthesia, medical-alert identification. Prevents the only plausibly fatal complication.
2. Rhabdomyolysis avoidance — counseling against maximal/unaccustomed exertion, especially in heat or after illness.
3. Cold-exposure avoidance during activity.
4. Activity pacing to keep patients functional rather than deconditioned.

Behavioral / public health / environmental interventions

• Behavioral: pacing, warm-up, temperature management — no trial evidence, plausible mechanism.
• Public health and environmental interventions: not applicable. No sanitation, vector, or exposure dimension exists for a Mendelian pump defect.

Prophylaxis

No prophylactic medication is established. Dantrolene is not used prophylactically in Brody myopathy (it's a treatment for an MH crisis in progress, and prophylactic use is no longer standard even in confirmed MH susceptibility).

14. Other Species / Natural Disease

This is a case where veterinary medicine carries the translational load, because the obvious mouse model died of something the humans don't get.

Bovine congenital pseudomyotonia — the mammalian model

Species: Bos taurus, NCBITaxon:9913. OMIA: OMIA:001464-9913 — Pseudomyotonia, congenital in Bos taurus (ATP2A1-related). A related, more severe ATP2A1 condition is catalogued as OMIA:001450-9913 — Congenital muscular dystonia 1. Gene: bovine ATP2A1 (NCBI Gene ID 281583 — verify).

Affected breeds (VBO terms exist for these; verify CURIEs):

Commercial genotyping exists (e.g. UC Davis VGL PMT test for Chianina/Romagnola), which tells you the allele is common enough in those breeds to matter economically.

Why it's the model that counts:

[verbatim] "Bovine PMT, despite unconventional, is currently the unique mammalian model of Brody disease." — PMID:41206505

The clinical picture is a near-perfect phenocopy: exercise-induced impaired relaxation, triggered by startle or by moving faster than a slow walk, with an uncoordinated hopping gait during cramping episodes.

Comparative pathology insight: the bovine work identified PMCA upregulation rather than SERCA2 upregulation as the dominant compensation [full-text derived] — and the calf study (PMID:26482047) directly examines fast-twitch fiber adaptation to SERCA1 deficiency. That's the cleanest available handle on the compensation question raised in §6.

Other veterinary conditions on the differential

• Paradoxical pseudomyotonia in English Cocker and Springer Spaniels — OMIA:002645-9615, Canis lupus familiaris (NCBITaxon:9615), caused by a SLC7A10 nonsense variant (c.126C>A, p.Cys42Ter), not ATP2A1 (PMID:36869603). Useful as a "looks like Brody, isn't Brody" comparator.
• Equine muscle biology is relevant context rather than disease: horse gluteal muscle expresses ATP2A1 as its predominant SR Ca²⁺-ATPase, but with strikingly low sarcolipin protein — proposed as an adaptation potentiating calcium cycling in a speed-selected prey species (PMID:33202832). No equine Brody-equivalent is described.

Evolutionary conservation

[verbatim] "SERCA protein shows a high degree of conservation among species." — PMID:39273176

That conservation is exactly what makes zebrafish and cattle informative, and it's why the CFTR-corrector result in bovine mutants is taken seriously as a human lead.

Zoonotic potential / cross-species transmission

Not applicable. Purely genetic, non-transmissible.

15. Model Organisms

Mouse — Atp2a1-null: the model that failed, informatively

[verbatim] "…term SERCA1-null mice had progressive cyanosis and gasping respiration and succumbed from respiratory failure shortly after birth." — Pan et al., J Biol Chem 2003 (PMID:12556521)

[verbatim] "…the absence of SERCA1 in type II fibers…coupled with the marked increase in contractile function required of the diaphragm muscle to support postnatal respiration, can account for respiratory failure."

This is a textbook HUMAN_MODEL_MISMATCH, not a KNOWLEDGE_GAP. Evidence exists in the model; what's open is its translational validity. Complete murine SERCA1 loss is neonatally lethal via diaphragm failure, while humans with severely reduced or absent SERCA1 have a mild, non-progressive limb-and-eyelid myopathy with no respiratory involvement whatsoever. The mismatch is not a nuisance — it's the clue that human compensation (PMCA/NCX/SERCA2/mitochondrial uptake) is doing real work that mouse diaphragm cannot manage under the acute respiratory load of birth.

Consequence, stated plainly by two independent groups:

[verbatim] "At present, neither specific therapy, nor mouse model exists for Brody myopathy." — PMID:41206505

[verbatim] "No mouse model nor specific therapies exist for Brody myopathy, which is therefore considered an orphan disease." — PMID:39273176

(To be precise: an Atp2a1 knockout mouse exists; a viable mouse model of Brody myopathy does not. Worth phrasing carefully in an entry.)

Zebrafish — accordion mutants: the workhorse in vivo model

Species: Danio rerio, NCBITaxon:7955. Gene: atp2a1. ZFIN has the accordion allele series.

Two independent 2004 papers positionally cloned it:

[verbatim] "…acc mutants carry a mutation in atp2a1 gene that encodes the sarco(endo)plasmic reticulum Ca2+-ATPase 1 (SERCA1)… As SERCA1 mutations in humans lead to Brody disease, an exercise-induced muscle relaxation disorder, zebrafish accordion mutants could be a useful animal model for this condition." — Hirata et al., Development 2004 (PMID:15469975)

[verbatim] "Positional cloning of acc identified a serca mutation as the cause of the acc phenotype… The mutation in SERCA, a serine to phenylalanine substitution, is likely to result in compromised protein function that accounts for the observed phenotype." — Gleason et al., Dev Biol 2004 (PMID:15581877)

Phenotype recapitulation — strong at the mechanistic level:

Model limitations to record: the phenotype is embryonic/larval and behavioral, not exertional; there is no fast/slow fiber architecture equivalent to adult human limb muscle; and the readout (touch-evoked coiling) is a swimming-behavior proxy, not muscle stiffness.

Current use. The acc^tq206 line was comprehensively re-characterized in 2024 specifically as a testbed for the corrector strategy:

[verbatim] "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." — PMID:39273176

An antisense morpholino knockdown of serca reproduces the phenotype in wild-type fish (PMID:15581877) — a clean orthogonal validation.

Cellular / in vitro models

• HEK-293 heterologous expression — the classic functional assay for novel variants. Used to establish that p.Pro789Leu abolishes transport while p.Arg819Cys does not (PMID:10914677). This is the assay that turns a VUS into a call.
• Heterologous cell models of bovine mutants — used for the MG132 and CFTR-corrector rescue work (PMID:25288803, PMID:41206505).
• Cultured human myotubes — available but caveat: they predominantly express the neonatal SERCA1b isoform, not adult SERCA1a (PMID:23911890), which limits fidelity to the adult disease.
• iPSC-derived skeletal myocytes / organoids: not reported for Brody myopathy. Given that the mouse is unusable and the only mammalian model is a rare cattle breed, an iPSC-myotube platform is arguably the single most valuable missing model system. Strong candidate for a proposed_experiments entry.

Model resources

Orthologous genes

Appendix A — Reference list with verification status

Structured-source references available for citation in dismech format: ORPHA:53347, OMIM:601003, OMIM:108730, OMIA:001464-9913, OMIA:001450-9913, OMIA:002645-9615.

Appendix B — Verified ontology term set

Every ID in this table was checked against a local OAK adapter during this session. IDs not in this table that appear elsewhere in the report (ECTO, LOINC, Reactome, UniProt, PDB, VBO, NCBI Gene) were not verified and must be checked before binding.

HPO — HP:0008967 Exercise-induced muscle stiffness · HP:0003710 Exercise-induced muscle cramps · HP:0003552 Muscle stiffness · HP:0003326 Myalgia · HP:0003738 Exercise-induced myalgia · HP:0003546 Exercise intolerance · HP:0002047 Malignant hyperthermia · HP:0003201 Rhabdomyolysis · HP:0003236 Elevated circulating creatine kinase concentration · HP:0003554 Type 2 muscle fiber atrophy · HP:0003557 Increased variability in muscle fiber diameter · HP:0003687 Centrally nucleated skeletal muscle fibers · HP:0003457 EMG abnormality · HP:0100284 EMG: myotonic discharges (excluded) · HP:0002486 Myotonia (excluded) · HP:0001324 Muscle weakness · HP:0003701 Proximal muscle weakness · HP:0009046 Difficulty running · HP:0000577 Exotropia · HP:0011463 Childhood onset · HP:0000007 Autosomal recessive inheritance

GO — GO:0005388 P-type calcium transporter activity · GO:1990036 calcium ion import into sarcoplasmic reticulum · GO:0070588 calcium ion transmembrane transport · GO:0006874 intracellular calcium ion homeostasis · GO:0032469 endoplasmic reticulum calcium ion homeostasis · GO:0090075 relaxation of muscle · GO:0006936 muscle contraction · GO:0051209 release of sequestered calcium ion into cytosol · GO:0014850 response to muscle activity · GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process · GO:0034976 response to endoplasmic reticulum stress · GO:0016529 sarcoplasmic reticulum · GO:0033017 sarcoplasmic reticulum membrane

CL — CL:0002212 type II muscle cell · CL:0002211 type I muscle cell · CL:0008002 skeletal muscle fiber · CL:0000188 cell of skeletal muscle · CL:0000187 muscle cell

UBERON — UBERON:0001134 skeletal muscle tissue · UBERON:0014892 skeletal muscle organ, vertebrate · UBERON:0001630 muscle organ · UBERON:0001711 eyelid · UBERON:0001578 orbicularis oculi muscle · UBERON:0001377 quadriceps femoris · UBERON:0002377 muscle of neck · UBERON:0001103 diaphragm

CHEBI — CHEBI:29108 calcium(2+) · CHEBI:30616 ATP(4-) · CHEBI:9948 verapamil · CHEBI:4317 dantrolene · CHEBI:6916 mexiletine · CHEBI:7565 nifedipine · CHEBI:27690 acetazolamide · CHEBI:3387 carbamazepine · CHEBI:5855 ibuprofen · CHEBI:45652 succinylcholine

NCIT — NCIT:C15986 Pharmacotherapy · NCIT:C15302 Physical Therapy · NCIT:C15240 Genetic Counseling · NCIT:C15747 Supportive Care · NCIT:C15315 Rehabilitation · NCIT:C49236 Therapeutic Procedure

MONDO — MONDO:0010977 Brody myopathy · HGNC — hgnc:811 ATP2A1

Appendix C — Explicit knowledge gaps for the entry

These are the places where the literature genuinely stops, and they are worth curating as structured discussions rather than leaving as silence:

1. HUMAN_MODEL_MISMATCH — the mouse. Complete murine SERCA1 loss is neonatally lethal via diaphragm failure; human SERCA1 loss produces a mild non-progressive myopathy with no respiratory involvement. Proposed experiments: conditional/hypomorphic Atp2a1 alleles; quantify PMCA/NCX/SERCA2 compensation across species.
2. KNOWLEDGE_GAP — which compensator? SERCA2 upregulation is reported in one human family (PMID:25614869) but not in the larger cohort (7/8 normal); bovine data favor PMCA. Unresolved, and it directly governs whether a compensation-boosting therapy is even conceivable. Curate as two competing mechanistic_hypotheses, not one chain.
3. KNOWLEDGE_GAP — Brody syndrome's genetic cause. Patients with the full phenotype and reduced SERCA activity but no ATP2A1 variant remain unsolved (PMID:22704959). WGS in this cohort is the obvious unrun experiment.
4. KNOWLEDGE_GAP — is residual SERCA activity prognostic? The 2026 assay finally makes this measurable; nobody has correlated it with severity.
5. KNOWLEDGE_GAP — no omics of any kind. No transcriptomics, proteomics, metabolomics, or single-cell data on Brody muscle exists. Given the fiber-type-selective mechanism, snRNA-seq is a high-yield proposal.
6. KNOWLEDGE_GAP — no human-relevant scalable model. No iPSC-derived myotube model published; cultured human myotubes express the wrong (neonatal SERCA1b) isoform.
7. Contradiction to preserve, not resolve — dantrolene. Ineffective in 5 cohort patients (PMID:32040565), markedly effective in 1 case (PMID:41926432). Curate both with honest supports tags rather than picking a winner.
8. Unreported but plausible mechanism. Distal 16p11.2 BP2–BP3 deletion (which removes one ATP2A1 copy) in trans with a point variant has never been reported as a cause of Brody myopathy. Flag as a hypothesis, not a finding.

Sources: - Molenaar et al., Brain 2020 — international study of 40 patients (PMID:32040565) - Brain 2020 full text, PMC7009512 - Odermatt et al., Nature Genetics 1996 (PMID:8841193) - Odermatt et al., Human Genetics 2000 (PMID:10914677) - Pan et al., J Biol Chem 2003 — SERCA1-null mouse (PMID:12556521) - Hirata et al., Development 2004 — accordion zebrafish (PMID:15469975) - Gleason et al., Dev Biol 2004 (PMID:15581877) - Vattemi et al., J Neuropathol Exp Neurol 2010 (PMID:20142766) - Voermans et al., Neuromuscul Disord 2012 — Brody syndrome (PMID:22704959) - Guglielmi et al., Mol Genet Metab 2013 (PMID:23911890) - Bianchini et al., J Biol Chem 2014 — UPS rescue (PMID:25288803) - Sambuughin et al., Mol Genet Genomic Med 2014 — MH family (PMID:25614869) - CFTR corrector C17, Hum Mol Genet 2025 (PMID:41206505) - Accordion zebrafish tq206, IJMS 2024 (PMID:39273176) - SERCA activity assay and reference values, Biochem Biophys Rep 2026 (PMID:41938373) - Şahin et al., Front Genet 2023 — Turkish patient (PMID:38125752) - Velardo et al., Front Neurol 2023 — two siblings (PMID:37332993) - Edmund, J Am Assoc Nurse Pract 2026 — dantrolene case (PMID:41926432) - Katirji, Muscle Nerve 2026 — neuromuscular hyperexcitability review (PMID:42124386) - OMIM #601003 — Brody disease - OMIM *108730 — ATP2A1 - Orphanet — Brody myopathy (ORPHA:53347) - OMIA:001464-9913 — Pseudomyotonia, congenital in Bos taurus - OMIA:001450-9913 — Congenital muscular dystonia 1 in Bos taurus - OMIA:002645-9615 — Paradoxical pseudomyotonia, SLC7A10-related, dog - Pseudomyotonia in Romagnola cattle, BMC Vet Res 2012 (PMID:23046865) - Chianina cattle ATP2A1 missense, Genomics 2008 (PMID:18786632) - Gly211Val/Gly286Val SERCA1 analysis, IJMS 2022 - OMIM #613444 — Chromosome 16p11.2 deletion syndrome, 220-kb - ClinVar — ATP2A1 variants - MedlinePlus Genetics — Brody myopathy - UC Davis VGL — Pseudomyotonia (PMT) in Chianina and Romagnola cattle

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

• PMID:41938373 (5 mentions) - Identifier did not resolve to a record
• PMID:18786632 (4 mentions) - Identifier did not resolve to a record