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Classifications

Harrison's Chapter

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Mappings

MONDO

MONDO:0800484 PRKAG2-related cardiomyopathy

The ClinGen-authored MONDO class whose definition ("variable cardiac hypertrophy, ventricular pre-excitation, and aberrant glycogen storage in the cardiac tissue due to a pathogenic variant in PRKAG2") is exactly the entity curated by this entry. Carries the gene association RO:0004003 HGNC:9386 (PRKAG2).

MONDO:0010946 hypertrophic cardiomyopathy 6 Not Yet Curated

MONDO:0010946 (CMH6; OMIM:600858; synonyms "CMH6", "PRKAG2 hypertrophic cardiomyopathy", "cardiomyopathy, familial hypertrophic, 6") is the OMIM-derived, disease-series-by-gene sibling name for the same PRKAG2 biology, and MONDO asserts it as a direct subclass of MONDO:0800484 ("is_a: MONDO:0800484 ! PRKAG2-related cardiomyopathy", verified with `runoak -i sqlite:obo:mondo info MONDO:0010946 -O obo`). Its own MONDO definition is the pure gene-series template - "Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the PRKAG2 gene" - which asserts no mechanism or phenotype beyond the gene, so it adds no curatable content over this entry. It is recorded here as a narrowMatch (the CMH-numbered-series framing of PRKAG2 disease) rather than curated as a separate dismech Disease; see the CMH6 paragraph in `notes` for the split rationale.

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Inheritance

1

Autosomal dominant HP:0000006

PRKAG2 cardiac syndrome segregates as an autosomal dominant trait with variable expressivity and age-dependent penetrance. Affected individuals are heterozygous for a missense variant; de novo occurrence is reported. Expressivity within a single family ranges from isolated pre-excitation without hypertrophy to progressive hypertrophy with early pacing and heart failure.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:11407343 SUPPORT Human Clinical

"We identified two families in which the Wolff-Parkinson-White syndrome segregated as an autosomal dominant disorder."

Direct statement of autosomal dominant segregation in the founding linkage study.

PMID:28431061 SUPPORT Human Clinical

"are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block"

Independent confirmation of the autosomal dominant mode alongside the clinical triad.

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Subtypes

1

Lethal congenital cardiac glycogenosis (OMIM 261740) MONDO:0009867

PRKAG2 hgnc:9386

The severe end of the PRKAG2 severity spectrum, and the form that makes this disease's genotype-phenotype axis prognostically consequential. Recurrent heterozygous p.Arg531Gln (R531Q) substitutions in the third CBS domain produce a massive non-lysosomal cardiac glycogenosis with symptomatic onset already in fetal life and a rapidly fatal course, rather than the juvenile-to-adult presentation of the classic triad. The molecular lesion is the same class of nucleotide-sensing defect as in the milder alleles, but quantitatively far more extreme - the R531Q protein loses AMP and ATP binding affinity by more than two orders of magnitude while gaining basal kinase activity, and the authors of the defining study explicitly describe the classic hypertrophic-cardiomyopathy alleles as producing perturbations "similar to--but less severe than" R531Q. Note the striking allelic contrast at the same codon: p.Arg531Gly causes childhood-onset pre-excitation and conduction disease WITHOUT hypertrophy (curated under `genetic.variants`), so residue 531 alone spans the full range from a hypertrophy-free electrical phenotype to neonatal death. Historically this form was misattributed to a heart-specific phosphorylase kinase deficiency; the defining study found no phosphorylase kinase mutations and reassigned the aetiology to PRKAG2, which is why MONDO:0009867 still carries "phosphorylase kinase deficiency of heart" as a synonym.

Show evidence (2 references)

PMID:15877279 SUPPORT Human Clinical

"recurrent heterozygous R531Q missense mutations in PRKAG2 give rise to a massive nonlysosomal cardiac glycogenosis of fetal symptomatic onset and rapidly fatal course, constituting a genotypically and clinically distinct variant of hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome"

Establishes the lethal congenital form as a distinct, R531Q-associated severity extreme of PRKAG2 disease with fetal onset and a rapidly fatal course.

PMID:15877279 SUPPORT Human Clinical

"Fatal congenital nonlysosomal cardiac glycogenosis has been attributed to a subtype of phosphorylase kinase deficiency, but the underlying genes and mutations have not been identified."

Documents the historical phosphorylase-kinase-deficiency attribution that the same study overturns, explaining the surviving MONDO/OMIM synonym.

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Mechanistic Hypotheses

3

Constitutive/Inappropriate AMPK Activation Model

constitutive_ampk_activation ALTERNATIVE

Evidence balance 2 support

CBS-domain variants relieve the normal adenine-nucleotide-dependent autoinhibition of the AMPK heterotrimer, leaving the kinase inappropriately active in the ATP-replete cardiomyocyte. Chronic AMPK activity drives GLUT4 translocation, glucose uptake, and glycogen synthase activity, so glycogen accumulates. This is the model supported by the yeast Snf4 two-hybrid data and by the N488I transgenic mouse, which shows elevated cardiac AMPK activity together with 30-fold glycogen accumulation.

Pathograph links

Dysregulated AMPK Nucleotide Sensing -> Excessive Cardiomyocyte Glycogen and Polyglucosan Accumulation INDIRECT KNOWN INTERMEDIATES Intermediates: Altered AMPK signalling to GLUT4 trafficking via AS160/TBC1D4 increases myocardial glucose uptake.; Upregulated glycogen synthase activity converts imported glucose into stored glycogen and, ultimately, poorly soluble polyglucosan.

Show evidence (2 references)

PMID:11827995 SUPPORT In Vitro

"We interpret these data to indicate that Thr400Asn and Asn488Ile mutations produce nonphysiologic, constitutive activation of AMP kinase."

Human PRKAG2 substitutions engineered into the yeast orthologue Snf4 produced glucose-insensitive Snf1-Snf4 interaction, interpreted by the authors as constitutive kinase activation. Evidence source is IN_VITRO because this is a yeast two-hybrid/reporter assay, not an animal study.

PMID:12782567 SUPPORT Model Organism

"Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction."

The N488I transgenic mouse directly couples elevated cardiac AMPK activity to massive glycogen accumulation and the full clinical triad, the central prediction of the activation model. Evidence source is MODEL_ORGANISM because this is transgenic mouse work.

Impaired AMP Sensing / Loss-of-Function Model

ampk_loss_of_function ALTERNATIVE

Evidence balance 2 support 1 partial

The same CBS-domain variants can be read as damaging the AMP-binding site rather than releasing autoinhibition, so the kinase loses its ability to be activated by rising AMP. Purified mutant complexes are not constitutively active but show markedly reduced AMP dependence, and the R302Q transgenic mouse - which reproduces the full human phenotype including inducible orthodromic atrioventricular reentrant tachycardia - has significantly REDUCED cardiac AMPK activity. This is the direct opposite of the activation model, and the field has not resolved which applies, or whether the direction is variant-, tissue-, and developmental-stage-specific.

Pathograph links

Dysregulated AMPK Nucleotide Sensing -> Excessive Cardiomyocyte Glycogen and Polyglucosan Accumulation INDIRECT KNOWN INTERMEDIATES Intermediates: Altered AMPK signalling to GLUT4 trafficking via AS160/TBC1D4 increases myocardial glucose uptake.; Upregulated glycogen synthase activity converts imported glucose into stored glycogen and, ultimately, poorly soluble polyglucosan.

Show evidence (3 references)

PMID:12397075 SUPPORT In Vitro

"in the absence of an appropriate stimulus the mutant complexes, like the wild-type complex, exist in an inactive form demonstrating that the mutations do not lead to constitutive activation of the kinase"

Direct biochemical assay of reconstituted mutant AMPK complexes refutes constitutive activation and instead localises the defect to AMP responsiveness, the core claim of the loss-of-function model.

PMID:15611370 SUPPORT Model Organism

"Enzymatic activity of AMPK in the mutant heart was significantly reduced (0.009+/-0.003 versus 0.025+/-0.001 nmol x min(-1) x g(-1) in nontransgenic mice), presumably owing to the mutation disrupting the AMP binding site."

In the R302Q transgenic mouse, which phenocopies the human disease, cardiac AMPK activity is reduced rather than elevated, attributed by the authors to disruption of the AMP binding site. Evidence source is MODEL_ORGANISM because this is transgenic mouse work.

PMID:12397075 PARTIAL In Vitro

"These results indicate that mutations in gamma(2) have different effects on AMPK function, suggesting that they may lead to abnormal development of the heart through distinct mechanisms."

Supports the reconciling possibility that different PRKAG2 variants act by genuinely different mechanisms, rather than one direction being correct for all of them. Marked PARTIAL because it argues against a single unified model rather than affirmatively supporting the loss-of-function direction.

Glycogen-Independent AMPK-gamma2/Myosin Interaction Model

glycogen_independent_myosin_interaction EMERGING

Evidence balance 2 support

A recent transgenic zebrafish study reports that variant AMPK-gamma2 binds myosin more avidly and relocalises to the myofilament, producing hypertrophy and electrophysiological abnormalities (slowed conduction, prolonged action potential and calcium-transient duration) at a developmental stage BEFORE any glycogen has accumulated, and not rescued by AMPK activation. If it holds in mammals, this would mean glycogen storage is not the sole proximate cause of the cardiac phenotype and would add a myofilament calcium-handling arm upstream of, or parallel to, the storage cascade. Preliminary and not yet replicated in human tissue.

Pathograph links

Dysregulated AMPK Nucleotide Sensing -> Enhanced AMPK-gamma2/Myosin Interaction DIRECT Under the emerging model, the variant subunit's principal proximate effect is a gain of binding to myosin rather than a change in kinase output.

Enhanced AMPK-gamma2/Myosin Interaction -> Glycogen-Independent Early Electrophysiological Abnormality INDIRECT KNOWN INTERMEDIATES Intermediates: Myofilament calcium retention reduces the free cytosolic calcium available for sodium/calcium-exchanger-mediated extrusion, prolonging the calcium transient and the action potential.

Glycogen-Independent Early Electrophysiological Abnormality -> Progressive Contractile Dysfunction INDIRECT UNKNOWN INTERMEDIATES In the same model the variant produces hypertrophic cardiomyocytes and progressive contractile abnormalities alongside the electrical changes, so under the emerging model part of the contractile phenotype would arise by a route independent of the storage cascade. The edge is deliberately pointed at contractile dysfunction rather than at pre-excitation, because the zebrafish study reports conduction slowing and contractile abnormality but does NOT report accessory pathways or pre-excitation; the intervening steps to the human phenotype are not established.

Show evidence (2 references)

PMID:42422944 SUPPORT Model Organism

"The PRKAG2 variant altered cardiac excitability, contractility, and Ca2+ handling during cardiogenesis, independent of glycogen accumulation."

States the model's defining claim: a glycogen-independent route from the PRKAG2 variant to the cardiac electrical and contractile phenotype. Evidence source is MODEL_ORGANISM because this is transgenic zebrafish work.

PMID:42422944 SUPPORT In Vitro

"Proximity ligation assays and coimmunoprecipitation identified a physical interaction between AMPKγ2 and myosin, enhanced by the R299Q variant and accompanied by increased AMPKγ2 localization to the myofilament."

Provides the proposed molecular basis - variant-enhanced AMPK-gamma2 binding to myosin with myofilament relocalisation. Evidence source is IN_VITRO rather than MODEL_ORGANISM because proximity ligation and co-immunoprecipitation are biochemical assays performed on harvested tissue outside the organism, even though the tissue came from transgenic zebrafish.

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Discussions and Knowledge Gaps

4

Do disease-causing PRKAG2 CBS-domain variants raise or lower cardiac AMPK activity in the human heart, and is the answer variant-specific, developmental-stage-specific, or both?

KNOWLEDGE GAP OPEN gap_prkag2_ampk_activity_direction

Attached to

pathophysiology#Dysregulated AMPK Nucleotide Sensing

This is the central unresolved mechanistic question of the disease, and the reason this entry declines to assert a direction. Yeast reconstitution of p.Thr400Asn and p.Asn488Ile indicates constitutive activation, and the N488I transgenic mouse shows ELEVATED cardiac AMPK activity with 30-fold glycogen accumulation. Against that, direct biochemical assay of reconstituted mutant complexes shows no constitutive activation but markedly reduced AMP dependence, and the R302Q transgenic mouse - which phenocopies the human disease including inducible AV reentrant tachycardia - has significantly REDUCED cardiac AMPK activity. Time-resolved work shows the direction flips within a single variant: acute p.Arg302Gln expression activates AMPK and upregulates glycogen synthase and AS160, whereas the chronically transgenic adult heart shows suppressed AMPK activity, apparently as feedback to stored glycogen. The question is not academic: it determines whether a rational therapy should activate or inhibit AMPK, and one of the founding papers explicitly proposed AMPK-lowering therapy on the basis of the activation model.

Proposed experiments

Direct AMPK activity and phosphorylation profiling in human PRKAG2 myocardium

exp_prkag2_human_myocardial_ampk_activity

Measure AMPK catalytic activity, alpha-subunit Thr172 phosphorylation, and downstream substrate phosphorylation (ACC, glycogen synthase, AS160) in genotyped human myocardial tissue obtained at transplantation or autopsy from carriers of the major alleles (p.Arg302Gln, p.Asn488Ile, p.Arg531Gly), against matched non-PRKAG2 hypertrophic and normal controls, stratified by disease stage and myocardial glycogen content. This is the missing human-tissue arm: every current activity measurement comes from yeast, reconstituted complexes, transgenic rodents, or zebrafish.

Allele-matched isogenic iPSC-cardiomyocyte AMPK activity time course

exp_prkag2_isogenic_ipsc_timecourse

In isogenic human iPSC-derived cardiomyocyte lines each carrying a single knock-in PRKAG2 allele, track AMPK activity, glycogen content, and electrophysiology across differentiation and prolonged culture, to test directly whether the direction of the AMPK change is allele-dependent, is stage-dependent, or reverses as glycogen accumulates.

Show evidence (2 references)

PMID:12397075 SUPPORT In Vitro

"These results indicate that mutations in gamma(2) have different effects on AMPK function, suggesting that they may lead to abnormal development of the heart through distinct mechanisms."

Explicitly states that different PRKAG2 variants have different effects on AMPK function, framing the unresolved question.

PMID:20031621 SUPPORT Other

"These findings are the first to highlight temporal differences in the effects of the PRKAG2 R302Q mutation on cardiac metabolic signaling events."

Establishes the temporal dimension of the question: the measured direction depends on when in the disease course it is assayed. Evidence source is OTHER because this concluding statement spans the study's cultured-myocyte and transgenic-mouse arms rather than reporting a single experimental system.

Do cardiac-restricted transgenic OVEREXPRESSION models of PRKAG2 variants faithfully represent the human disease, in which a single variant allele is expressed heterozygously at physiological level - and does the opposite direction of AMPK activity change between the N488I and R302Q mouse models reflect real allele biology or an artefact of transgene dosage?

HUMAN MODEL MISMATCH OPEN mismatch_prkag2_transgenic_overexpression_vs_human

Attached to

pathophysiology#Dysregulated AMPK Nucleotide Sensing pathophysiology#Excessive Cardiomyocyte Glycogen and Polyglucosan Accumulation

Almost everything mechanistically known about this disease comes from alpha-myosin-heavy-chain-promoter transgenic mice OVEREXPRESSING a variant PRKAG2 cDNA on a normal endogenous background - a fundamentally different genetic architecture from the human heterozygote, where one endogenous allele is variant and total gamma-2 dosage is normal. The models are compelling in that they reproduce the human triad closely, including anatomically demonstrated annulus fibrosus disruption and inducible AV reentrant tachycardia. But they disagree with each other on the most basic biochemistry - the N488I model shows elevated cardiac AMPK activity while the R302Q model shows reduced activity - and overexpression is a plausible explanation for a discrepancy of that kind. The stakes are concrete: the inducible N488I model's demonstration that suppressing the transgene REVERSES established cardiomyopathy, conduction disease, and pre-excitation is the single strongest argument that the human disease is in principle pharmacologically reversible, and that argument is only as good as the model's fidelity. Evidence exists here in abundance; what is uncertain is its translational validity, which is why this is recorded as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP.

Proposed experiments

Heterozygous Prkag2 knock-in mice at endogenous expression level

exp_prkag2_knockin_heterozygous_mouse

Generate heterozygous knock-in mice carrying the murine equivalents of p.Arg302Gln and p.Asn488Ile at the endogenous Prkag2 locus, so that expression level and allelic ratio match the human heterozygote. Compare cardiac AMPK activity, glycogen and polyglucosan content, annulus fibrosus integrity, and electrophysiology against the corresponding overexpression transgenics, to determine which findings survive removal of the transgene dosage confound and whether the N488I-versus-R302Q activity discrepancy persists.

Reversibility testing in an endogenous-expression model

exp_prkag2_reversibility_endogenous_expression

Repeat the transgene-suppression reversibility experiment in a system with physiological expression - for example allele-selective knockdown of the variant transcript in heterozygous knock-in mice, or in variant human iPSC-derived engineered heart tissue - to establish whether reversal of established storage cardiomyopathy is a property of the disease or an artefact of switching off a supraphysiological transgene.

Show evidence (2 references)

PMID:18158359 SUPPORT Model Organism

"Using an externally modifiable transgenic system, cardiomyopathy, cardiac dysfunction, and electrophysiological disorders were demonstrated to be reversible processes in PRKAG2 disease."

The reversibility claim whose translational validity is at stake, obtained in a tetracycline-repressible cardiac overexpression transgenic mouse, not in a physiological-expression heterozygote.

PMID:18158359 PARTIAL Model Organism

"Transgene suppression during early postnatal development prevented the development of accessory electrical pathways but not cardiomyopathy or conduction system degeneration."

Shows the three disease arms have different critical windows in the model, a dissociation whose relevance to human disease timing is untested. Marked PARTIAL because it complicates rather than straightforwardly supports the reversibility claim.

Does the glycogen-independent AMPK-gamma2/myosin interaction reported in transgenic zebrafish contribute to the human PRKAG2 cardiac phenotype, and if so does it operate before, alongside, or instead of glycogen storage?

HUMAN MODEL MISMATCH OPEN mismatch_prkag2_glycogen_independent_arm

Attached to

pathophysiology#Enhanced AMPK-gamma2/Myosin Interaction pathophysiology#Glycogen-Independent Early Electrophysiological Abnormality

The entire causal architecture of this entry, and of the field, routes the cardiac phenotype through glycogen and polyglucosan accumulation. A 2026 zebrafish study challenges that by showing hypertrophy plus slowed conduction and prolonged action-potential and calcium-transient duration at a developmental stage with NO glycogen accumulation, not rescued by AMPK activation, and attributable to variant-enhanced AMPK-gamma2 binding to myosin with myofilament relocalisation. If this generalises, part of the disease is a myofilament calcium-handling disorder rather than purely a storage disorder, and glycogen-lowering strategies would address only part of the phenotype. Zebrafish cardiac development, myosin isoform composition, and calcium handling differ substantially from human, and the finding is single-model and unreplicated - so this is a model-fidelity question rather than an absence of evidence. Notably it also cuts against BOTH established AMPK-direction hypotheses, since AMPK activation failed to rescue the phenotype.

Proposed experiments

AMPK-gamma2/myosin interaction in human PRKAG2 myocardium and iPSC-cardiomyocytes

exp_prkag2_myosin_interaction_human_tissue

Test for enhanced AMPK-gamma2/myosin association and myofilament relocalisation by proximity ligation and co-immunoprecipitation in genotyped human PRKAG2 myocardium and in isogenic variant human iPSC-derived cardiomyocytes, and determine whether calcium-transient and action-potential prolongation precede detectable glycogen accumulation during human cardiomyocyte differentiation.

Myosin-inhibitor rescue of the electrophysiological phenotype in a mammalian model

exp_prkag2_myosin_inhibitor_rescue_mammalian

Test whether a myosin inhibitor such as mavacamten reduces AMPK-gamma2/myosin association and rescues conduction slowing and calcium-transient prolongation in mammalian PRKAG2 models and in human variant engineered heart tissue, as it did in zebrafish. A positive result would both validate the mechanism across species and identify a repurposable pharmacological entry point.

Show evidence (2 references)

PMID:42422944 SUPPORT Other

"Although prior studies associated PRKAG2-related hypertrophy with increased glycogen storage, many hypertrophic cardiomyopathy phenotypes remain unexplained."

States the explanatory shortfall of the glycogen-centred model that motivates the alternative arm. Evidence source is OTHER because this is a background statement about what the prior literature leaves UNEXPLAINED - an assertion about absent evidence - rather than a result from the zebrafish experiments reported in this paper.

PMID:42422944 SUPPORT Model Organism

"We observed decreased AMPK (AMP-activated protein kinase) phosphorylation in the TgR299Q hearts. However, AMPK activation did not rescue the electrophysiological abnormalities in TgR299Q."

Shows the electrophysiological phenotype is not corrected by restoring AMPK activity, arguing that this arm is not downstream of the AMPK activity change itself.

Do the accessory atrioventricular connections in PRKAG2 disease arise from persistence of embryonic atrioventricular connections that normally regress, or from de novo activation of quiescent pathways by metabolic deposits in the postnatal heart?

KNOWLEDGE GAP OPEN gap_prkag2_accessory_pathway_origin

Attached to

pathophysiology#Disruption of the Annulus Fibrosus by Glycogen-Laden Myocytes pathophysiology#Accessory Atrioventricular Connections and Ventricular Pre-excitation

The annulus fibrosus mechanism is well established, but the developmental origin of the conducting strands is not. The two candidate explanations were posed as alternatives in the original human pathology paper and remain unresolved. The inducible mouse work is suggestive but not decisive: transgene suppression during early postnatal development PREVENTED accessory-pathway development while failing to prevent cardiomyopathy and conduction-system degeneration, implying a restricted developmental window for the pre-excitation arm specifically. Resolving this matters clinically because it determines whether accessory pathways in a variant-positive child can still be prevented, or only treated once formed.

Proposed experiments

Lineage tracing of atrioventricular canal myocardium in a PRKAG2 model

exp_prkag2_av_canal_lineage_tracing

Use inducible lineage tracing of embryonic atrioventricular canal myocardium in a PRKAG2 variant mouse to determine whether the myocytes forming the accessory connections descend from embryonic AV canal myocardium that failed to regress, or are working myocytes that breached the annulus postnatally. Pair with staged histology of annulus fibrosus integrity across development.

Show evidence (2 references)

PMID:11827995 SUPPORT Other

"either embryonic atrioventricular connections that normally regress during heart development persist in individuals with PRKAG2 mutations, or metabolic deposits activate quiescent accessory pathways"

States the two competing explanations as an explicitly open question. Evidence source is OTHER because this is the authors' framing of an unresolved problem in discussion, not a data-supported finding.

PMID:18158359 PARTIAL Model Organism

"Transgene suppression during early postnatal development prevented the development of accessory electrical pathways but not cardiomyopathy or conduction system degeneration."

Establishes a developmental window specific to the accessory-pathway arm, which bears on but does not settle the origin question. Marked PARTIAL for that reason.

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Pathophysiology

14

PRKAG2 Missense Variant in the AMPK Gamma-2 CBS Domains

A heterozygous germline missense variant in PRKAG2 alters a highly conserved residue within, or immediately adjacent to, the tandem cystathionine-beta-synthase (CBS/Bateman) domains of the AMPK gamma-2 regulatory subunit. These domains constitute the adenine-nucleotide-sensing module that binds AMP, ADP, and ATP competitively and thereby sets the activation state of the alpha catalytic subunit. Recurrent alleles include p.Arg302Gln (the most frequently reported, in CBS1), p.Asn488Ile, p.Thr400Asn, and p.Arg531Gly. The variants do not abolish assembly of the heterotrimer; they corrupt its nucleotide-dependent regulation.

Cardiomyocyte CL:0000746

PRKAG2 hgnc:9386

AMP binding by the gamma-2 CBS domains GO:0016208 ⚠ ABNORMAL

Downstream

Dysregulated AMPK Nucleotide Sensing Corruption of the CBS nucleotide-binding module directly deranges the allosteric regulation of the AMPK heterotrimer.

Show evidence (2 references)

PMID:11407343 SUPPORT Human Clinical

"We identified a missense mutation in the gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein."

The original linkage study identifying PRKAG2 p.Arg302Gln as the cause of familial ventricular pre-excitation with hypertrophy.

PMID:12397075 SUPPORT In Vitro

"Two of these mutations lead to a marked decrease in AMP dependence, whereas the third reduces AMP sensitivity. These findings suggest that the CBS domains play an important role in AMP-binding within the complex."

Localises the functional lesion of the disease-causing variants to AMP binding within the CBS domains, the defining feature of this node.

Dysregulated AMPK Nucleotide Sensing

The variant gamma-2 subunit no longer couples AMPK activity correctly to the cellular adenine-nucleotide charge. The DIRECTION of the resulting change in kinase activity is genuinely unresolved in the literature and this entry does not assert one: yeast reconstitution and the N488I transgenic mouse support inappropriate/constitutive ACTIVATION, whereas biochemical assay of purified mutant complexes and the R302Q transgenic mouse support LOSS of AMP-dependent activation, with reduced cardiac AMPK activity. Time-resolved work adds a further wrinkle: acute expression of gamma-2 R302Q activates AMPK and upregulates glycogen synthase and AS160, but in the chronically transgenic adult heart AMPK activity is suppressed, apparently as feedback to the glycogen already stored - so measured activity depends on when in the disease course it is sampled. The competing readings are curated as `mechanistic_hypotheses` and carried on the outgoing edges.

Constitutive/Inappropriate AMPK Activation Model Glycogen-Independent AMPK-gamma2/Myosin Interaction Model Impaired AMP Sensing / Loss-of-Function Model

Cardiomyocyte CL:0000746

AMP-activated protein kinase activity GO:0004679 ⚠ ABNORMAL

Downstream

Excessive Cardiomyocyte Glycogen and Polyglucosan Accumulation

Enhanced AMPK-gamma2/Myosin Interaction Under the emerging model, the variant subunit's principal proximate effect is a gain of binding to myosin rather than a change in kinase output.

Show evidence (3 references)

PMID:20031621 SUPPORT In Vitro

"acute expression of gamma(2)R302Q induces AMPK activation and upregulation of glycogen synthase and AS160, with an associated increase in glycogen content"

The ACUTE arm of this study, showing AMPK activation, is performed by transient expression in cultured neonatal rat cardiomyocytes, so this item is IN_VITRO. It provides the activation half of the temporal picture that makes this node direction-agnostic.

PMID:20031621 SUPPORT Model Organism

"AMPK activity, glycogen synthase activity, and AS160 expression are reduced in hearts from TGgamma(2)R302Q mice, likely in response to the existing 37-fold increase in glycogen."

The CHRONIC arm, showing suppressed AMPK activity, is measured in hearts from transgenic mice, so this item is MODEL_ORGANISM. Split from the acute in-vitro item above because the original sentence spans two different experimental systems and each evidence item must carry a single evidence_source.

PMID:20031621 SUPPORT Other

"These findings are the first to highlight temporal differences in the effects of the PRKAG2 R302Q mutation on cardiac metabolic signaling events."

Explicitly frames the temporal dependence of the signalling phenotype. Evidence source is OTHER because this concluding statement synthesises across both arms of the study - cultured neonatal rat cardiomyocytes and transgenic mouse hearts - so it belongs to neither IN_VITRO nor MODEL_ORGANISM alone; the per-arm data are cited separately above.

Excessive Cardiomyocyte Glycogen and Polyglucosan Accumulation

Cardiomyocytes accumulate large amounts of glycogen and of poorly soluble, amylopectin-like polyglucosan within non-lysosomal cytosolic vacuoles. This is the biochemical event that makes PRKAG2 disease a cardiac glycogenosis rather than a cardiomyopathy of the contractile apparatus, and it is the hub from which the three clinical arms - hypertrophy, pre-excitation, and conduction disease - all descend. In the N488I transgenic mouse cardiac glycogen reaches roughly thirty times normal.

Cardiomyocyte CL:0000746

Glycogen biosynthetic process GO:0005978 ↑ INCREASED Glycogen metabolic process GO:0005977 ⚠ ABNORMAL

Downstream

Cardiomyocyte Vacuolation and Storage-Driven Myocyte Enlargement

Disruption of the Annulus Fibrosus by Glycogen-Laden Myocytes

Glycogen Infiltration and Degeneration of the Cardiac Conduction System

Show evidence (3 references)

PMID:12782567 SUPPORT Model Organism

"Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction."

Quantifies the magnitude of glycogen accumulation and links it to the full phenotypic triad in the transgenic mouse model.

PMID:12782567 SUPPORT Other

"Pathological examinations of affected human hearts reveal vacuoles containing amylopectin, a glycogen-related substance."

Confirms that the stored material in HUMAN hearts is amylopectin-like polyglucosan, not simply soluble glycogen. Evidence source is OTHER because this is a background statement in a mouse study summarising prior human pathology rather than primary data from the cited experiment.

PMID:15673802 SUPPORT Human Clinical

"Because mutations in the gene for AMP-activated protein kinase gamma2 (PRKAG2) cause an accumulation of cardiac glycogen and left ventricular hypertrophy that mimics hypertrophic cardiomyopathy"

States the human clinical premise that PRKAG2 variants cause cardiac glycogen accumulation producing HCM-mimicking hypertrophy.

Enhanced AMPK-gamma2/Myosin Interaction

Under the emerging glycogen-independent model, variant AMPK-gamma2 binds myosin more strongly and relocalises to the myofilament. The proposed consequence is retention of calcium at the myofilament, reducing the free cytosolic calcium available for sodium/calcium-exchanger extrusion and thereby prolonging the calcium transient and action potential. This arm is reported only in transgenic zebrafish and is curated as EMERGING; it is not asserted as an established human mechanism.

Glycogen-Independent AMPK-gamma2/Myosin Interaction Model

Cardiomyocyte CL:0000746

Downstream

Glycogen-Independent Early Electrophysiological Abnormality

Show evidence (1 reference)

PMID:42422944 SUPPORT In Vitro

"Proximity ligation assays and coimmunoprecipitation identified a physical interaction between AMPKγ2 and myosin, enhanced by the R299Q variant and accompanied by increased AMPKγ2 localization to the myofilament."

Establishes the variant-enhanced physical interaction and myofilament relocalisation that define this node. Evidence source is IN_VITRO because proximity ligation and co-immunoprecipitation are biochemical assays run on harvested tissue outside the organism; the in-vivo zebrafish phenotype is carried by the separate MODEL_ORGANISM items on the downstream node.

Glycogen-Independent Early Electrophysiological Abnormality

In the zebrafish model the variant heart shows reduced conduction velocity and prolonged action-potential and calcium-transient durations at a developmental stage at which no glycogen has yet accumulated, and AMPK activation does not rescue these abnormalities. This would place part of the electrical phenotype upstream of, or parallel to, glycogen storage rather than downstream of it. Reported in one non-mammalian model only.

Glycogen-Independent AMPK-gamma2/Myosin Interaction Model

Cardiomyocyte CL:0000746

Cardiac conduction GO:0061337 ⚠ ABNORMAL

Downstream

Progressive Contractile Dysfunction In the same model the variant produces hypertrophic cardiomyocytes and progressive contractile abnormalities alongside the electrical changes, so under the emerging model part of the contractile phenotype would arise by a route independent of the storage cascade. The edge is deliberately pointed at contractile dysfunction rather than at pre-excitation, because the zebrafish study reports conduction slowing and contractile abnormality but does NOT report accessory pathways or pre-excitation; the intervening steps to the human phenotype are not established.

Show evidence (2 references)

PMID:42422944 SUPPORT Model Organism

"Despite the absence of glycogen accumulation at 6 days postfertilization, TgR299Q hearts showed electrical abnormalities, including reduced conduction velocity and prolonged action potential and Ca2+ transient durations."

Documents electrical abnormality preceding glycogen accumulation, the observation that motivates the glycogen-independent arm.

PMID:42422944 SUPPORT Model Organism

"Cardiomyocyte glycogen was elevated in adult but not embryonic hearts."

Confirms the temporal dissociation between the electrical phenotype and the onset of glycogen storage in this model.

Cardiomyocyte Vacuolation and Storage-Driven Myocyte Enlargement

Storage material distends the cardiomyocyte, producing the large isolated cytosolic vacuoles seen on biopsy and enlarging the cell. Critically, the added mass is stored polysaccharide and water rather than new contractile apparatus, and the myofibrillar architecture is preserved - myofibre disarray and significant interstitial fibrosis, the histological signatures of sarcomeric HCM, are absent.

Cardiomyocyte CL:0000746

Cardiac muscle hypertrophy GO:0003300 ↑ INCREASED

Downstream

Ventricular Hypertrophy Mimicking Sarcomeric Hypertrophic Cardiomyopathy

Show evidence (3 references)

PMID:11827995 SUPPORT Human Clinical

"Marked ventricular hypertrophy was evident on gross inspection, and myocytes were enlarged"

Human cardiac specimens from PRKAG2 variant carriers show myocyte enlargement accompanying gross ventricular hypertrophy.

PMID:11827995 SUPPORT Human Clinical

"all five specimens demonstrated isolated, large cytosolic vacuoles in cardiomyocytes"

Documents the vacuolation in every human specimen examined.

PMID:11827995 SUPPORT Other

"Excess glycogen storage and water in cardiomyocytes appear to account for increased cardiac mass in affected individuals"

Attributes the increased cardiac mass to stored polysaccharide and water rather than to contractile-protein hypertrophy - the mechanistic reason PRKAG2 hypertrophy is not neurohormonal remodeling. Evidence source is OTHER because this is the authors' interpretive synthesis in discussion.

Ventricular Hypertrophy Mimicking Sarcomeric Hypertrophic Cardiomyopathy

At the organ level the accumulated storage material manifests as increased left ventricular wall thickness indistinguishable on echocardiography from sarcomeric hypertrophic cardiomyopathy, which is why PRKAG2 disease is routinely first labelled HCM. It is present in about two-thirds of carriers at first assessment in the largest cohort and accrues further over follow-up. The tell that separates it from sarcomeric HCM is not the hypertrophy itself but the accompanying electrophysiology and the biopsy findings.

Cardiomyocyte CL:0000746

Downstream

Progressive Contractile Dysfunction After years to decades the hypertrophic phase gives way to declining pump function; the intervening steps in PRKAG2 disease specifically are not well characterised.

Show evidence (2 references)

PMID:32646569 SUPPORT Human Clinical

"Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline."

Quantifies the burden of left ventricular hypertrophy in the largest multicentre PRKAG2 cohort.

PMID:15673802 SUPPORT Human Clinical

"The glycogen-storage cardiomyopathy produced by LAMP2 or PRKAG2 mutations resembles hypertrophic cardiomyopathy but is distinguished by electrophysiological abnormalities, particularly ventricular preexcitation."

States both halves of the claim: the phenotypic mimicry of HCM and the electrophysiological feature that distinguishes it.

Disruption of the Annulus Fibrosus by Glycogen-Laden Myocytes

The annulus fibrosus of the cardiac skeleton is the fibrous ring that electrically insulates the atria from the ventricles, restricting normal atrioventricular conduction to the AV node. Glycogen-engorged cardiomyocytes breach this ring, creating microscopic strands of muscle continuity across it. This is the single most mechanistically distinctive feature of PRKAG2 disease: the pre-excitation is ANATOMICAL in origin - a failure of insulation - rather than a morphologically discrete accessory bundle as in idiopathic Wolff-Parkinson-White syndrome, and rather than an ion-channel abnormality. The same mechanism was proposed to explain pre-excitation in other glycogen storage cardiomyopathies including Pompe and Danon disease.

Cardiomyocyte CL:0000746

Annulus fibrosus of the heart UBERON:0004292

Downstream

Accessory Atrioventricular Connections and Ventricular Pre-excitation

Show evidence (2 references)

PMID:12782567 SUPPORT Model Organism

"Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes."

The primary histopathological demonstration that glycogen-filled myocytes breach the insulating annulus fibrosus. Evidence source is MODEL_ORGANISM because the histopathology reported is from transgenic mice.

PMID:12782567 SUPPORT Model Organism

"These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation."

Establishes that the substrate is diffuse microscopic AV continuity rather than a discrete bypass tract - the point that distinguishes PRKAG2 pre-excitation from idiopathic WPW and that explains poor ablation durability.

Accessory Atrioventricular Connections and Ventricular Pre-excitation

The muscle strands crossing the breached annulus conduct atrial impulses to the ventricle ahead of the AV node, producing a short PR interval and delta wave, and completing a macro-reentrant circuit that supports atrioventricular reentrant tachycardia. Electrophysiological study in human carriers demonstrates one or more accessory atrioventricular pathways, and the R302Q transgenic mouse reproduces both the distinct accessory pathway and inducible orthodromic AV reentrant tachycardia.

Cardiomyocyte CL:0000746

Cardiac conduction GO:0061337 ⚠ ABNORMAL

Downstream

Supraventricular Tachyarrhythmia and Atrial Fibrillation

Show evidence (2 references)

PMID:11827995 SUPPORT Human Clinical

"Electrophysiologic studies in ten affected individuals demonstrated one or more accessory atrioventricular pathways."

Human electrophysiological confirmation of accessory atrioventricular pathways in PRKAG2 variant carriers.

PMID:15611370 SUPPORT Model Organism

"A distinct AV accessory pathway was confirmed by electrical and pharmacological stimulation and substantiated by induction of orthodromic AV reentrant tachycardia."

Demonstrates in the R302Q transgenic mouse both the accessory pathway and the reentrant tachycardia it supports. Evidence source is MODEL_ORGANISM because this is transgenic mouse work.

Glycogen Infiltration and Degeneration of the Cardiac Conduction System

Specialised conduction tissue - sinoatrial node, atrioventricular node, and the His-Purkinje system - is subject to the same storage process as working myocardium, and degenerates progressively with age. Unlike the accessory-pathway arm, which is often present from childhood, this arm accrues over decades and is what makes early pacemaker dependence a diagnostic red flag.

Cardiac conduction system myocyte CL:0002086 Atrioventricular node myocyte CL:1000410

Cardiac conduction GO:0061337 ↓ DECREASED

Central cardiac conduction system UBERON:2005074

Downstream

Progressive Atrioventricular Block and Bradyarrhythmia

Show evidence (3 references)

PMID:12782567 SUPPORT Model Organism

"Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction."

Establishes sinus node dysfunction alongside glycogen accumulation in the transgenic mouse model.

PMID:18158359 SUPPORT Model Organism

"Tg(ON) mice developed cardiac hypertrophy followed by dilatation, ventricular preexcitation involving multiple accessory pathways, and conduction system disease, including sinus and atrioventricular node dysfunction."

Documents the full natural history in the inducible transgenic mouse model, including sinoatrial and atrioventricular nodal involvement.

PMID:11827995 SUPPORT Human Clinical

"With increasing age, affected individuals progressively developed slower heart rates."

Human evidence for the progressive, age-dependent character of the conduction-system arm.

Progressive Atrioventricular Block and Bradyarrhythmia

Clinically, conduction-system degeneration presents as sinus bradycardia, chronotropic incompetence, and progressive degrees of atrioventricular block, culminating in permanent pacemaker implantation at an age far younger than degenerative conduction disease would predict - a median of the mid-thirties in the largest cohort. Roughly a third of affected individuals in early series required pacing.

Regulation of heart rate by cardiac conduction GO:0086091 ⚠ ABNORMAL

Show evidence (2 references)

PMID:11827995 SUPPORT Human Clinical

"Sinus bradycardia and/or variable degrees of atrioventricular block resulted in pacemaker implantation in 24 (35%) affected individuals."

Quantifies the bradyarrhythmia burden and pacing requirement in human PRKAG2 families.

PMID:32646569 SUPPORT Human Clinical

"Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age."

Establishes young-age pacemaker requirement as the clinical signal of this node.

Supraventricular Tachyarrhythmia and Atrial Fibrillation

The accessory connections support atrioventricular reentrant tachycardia, and atrial fibrillation becomes increasingly prevalent with age. Rapid conduction of atrial fibrillation over an accessory pathway is a recognised route to haemodynamic collapse and sudden death in pre-excitation syndromes, and this arm together with progressive heart failure underlies the life-threatening arrhythmia burden of the disease.

Regulation of heart rate by cardiac conduction GO:0086091 ⚠ ABNORMAL

Show evidence (2 references)

PMID:11827995 SUPPORT Human Clinical

"WPW usually manifested early in life with tachyarrhythmias (atrial fibrillation and other supraventricular arrhythmias) and sometimes caused syncope."

Links the pre-excitation substrate to supraventricular tachyarrhythmia, atrial fibrillation, and syncope in human carriers.

PMID:32646569 SUPPORT Human Clinical

"PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias."

Summarises the arrhythmic burden of the disease from the largest cohort.

Progressive Contractile Dysfunction

Over years to decades the hypertrophic phase is followed in a substantial minority by declining pump function - a transition sometimes described as a burned-out, dilated phase. At this point the disease converges on the generic structural-cardiomyopathy pathway, which is why conformance to the maladaptive-remodeling module is declared HERE and not at the upstream hypertrophy node: the earlier increase in wall thickness is storage mass, not neurohormonally driven remodeling.

Cardiomyocyte CL:0000746

Heart contraction GO:0060047 ↓ DECREASED

Downstream

Advanced Heart Failure and End-Stage Cardiomyopathy

Show evidence (3 references)

PMID:11827995 SUPPORT Human Clinical

"Left ventricular function markedly deteriorated in five affected adult individuals and necessitated cardiac transplantation in one; sudden death occurred in four."

Documents progression from hypertrophy to overt systolic deterioration requiring transplantation in human PRKAG2 carriers.

PMID:18158359 SUPPORT Model Organism

"Tg(ON) mice developed cardiac hypertrophy followed by dilatation, ventricular preexcitation involving multiple accessory pathways, and conduction system disease, including sinus and atrioventricular node dysfunction."

Recapitulates the hypertrophy-then-dilatation sequence in the inducible transgenic mouse model.

PMID:33244021 SUPPORT Human Clinical

"11 patients (50%) developed progressive worsening in NYHA functional class"

Human prospective evidence for the functional decline arm of this node: half of a cohort that began entirely in NYHA class I-II deteriorated over seven years, quantifying the "substantial minority to half" framing of the transition out of the compensated hypertrophic phase.

Advanced Heart Failure and End-Stage Cardiomyopathy

The terminal state is heart failure requiring hospitalisation, and in a minority transplantation or death. In the largest multicentre cohort, over a median six years of follow-up, 14 percent required heart-failure admission, 8 percent had sudden cardiac death or an equivalent event, 4 percent were transplanted, and 13 percent died.

Heart contraction GO:0060047 ⚠ ABNORMAL

Show evidence (2 references)

PMID:32646569 SUPPORT Human Clinical

"14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died."

Quantifies the end-stage outcomes of PRKAG2 cardiac syndrome in the largest natural-history cohort.

PMID:28431061 SUPPORT Human Clinical

"This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications."

Independent cohort confirming the high burden of cardiac complications.

✶

Histopathology

4

PAS-positive, diastase-resistant polyglucosan inclusions in cardiomyocytes

The defining microscopic finding of PRKAG2 cardiac syndrome. Cardiomyocyte vacuoles contain granular material that stains strongly with periodic acid-Schiff and, critically, RESISTS diastase digestion. Diastase removes ordinary glycogen; resistance therefore identifies the stored material as polyglucosan (an amylopectin-like, poorly branched, poorly soluble polysaccharide) rather than simple glycogen. Electron microscopy confirms densely packed granular and fibrillar electron-dense material characteristic of amylopectin. This single stain pair separates PRKAG2 disease from sarcomeric HCM and, together with the clinical context, from Danon and Pompe disease.

Show evidence (2 references)

PMID:11827995 SUPPORT Human Clinical

"was diastase-resistant, a pattern that is characteristic of polyglucan"

Establishes diastase resistance of the PAS-positive inclusions in human PRKAG2 cardiac specimens, identifying the stored material as polyglucosan.

PMID:11827995 SUPPORT Human Clinical

"features that are characteristic of amylopectin, a nonsoluble product of glycogen metabolism"

Ultrastructural confirmation that the inclusions have the features of amylopectin, corroborating the histochemical finding.

Vacuolated cardiomyocytes

Large isolated cytosolic vacuoles within enlarged cardiomyocytes, present in every human specimen examined in the defining pathological series. The vacuoles are non-lysosomal, distinguishing the storage compartment from that of Danon disease (autophagic vacuoles with sarcolemmal features) and Pompe disease (lysosomal).

Show evidence (1 reference)

PMID:11827995 SUPPORT Human Clinical

"all five specimens demonstrated isolated, large cytosolic vacuoles in cardiomyocytes"

Documents the vacuolation in all five human PRKAG2 cardiac specimens examined.

Absence of myofibre disarray

Myofibre (myocyte) disarray, the histological signature of sarcomeric hypertrophic cardiomyopathy, is ABSENT in PRKAG2 hearts, and interstitial fibrosis is minimal and focal. This negative finding carries as much diagnostic weight as the positive storage findings, and is the histological basis for treating PRKAG2 disease as a genocopy of HCM rather than a form of it.

Show evidence (2 references)

PMID:11827995 SUPPORT Human Clinical

"myofiber disarray, the characteristic feature of HCM, was not detected in any sample"

Direct statement that the defining histological feature of sarcomeric HCM is absent from PRKAG2 cardiac specimens.

PMID:11827995 SUPPORT Human Clinical

"Interstitial fibrosis was minimal and focal."

Documents the minimal fibrosis that accompanies the absence of disarray, further separating PRKAG2 disease from sarcomeric HCM.

Positive glycogen staining on endomyocardial biopsy

In life, endomyocardial biopsy demonstrating positive glycogen staining supports the diagnosis of a cardiac glycogenosis in a patient with otherwise unexplained hypertrophy.

Show evidence (1 reference)

PMID:40149727 SUPPORT Human Clinical

"In the EMB of one of the patients, staining for glycogen deposits was positive."

Contemporary cohort documenting positive glycogen staining on endomyocardial biopsy in a PRKAG2 carrier.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

15

Cardiovascular 7

Wolff-Parkinson-White syndrome Wolff-Parkinson-White syndrome HP:0001716

Show evidence (2 references)

PMID:12015471 SUPPORT Other

"Recently, we identified the genetic cause of a familial arrhythmogenic syndrome characterized by ventricular preexcitation and tachyarrhythmias (Wolff-Parkinson-White syndrome), progressive conduction system disease, and cardiac hypertrophy."

Names WPW as a defining component of the PRKAG2 triad. Evidence source is OTHER because this is a narrative review summarising the authors' prior work rather than reporting primary data.

PMID:11748095 SUPPORT Human Clinical

"We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy."

Documents WPW as a childhood-onset PRKAG2 presentation that can precede or occur without hypertrophy.

Left ventricular hypertrophy FREQUENT Left ventricular hypertrophy HP:0001712

Course: PROGRESSIVE

Show evidence (3 references)

PMID:32646569 SUPPORT Human Clinical

"Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline."

Direct quantitative support for both the phenotype and the FREQUENT band, at 67 percent.

PMID:32646569 SUPPORT Human Clinical

"71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers"

Shows the prevalence of LVH rising over follow-up, supporting the PROGRESSIVE clinical course qualifier.

PMID:33244021 SUPPORT Human Clinical

"Left ventricular hypertrophy was present in 19 individuals (86%) at baseline."

Independent replication of the FREQUENT band in a separate ancestry group (22-patient South Asian cohort), at the high end of the range.

Atrioventricular block OCCASIONAL Atrioventricular block HP:0001678

Course: PROGRESSIVE

Show evidence (2 references)

PMID:28431061 SUPPORT Human Clinical

"In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%."

Supports both the phenotype and the OCCASIONAL band, since 22 percent falls in the 5-29 percent HPO range.

PMID:11827995 SUPPORT Human Clinical

"Sinus bradycardia and/or variable degrees of atrioventricular block resulted in pacemaker implantation in 24 (35%) affected individuals."

Independent human series documenting variable-degree AV block leading to pacing.

Atrial fibrillation OCCASIONAL Atrial fibrillation HP:0005110

Show evidence (2 references)

PMID:32646569 SUPPORT Human Clinical

"16 (18%) had atrial fibrillation"

Supports both the phenotype and the OCCASIONAL band, at 18 percent at baseline, within the 5-29 percent HPO range.

PMID:32646569 SUPPORT Human Clinical

"71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers"

Shows the atrial fibrillation prevalence rising to 29 percent over follow-up, still within the OCCASIONAL band.

Syncope Syncope HP:0001279

Show evidence (1 reference)

PMID:11827995 SUPPORT Human Clinical

"WPW usually manifested early in life with tachyarrhythmias (atrial fibrillation and other supraventricular arrhythmias) and sometimes caused syncope."

Attributes syncope in PRKAG2 carriers to the tachyarrhythmic manifestations of pre-excitation.

Congestive heart failure OCCASIONAL Congestive heart failure HP:0001635

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:32646569 SUPPORT Human Clinical

"14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died."

Supports both the phenotype and the OCCASIONAL band, at 14 percent, within the 5-29 percent HPO range.

Sudden cardiac death OCCASIONAL Sudden cardiac death HP:0001645

Show evidence (2 references)

PMID:32646569 SUPPORT Human Clinical

"14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died."

Supports the phenotype and the OCCASIONAL band, at 8 percent.

PMID:28431061 SUPPORT Human Clinical

"In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%."

Independent cumulative-risk estimate of 20 percent by age 40, at the top of the OCCASIONAL band.

Nervous System 4

Intellectual disability and neurocognitive impairment Intellectual disability HP:0001249

Show evidence (2 references)

PMID:39082507 SUPPORT Human Clinical

"Extracardiac involvement, such as in neurocognitive and psychiatric disorders, has been observed only in carriers of mutations."

Establishes that the neurocognitive involvement segregated with carrier status within the kindred rather than being background family morbidity.

PMID:39082507 PARTIAL Human Clinical

"Further research may uncover the potential connections between intellectual disability, miscarriage, and neonatal death in individuals with this syndrome."

Names intellectual disability explicitly, but is graded PARTIAL because the authors state the connection as a hypothesis for further research rather than an established disease-phenotype association.

Anxiety Anxiety HP:0000739

Show evidence (1 reference)

PMID:39082507 SUPPORT Human Clinical

"neurocognitive delay, seizures, difficulties walking, learning disabilities, anxiety, aggressiveness, speech disorders, and changes in mood and behavior"

Direct enumeration of anxiety among the extracardiac features of two carriers described individually in the results.

Aggressive behavior Aggressive behavior HP:0000718

Show evidence (1 reference)

PMID:39082507 SUPPORT Human Clinical

"neurocognitive delay, seizures, difficulties walking, learning disabilities, anxiety, aggressiveness, speech disorders, and changes in mood and behavior"

Direct enumeration of aggressiveness among the extracardiac features of the individually described carriers.

Speech disorder Abnormal speech pattern HP:0002167

Show evidence (1 reference)

PMID:39082507 SUPPORT Human Clinical

"neurocognitive delay, seizures, difficulties walking, learning disabilities, anxiety, aggressiveness, speech disorders, and changes in mood and behavior"

Direct enumeration of speech disorder among the extracardiac features. The HPO parent term "Abnormal speech pattern" is used because the source does not characterise the speech disorder further.

Other 4

Ventricular pre-excitation FREQUENT Ventricular preexcitation HP:0004309

Show evidence (2 references)

PMID:32646569 SUPPORT Human Clinical

"Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation"

Supports both the phenotype and the FREQUENT band, since 33 percent falls in the 30-79 percent HPO range.

PMID:28431061 SUPPORT Human Clinical

"In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%."

Independent time-to-event estimate of 70 percent cumulative pre-excitation risk by age 40, corroborating the FREQUENT band.

Sinus bradycardia Sinus bradycardia HP:0001688

Course: PROGRESSIVE

Show evidence (2 references)

PMID:11827995 SUPPORT Human Clinical

"With increasing age, affected individuals progressively developed slower heart rates."

Documents progressive resting heart-rate slowing in PRKAG2 carriers.

PMID:40149727 SUPPORT Human Clinical

"After a median follow-up of 13.1 years, 6 carriers had LVH, 3 required admission for HF, and 1 had sustained ventricular tachycardia with subsequent cardioverter defibrillator implantation, and despite this, died suddenly; there were two de novo pacemaker implantations due to symptomatic bradycardia."

Documents symptomatic bradycardia as an independent pacing indication in a long-followed contemporary cohort.

Supraventricular tachycardia Supraventricular tachycardia HP:0004755

Show evidence (1 reference)

PMID:11827995 SUPPORT Human Clinical

"WPW usually manifested early in life with tachyarrhythmias (atrial fibrillation and other supraventricular arrhythmias) and sometimes caused syncope."

Documents supraventricular arrhythmia as an early manifestation in human PRKAG2 families.

Adverse pregnancy outcome in affected female carriers Abnormal delivery HP:0001787

Show evidence (2 references)

PMID:39082507 SUPPORT Human Clinical

"four premature neonatal deaths, two spontaneous abortions, five forceps deliveries, and 12 cesarean procedures"

Direct enumeration of the obstetric and perinatal events observed in the carrier group.

PMID:39082507 SUPPORT Human Clinical

"Mutations carriers were advised to avoid pregnancy."

Shows the authors treated the obstetric burden as clinically actionable counselling content, not an incidental observation.

🧬

Genetic Associations

1

PRKAG2 (Causative)

Gene: PRKAG2 hgnc:9386 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:11407343 SUPPORT Human Clinical

"We identified a missense mutation in the gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein."

Establishes PRKAG2 as the causative gene by positional cloning in two independent families.

💊

Medical Actions

7

Permanent pacemaker implantation

Action: Pacemaker placement Ontology label: Pacemaker Placement NCIT:C80434

The mainstay intervention for the conduction-disease arm. Progressive atrioventricular block and symptomatic bradycardia require permanent pacing, typically at a strikingly young age - a median in the mid-thirties in the largest cohort, and about a third of affected individuals in early series. Pacing does not modify the underlying storage process; it substitutes for the degenerating conduction system.

Mechanism Target:

BYPASSES Progressive Atrioventricular Block and Bradyarrhythmia — Artificial pacing restores an adequate ventricular rate by providing an alternative activation source; it circumvents the diseased conduction tissue rather than reversing its degeneration.

Target Phenotypes: Atrioventricular block HP:0001678 Sinus bradycardia HP:0001688

Show evidence (3 references)

PMID:11827995 SUPPORT Human Clinical

"Sinus bradycardia and/or variable degrees of atrioventricular block resulted in pacemaker implantation in 24 (35%) affected individuals."

Documents pacemaker implantation as the response to bradyarrhythmia and AV block in about a third of affected individuals.

PMID:32646569 SUPPORT Human Clinical

"Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years)."

Quantifies pacemaker use and the strikingly young median age at implantation.

PMID:33244021 SUPPORT Human Clinical

"8 patients (36%) underwent permanent pacemaker implantation (atrio-ventricular blocks-5; sinus node disease-2)"

Independent replication of the high pacing burden in a separate South Asian cohort, and shows the indication split between atrioventricular block and sinus node disease.

Implantable cardioverter-defibrillator

Action: Implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Considered for secondary prevention after sustained ventricular arrhythmia, and for primary prevention in individuals judged at high arrhythmic risk. The evidence base is observational: no PRKAG2-specific risk-stratification model exists, and a defibrillator does not protect against the bradyarrhythmic or heart-failure modes of death. In one contemporary cohort a patient died suddenly despite defibrillator implantation.

Target Phenotypes: Sudden cardiac death HP:0001645

Show evidence (2 references)

PMID:40149727 PARTIAL Human Clinical

"After a median follow-up of 13.1 years, 6 carriers had LVH, 3 required admission for HF, and 1 had sustained ventricular tachycardia with subsequent cardioverter defibrillator implantation, and despite this, died suddenly; there were two de novo pacemaker implantations due to symptomatic bradycardia."

Documents defibrillator use after sustained ventricular tachycardia while also showing it did not prevent sudden death in that patient, hence PARTIAL rather than SUPPORT.

PMID:28431061 SUPPORT Human Clinical

"Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant."

Independent cohort documenting defibrillator implantation as part of the device burden of PRKAG2 syndrome.

Catheter ablation of accessory atrioventricular pathways

Action: Cardiac ablation Ontology label: Cardiac Ablation NCIT:C100068

Catheter ablation is used for symptomatic accessory-pathway-mediated tachyarrhythmia, and a third of the largest cohort had either pre-excitation or prior accessory-pathway ablation. Its durability is limited by the underlying anatomy: because the substrate is diffuse microscopic muscle continuity across a breached annulus fibrosus rather than a single discrete bypass tract, multiple pathways are common and arrhythmia recurrence after ablation is a recognised problem. This is a direct clinical consequence of the mechanism curated in the pathophysiology graph.

Mechanism Target:

INHIBITS Accessory Atrioventricular Connections and Ventricular Pre-excitation — Radiofrequency ablation destroys conducting tissue at the site of an accessory connection, interrupting the pre-excitation and the reentrant circuit. Because the anatomical substrate is diffuse rather than discrete, the interruption is often incomplete or non-durable.

Show evidence (1 reference)

PMID:12782567 PARTIAL Model Organism

"These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation."

Explains why an ablation strategy designed for discrete bypass tracts is mechanistically mismatched to the PRKAG2 substrate. Marked PARTIAL because it characterises the substrate rather than reporting ablation outcomes.

Target Phenotypes: Ventricular preexcitation HP:0004309 Supraventricular tachycardia HP:0004755

Show evidence (2 references)

PMID:32646569 SUPPORT Human Clinical

"Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation"

Documents accessory-pathway ablation as part of standard management in the largest PRKAG2 cohort.

PMID:11827995 SUPPORT Human Clinical

"Electrophysiologic studies in ten affected individuals demonstrated one or more accessory atrioventricular pathways."

Documents that carriers frequently have MULTIPLE accessory pathways, the anatomical reason single-target ablation may not be curative.

Anticoagulation for atrial fibrillation

Action: Anticoagulation therapy Ontology label: Anticoagulation Therapy NCIT:C63341

Agent: anticoagulant agent NCIT:C263

Stroke prevention in the atrial-arrhythmia arm of the disease. Atrial fibrillation and atrial flutter are curated here both as a phenotype and as a pathophysiology node, and they arrive early - a median age of 43 years in the largest cohort - so the cumulative thromboembolic exposure is long. The Brazilian kindred followed for 18 years recorded four strokes among nineteen carriers, and individual carriers in that series were managed with warfarin, rivaroxaban, apixaban, and dabigatran for intracardiac thrombus, inferior vena cava thrombosis, pulmonary embolism, and embolic stroke. Anticoagulation is named by the authors as one of the interventions that improved symptoms and survival. Important scope limit: there is no PRKAG2-specific anticoagulation trial and no PRKAG2-specific stroke-risk score; the practice is extrapolated from general AF stroke-prevention management, and the observational cohort evidence below reports it as part of a bundle of early interventions rather than as an isolated, separately evaluated therapy. No `target_mechanisms` link is declared to the "Supraventricular Tachyarrhythmia and Atrial Fibrillation" node on purpose: anticoagulation neither inhibits, activates, modulates, bypasses, nor restores that mechanism - it interrupts a thromboembolic consequence downstream of it - and none of the five permissible `treatment_effect` values would describe that honestly.

Target Phenotypes: Atrial fibrillation HP:0005110

Show evidence (3 references)

PMID:39082507 SUPPORT Human Clinical

"Early diagnosis and intervention through antiarrhythmic drugs, anticoagulation, pacemaker implantation, radiofrequency catheter ablation, and cesarean section surgery improved the symptoms and survival rates."

Names anticoagulation explicitly as part of the management bundle credited with improved symptoms and survival in an 18-year PRKAG2 cohort. Graded SUPPORT for the practice, but note the effect is attributed to the bundle, not to anticoagulation in isolation.

PMID:39082507 SUPPORT Human Clinical

"This group experienced many malignant events, including eight pacemaker implants, three sudden cardiac deaths, five aborted cardiac arrests, four strokes"

Quantifies the stroke burden in variant carriers that makes stroke prevention a first-order management concern in this disease.

PMID:32646569 SUPPORT Human Clinical

"16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years)"

Establishes the prevalence and the early median onset of the atrial fibrillation that creates the anticoagulation indication.

Septal myectomy

Action: Septal myectomy Ontology label: Myectomy NCIT:C51591

Surgical septal reduction for left ventricular outflow tract obstruction, used in selected PRKAG2 patients whose hypertrophy is obstructive. It is documented in PRKAG2 disease only at case-report level, including in an infant with severe biventricular hypertrophy and pre-excitation carrying a novel p.Glu506Gln allele. It is listed here deliberately as a low-certainty, selected-case option rather than a mainstay: the hypertrophy in PRKAG2 disease is storage-driven mass accrual rather than sarcomeric myocyte hypertrophy with disarray (see `notes`, LUMP-VS-SPLIT), so the sarcomeric-HCM evidence base for septal reduction does not transfer, and no PRKAG2 series has evaluated outcomes. The dominant surgical intervention in this disease remains transplantation for end-stage disease.

Target Phenotypes: Left ventricular hypertrophy HP:0001712

Show evidence (1 reference)

PMID:19787389 PARTIAL Human Clinical

"An infant was assigned a diagnosis of ventricular preexcitation and severe biventricular HCM requiring septal myectomy."

Documents septal myectomy actually being performed in genetically confirmed PRKAG2 disease. Graded PARTIAL because it is a single case report that records the procedure without reporting an outcome or comparing it with alternatives, so it supports availability of the option, not its efficacy.

Heart transplantation

Action: Heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Definitive therapy for end-stage disease. Because the lesion is confined to the heart, transplantation is curative of the cardiac phenotype. About 4 percent of the largest cohort were transplanted over a median six years of follow-up, and transplantation is documented from the earliest human series.

Mechanism Target:

RESTORES Advanced Heart Failure and End-Stage Cardiomyopathy — Replacement of the storage-affected heart with a genotypically normal allograft removes the entire diseased organ, restoring pump function and normal conduction.

Target Phenotypes: Congestive heart failure HP:0001635

Show evidence (2 references)

PMID:32646569 SUPPORT Human Clinical

"14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died."

Quantifies the proportion of the cohort proceeding to transplantation.

PMID:11827995 SUPPORT Human Clinical

"Left ventricular function markedly deteriorated in five affected adult individuals and necessitated cardiac transplantation in one; sudden death occurred in four."

Documents transplantation for end-stage PRKAG2 cardiomyopathy in the original human series.

Genetic counselling and cascade family screening

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Because inheritance is autosomal dominant with age-dependent, incomplete penetrance, first-degree relatives of a proband should be offered genetic testing, and variant-positive relatives require LONGITUDINAL surveillance (serial ECG and echocardiography) rather than a single clearing assessment. The case for this is strong: pre-excitation can precede hypertrophy by years, and pacemaker requirement can be the first manifestation.

Show evidence (2 references)

PMID:11407343 SUPPORT Human Clinical

"We identified two families in which the Wolff-Parkinson-White syndrome segregated as an autosomal dominant disorder."

Establishes the autosomal dominant transmission that makes cascade family screening appropriate.

PMID:11748095 SUPPORT Human Clinical

"We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy."

Demonstrates that variant-positive relatives may manifest in childhood without hypertrophy, supporting longitudinal rather than one-time screening.

{ }

Source YAML

click to show

name: PRKAG2 Cardiac Syndrome
creation_date: "2026-07-31T00:00:00Z"
synonyms:
- PRKAG2 syndrome
- PRKAG2 cardiomyopathy
- PRKAG2-related cardiomyopathy
- Glycogen storage cardiomyopathy due to PRKAG2 mutation
- Familial Wolff-Parkinson-White syndrome with cardiac hypertrophy
- Hypertrophic cardiomyopathy 6
- CMH6
- PRKAG2 hypertrophic cardiomyopathy
- Cardiomyopathy, familial hypertrophic, 6
description: >-
  PRKAG2 cardiac syndrome is a rare autosomal dominant, non-lysosomal glycogen
  storage disease of the heart caused by missense variants in PRKAG2, which
  encodes the gamma-2 regulatory subunit of AMP-activated protein kinase (AMPK).
  Variants cluster in the tandem cystathionine-beta-synthase (CBS) domains that
  form the adenine-nucleotide-sensing module of the gamma subunit, disrupting
  normal AMP/ADP/ATP-dependent regulation of the kinase. The result is excessive
  accumulation of glycogen and polyglucosan (amylopectin-like) material inside
  cardiomyocytes, which produces the disease's characteristic clinical triad:
  left ventricular hypertrophy that mimics sarcomeric hypertrophic
  cardiomyopathy, ventricular pre-excitation (Wolff-Parkinson-White syndrome)
  arising from glycogen-laden myocytes breaching the annulus fibrosus, and
  progressive degenerative conduction-system disease leading to atrioventricular
  block and early pacemaker dependence. It is a genocopy - not a form - of
  sarcomeric hypertrophic cardiomyopathy, and endomyocardial biopsy separates the
  two: PRKAG2 hearts show vacuolated myocytes with PAS-positive,
  diastase-resistant polyglucosan inclusions, minimal fibrosis, and an absence of
  the myofibre disarray that defines sarcomeric HCM.
category: Mendelian
parents:
- Cardiovascular Disease
- Genetic Disorder
- Metabolic Disorder
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  icimd_category:
  - classification_value: glycogen_metabolism
    notes: >-
      PRKAG2 cardiac syndrome is a non-lysosomal cardiac glycogenosis: the
      primary biochemical lesion is dysregulated AMPK control of myocardial
      glycogen synthesis, producing intracytoplasmic glycogen and polyglucosan
      storage. It is distinguished from the enzyme-deficiency glycogen storage
      diseases (Pompe/GAA, GSD IV/GBE1) and from the lysosomal trafficking
      defect of Danon disease (LAMP2), which are separate entries.
disease_term:
  preferred_term: PRKAG2 cardiac syndrome
  term:
    id: MONDO:0800484
    label: PRKAG2-related cardiomyopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0800484
      label: PRKAG2-related cardiomyopathy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The ClinGen-authored MONDO class whose definition ("variable cardiac
      hypertrophy, ventricular pre-excitation, and aberrant glycogen storage in
      the cardiac tissue due to a pathogenic variant in PRKAG2") is exactly the
      entity curated by this entry. Carries the gene association RO:0004003
      HGNC:9386 (PRKAG2).
  - term:
      id: MONDO:0010946
      label: hypertrophic cardiomyopathy 6
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0010946 (CMH6; OMIM:600858; synonyms "CMH6", "PRKAG2 hypertrophic
      cardiomyopathy", "cardiomyopathy, familial hypertrophic, 6") is the
      OMIM-derived, disease-series-by-gene sibling name for the same PRKAG2
      biology, and MONDO asserts it as a direct subclass of MONDO:0800484
      ("is_a: MONDO:0800484 ! PRKAG2-related cardiomyopathy", verified with
      `runoak -i sqlite:obo:mondo info MONDO:0010946 -O obo`). Its own MONDO
      definition is the pure gene-series template - "Any hypertrophic
      cardiomyopathy in which the cause of the disease is a mutation in the
      PRKAG2 gene" - which asserts no mechanism or phenotype beyond the gene,
      so it adds no curatable content over this entry. It is recorded here as
      a narrowMatch (the CMH-numbered-series framing of PRKAG2 disease) rather
      than curated as a separate dismech Disease; see the CMH6 paragraph in
      `notes` for the split rationale.

notes: >-
  SCOPE AND ENTITY IDENTITY. This entry models PRKAG2-related cardiac
  glycogenosis under MONDO:0800484 ("PRKAG2-related cardiomyopathy"; synonym
  "PRKAG2 cardiac syndrome"), whose MONDO definition - "variable cardiac
  hypertrophy, ventricular pre-excitation, and aberrant glycogen storage in the
  cardiac tissue due to a pathogenic variant in PRKAG2" - is exactly the entity
  curated here, and which carries the gene association RO:0004003 HGNC:9386
  (PRKAG2).

  CMH6 / MONDO:0010946 IS SUBSUMED HERE - NO SEPARATE ENTRY. A subsequent
  curation request targeted "hypertrophic cardiomyopathy 6" (MONDO:0010946,
  CMH6, OMIM:600858, gene PRKAG2) as if it were an uncurated disease. It is
  not a distinct disease from the one modeled here. MONDO asserts
  "is_a: MONDO:0800484 ! PRKAG2-related cardiomyopathy" on MONDO:0010946, and
  MONDO:0010946's definition is the bare disease-series-by-gene template ("Any
  hypertrophic cardiomyopathy in which the cause of the disease is a mutation
  in the PRKAG2 gene"), generated from the OMIM CMH-numbered series rather
  than authored against distinguishing biology. The two MONDO classes are
  therefore two names - one ClinGen-authored and mechanism-bearing, one
  OMIM-series and gene-only - for a single entity: same gene (PRKAG2/HGNC:9386),
  same CBS-domain gain-of-function alleles, same glycogen/polyglucosan storage,
  same WPW-plus-conduction-disease triad, same management. Nothing in
  MONDO:0010946 licenses a pathophysiology node, phenotype, or treatment that
  is not already curated in this file. Creating a parallel
  `Hypertrophic_Cardiomyopathy_6` entry would fragment PRKAG2 disease across
  two files with duplicated evidence and no mechanistic distinction, so
  MONDO:0010946 is instead recorded as a `skos:narrowMatch` in `mappings` and
  its OMIM/DOID-side names (CMH6; "cardiomyopathy, familial hypertrophic, 6";
  "PRKAG2 hypertrophic cardiomyopathy") are carried in `synonyms` so lookups
  by the CMH6 name resolve here. Note the naming trap this closes: CMH6's
  label places PRKAG2 disease inside the hypertrophic-cardiomyopathy numbered
  series alongside genuinely sarcomeric members (CMH1/MYH7, CMH4/MYBPC3,
  CMH3/TPM1, CMH7/TNNI3), which is precisely the sarcomeric-HCM conflation the
  LUMP-VS-SPLIT paragraph below rejects on mechanistic grounds. The series
  membership is a nosological artifact of OMIM's numbering, not a claim that
  PRKAG2 disease is a sarcomeropathy.

  NAMED-ENTITY-CONFUSION (NEC) FINDING. The curation request that produced this
  entry named "cardiomyopathy, familial hypertrophic, 29, with polyglucosan
  bodies" / MONDO:0859372 as the target, but described PRKAG2 biology throughout
  (gene, CBS-domain alleles, WPW triad, annulus fibrosus mechanism). The NEC
  preflight (`runoak -i sqlite:obo:mondo info MONDO:0859372 -O obo`) shows that
  MONDO:0859372 is CMH29, OMIM:620236, carrying the gene association RO:0004003
  HGNC:25947 - that is KLHL24, not PRKAG2. The two are distinct diseases that
  were conflated because both feature myocardial polyglucosan. A gene-frequency
  check of the deep-research report corroborates this: PRKAG2 is mentioned 53
  times and KLHL24 zero times, so the report (and the curation intent) is
  unambiguously about PRKAG2. MONDO:0859372 / KLHL24-related CMH29 remains
  UNCURATED in dismech and is available as a separate future entry; nothing in
  this file should be read as covering it. The CMH numbered series (CMH1-CMH30)
  is a documented high-NEC-risk class, and this is a worked instance of it.

  LUMP-VS-SPLIT versus sarcomeric HCM. `kb/disorders/Hypertrophic_Cardiomyopathy.yaml`
  already covers sarcomere-protein-gene HCM. PRKAG2 cardiac syndrome is
  deliberately kept SPLIT from it rather than folded in as a subtype, because the
  two share only the gross phenotype (increased left ventricular wall thickness)
  and differ at every mechanistic level that dismech models: the primary lesion
  (nucleotide-sensing regulatory subunit vs. contractile sarcomere protein), the
  proximate cause of the increased mass (intracellular glycogen and water vs.
  myocyte hypertrophy with disarray), the histopathology (vacuolated myocytes
  with diastase-resistant polyglucosan and minimal fibrosis vs. myofibre disarray
  with interstitial fibrosis), the characteristic electrophysiology (anatomically
  mediated accessory atrioventricular connections plus degenerative conduction
  disease, both atypical of sarcomeric HCM), and the management implications
  (early pacing, accessory-pathway ablation, and transplant referral rather than
  sarcomere-directed therapy). Arad et al. explicitly established this
  distinction (PMID:15673802, PMID:11827995). The other two classic
  hypertrophy-with-pre-excitation phenocopies are also separate entries:
  `Danon_disease` (LAMP2, X-linked, lysosomal, with retinopathy and skeletal
  myopathy) and `Fabry_Disease` (GLA, X-linked, glycosphingolipid rather than
  glycogen storage, with systemic angiokeratoma/renal/neuropathic features).

  MODULE CONFORMANCE DECISIONS. Two cardiac mechanism modules were evaluated.
  (1) `cardiac_ion_channel_repolarization` - NOT conformed to. That module models
  arrhythmia arising from ion-channel/calcium-handling variants altering action
  potential duration in structurally normal hearts. PRKAG2 pre-excitation is
  anatomical, not electrophysiological in that sense: the substrate is a physical
  breach of the annulus fibrosus by glycogen-engorged myocytes creating
  microscopic atrioventricular muscle continuity (PMID:12782567), and the
  bradyarrhythmia arm is degenerative conduction-tissue infiltration, not
  pacemaker-channel loss of function. Declaring conformance would misrepresent
  the mechanism. An emerging AMPK-gamma2/myosin calcium-handling arm
  (PMID:42422944) does touch action-potential and calcium-transient duration, but
  it is a zebrafish finding under an EMERGING hypothesis and is too preliminary
  to anchor a module conformance claim.
  (2) `cardiomyopathy_maladaptive_remodeling` - conformed to PARTIALLY, only at
  the two late nodes. The module's upstream chain (primary contractile insult to
  neurohormonal activation to ventricular remodeling) does not describe PRKAG2
  hypertrophy, which is storage-driven mass accrual - "excess glycogen storage
  and water in cardiomyocytes appear to account for increased cardiac mass"
  (PMID:11827995) - not neurohormonally driven remodeling of a failing ventricle.
  But the late course does converge on the module: after decades the hypertrophic
  phase gives way to progressive contractile dysfunction, heart failure
  admission, transplantation, and death (PMID:32646569). Conformance is therefore
  declared only on "Progressive Contractile Dysfunction" and "Advanced Heart
  Failure and End-Stage Cardiomyopathy".

  DEEP RESEARCH PROVENANCE. A Claude Code deep-research report was generated
  (`research/PRKAG2_Cardiac_Syndrome-deep-research-claude_code.md`) and used as a
  lead-generation source only. Two of its assertions were checked against
  authoritative sources and REJECTED: it gave the PRKAG2 HGNC ID as HGNC:9385
  (OAK confirms hgnc:9386), and it described the biopsy glycogen as
  "diastase-sensitive" (the primary source, PMID:11827995, reports the inclusions
  as PAS-positive and diastase-RESISTANT, i.e. polyglucosan - which is the whole
  diagnostic point). It also asserted flatly that all PRKAG2 variants are
  gain-of-function; this entry does not take that side (see
  `mechanistic_hypotheses`). Every PMID and snippet in this file was
  independently fetched and verified against the cached reference.

  EXTRACARDIAC SCOPE. The disease is cardiac-dominant, but this entry does NOT
  claim the phenotype is cardiac-exclusive. A neurocognitive/psychiatric cluster
  and an obstetric cluster are curated below from the single study that reports
  them systematically (PMID:39082507, a 66-member Brazilian p.K290I kindred
  followed 18 years), with the single-kindred provenance stated on each entry and
  no `frequency:` band asserted, because the paper's denominators mix carriers,
  pregnancies, and deliveries and a band cannot be read off it without inventing a
  denominator. Two further extracardiac signals named in the deep-research report
  are deliberately NOT curated: (i) skeletal-muscle glycogen storage/myopathy,
  which the report itself describes as inconsistently observed and absent from the
  Brazilian cohort, and for which no primary paper with a quotable PRKAG2-specific
  abstract sentence was located; and (ii) liver cirrhosis, a single-family
  observation the report cites only as a PMC link with no PMID. Both are recorded
  here as known gaps rather than curated on weak sourcing.

  HPO TERM-SEARCH RECORD for the obstetric cluster, all run 2026-08-01 with
  `uv run runoak -i sqlite:obo:hp`. (1) `search 'l~abortion'` returns exactly two
  classes, HP:0030449 (Therapeutic abortion) and HP:0200067 (Recurrent spontaneous
  abortion); there is no generic "spontaneous abortion" class. HP:0200067 was
  audited and rejected on two grounds - the source reports two abortions across a
  whole kindred rather than recurrent loss in one individual, and `ancestors
  HP:0200067 -p i` places it under HP:0032443 (Past medical history), not under
  HP:0000118, so it is not a legal `PhenotypeTerm` value in this schema. (2)
  `search 'l~neonatal death'`, `'l~death in infancy'`, `'l~perinatal death'`, and
  `'l~fetal death'` together return only HP:0003811 (Neonatal death) and
  HP:0001522 (Death in infancy); `ancestors` shows both sit under HP:0040006
  (Mortality/Aging) in the Clinical-modifier subontology, which is likewise not
  reachable from HP:0000118. HP:0003811 was tried first and rejected by `just
  validate-terms` for exactly this reason. (3) The operative-delivery component
  does have a usable class: `ancestors HP:0011411 -p i` resolves through
  HP:0001787 (Abnormal delivery) and HP:0001197 to HP:0000118. The obstetric
  phenotype is therefore anchored on HP:0001787, with the pregnancy-loss and
  neonatal-death observations carried in its description. This is an HPO/schema
  coverage limitation, not an absence of evidence.

  PREVALENCE SCOPE. A second `prevalence` record now carries the referral-cohort
  figure (0.23-1% among patients with left ventricular hypertrophy, PMID:39273120)
  alongside the original UNKNOWN population-prevalence record. The two are not the
  same quantity and are deliberately kept as separate records rather than merged.

has_subtypes:
- name: Lethal Congenital
  display_name: Lethal congenital cardiac glycogenosis (OMIM 261740)
  subtype_term:
    preferred_term: lethal congenital glycogen storage disease of heart
    term:
      id: MONDO:0009867
      label: lethal congenital glycogen storage disease of heart
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0009867
        label: lethal congenital glycogen storage disease of heart
      mapping_predicate: skos:exactMatch
      mapping_source: OMIM:261740
      mapping_justification: >-
        NEC-checked with `runoak -i sqlite:obo:mondo info MONDO:0009867 -O obo`
        (2026-08-01). MONDO:0009867 carries xref OMIM:261740, is asserted `is_a
        MONDO:0800484` (the parent entity of this entry), and has the gene
        association RO:0004003 HGNC:9386 - PRKAG2, not another gene. It is
        therefore the correct MONDO node for the lethal congenital form and is a
        genuine child of the curated disease, unlike MONDO:0859372 (KLHL24/CMH29),
        which is documented above as a rejected mapping.
  description: >-
    The severe end of the PRKAG2 severity spectrum, and the form that makes this
    disease's genotype-phenotype axis prognostically consequential. Recurrent
    heterozygous p.Arg531Gln (R531Q) substitutions in the third CBS domain produce
    a massive non-lysosomal cardiac glycogenosis with symptomatic onset already in
    fetal life and a rapidly fatal course, rather than the juvenile-to-adult
    presentation of the classic triad. The molecular lesion is the same class of
    nucleotide-sensing defect as in the milder alleles, but quantitatively far more
    extreme - the R531Q protein loses AMP and ATP binding affinity by more than two
    orders of magnitude while gaining basal kinase activity, and the authors of the
    defining study explicitly describe the classic hypertrophic-cardiomyopathy
    alleles as producing perturbations "similar to--but less severe than" R531Q.
    Note the striking allelic contrast at the same codon: p.Arg531Gly causes
    childhood-onset pre-excitation and conduction disease WITHOUT hypertrophy
    (curated under `genetic.variants`), so residue 531 alone spans the full range
    from a hypertrophy-free electrical phenotype to neonatal death. Historically
    this form was misattributed to a heart-specific phosphorylase kinase
    deficiency; the defining study found no phosphorylase kinase mutations and
    reassigned the aetiology to PRKAG2, which is why MONDO:0009867 still carries
    "phosphorylase kinase deficiency of heart" as a synonym.
  genes:
  - preferred_term: PRKAG2
    term:
      id: hgnc:9386
      label: PRKAG2
  evidence:
  - reference: PMID:15877279
    reference_title: "Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent heterozygous R531Q missense mutations in PRKAG2 give rise to a massive nonlysosomal cardiac glycogenosis of fetal symptomatic onset and rapidly fatal course, constituting a genotypically and clinically distinct variant of hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome"
    explanation: >-
      Establishes the lethal congenital form as a distinct, R531Q-associated
      severity extreme of PRKAG2 disease with fetal onset and a rapidly fatal
      course.
  - reference: PMID:15877279
    reference_title: "Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fatal congenital nonlysosomal cardiac glycogenosis has been attributed to a subtype of phosphorylase kinase deficiency, but the underlying genes and mutations have not been identified."
    explanation: >-
      Documents the historical phosphorylase-kinase-deficiency attribution that
      the same study overturns, explaining the surviving MONDO/OMIM synonym.

mechanistic_hypotheses:
- hypothesis_group_id: constitutive_ampk_activation
  hypothesis_label: Constitutive/Inappropriate AMPK Activation Model
  status: ALTERNATIVE
  description: >-
    CBS-domain variants relieve the normal adenine-nucleotide-dependent
    autoinhibition of the AMPK heterotrimer, leaving the kinase inappropriately
    active in the ATP-replete cardiomyocyte. Chronic AMPK activity drives GLUT4
    translocation, glucose uptake, and glycogen synthase activity, so glycogen
    accumulates. This is the model supported by the yeast Snf4 two-hybrid data
    and by the N488I transgenic mouse, which shows elevated cardiac AMPK activity
    together with 30-fold glycogen accumulation.
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We interpret these data to indicate that Thr400Asn and Asn488Ile mutations produce nonphysiologic, constitutive activation of AMP kinase."
    explanation: >-
      Human PRKAG2 substitutions engineered into the yeast orthologue Snf4
      produced glucose-insensitive Snf1-Snf4 interaction, interpreted by the
      authors as constitutive kinase activation. Evidence source is IN_VITRO
      because this is a yeast two-hybrid/reporter assay, not an animal study.
  - reference: PMID:12782567
    reference_title: "Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction."
    explanation: >-
      The N488I transgenic mouse directly couples elevated cardiac AMPK activity
      to massive glycogen accumulation and the full clinical triad, the central
      prediction of the activation model. Evidence source is MODEL_ORGANISM
      because this is transgenic mouse work.
- hypothesis_group_id: ampk_loss_of_function
  hypothesis_label: Impaired AMP Sensing / Loss-of-Function Model
  status: ALTERNATIVE
  description: >-
    The same CBS-domain variants can be read as damaging the AMP-binding site
    rather than releasing autoinhibition, so the kinase loses its ability to be
    activated by rising AMP. Purified mutant complexes are not constitutively
    active but show markedly reduced AMP dependence, and the R302Q transgenic
    mouse - which reproduces the full human phenotype including inducible
    orthodromic atrioventricular reentrant tachycardia - has significantly
    REDUCED cardiac AMPK activity. This is the direct opposite of the activation
    model, and the field has not resolved which applies, or whether the direction
    is variant-, tissue-, and developmental-stage-specific.
  evidence:
  - reference: PMID:12397075
    reference_title: "Functional analysis of mutations in the gamma 2 subunit of AMP-activated protein kinase associated with cardiac hypertrophy and Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "in the absence of an appropriate stimulus the mutant complexes, like the wild-type complex, exist in an inactive form demonstrating that the mutations do not lead to constitutive activation of the kinase"
    explanation: >-
      Direct biochemical assay of reconstituted mutant AMPK complexes refutes
      constitutive activation and instead localises the defect to AMP
      responsiveness, the core claim of the loss-of-function model.
  - reference: PMID:15611370
    reference_title: "Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Enzymatic activity of AMPK in the mutant heart was significantly reduced (0.009+/-0.003 versus 0.025+/-0.001 nmol x min(-1) x g(-1) in nontransgenic mice), presumably owing to the mutation disrupting the AMP binding site."
    explanation: >-
      In the R302Q transgenic mouse, which phenocopies the human disease, cardiac
      AMPK activity is reduced rather than elevated, attributed by the authors to
      disruption of the AMP binding site. Evidence source is MODEL_ORGANISM
      because this is transgenic mouse work.
  - reference: PMID:12397075
    reference_title: "Functional analysis of mutations in the gamma 2 subunit of AMP-activated protein kinase associated with cardiac hypertrophy and Wolff-Parkinson-White syndrome."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "These results indicate that mutations in gamma(2) have different effects on AMPK function, suggesting that they may lead to abnormal development of the heart through distinct mechanisms."
    explanation: >-
      Supports the reconciling possibility that different PRKAG2 variants act by
      genuinely different mechanisms, rather than one direction being correct for
      all of them. Marked PARTIAL because it argues against a single unified
      model rather than affirmatively supporting the loss-of-function direction.
- hypothesis_group_id: glycogen_independent_myosin_interaction
  hypothesis_label: Glycogen-Independent AMPK-gamma2/Myosin Interaction Model
  status: EMERGING
  description: >-
    A recent transgenic zebrafish study reports that variant AMPK-gamma2 binds
    myosin more avidly and relocalises to the myofilament, producing hypertrophy
    and electrophysiological abnormalities (slowed conduction, prolonged action
    potential and calcium-transient duration) at a developmental stage BEFORE any
    glycogen has accumulated, and not rescued by AMPK activation. If it holds in
    mammals, this would mean glycogen storage is not the sole proximate cause of
    the cardiac phenotype and would add a myofilament calcium-handling arm
    upstream of, or parallel to, the storage cascade. Preliminary and not yet
    replicated in human tissue.
  evidence:
  - reference: PMID:42422944
    reference_title: "AMPKγ2 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The PRKAG2 variant altered cardiac excitability, contractility, and Ca2+ handling during cardiogenesis, independent of glycogen accumulation."
    explanation: >-
      States the model's defining claim: a glycogen-independent route from the
      PRKAG2 variant to the cardiac electrical and contractile phenotype.
      Evidence source is MODEL_ORGANISM because this is transgenic zebrafish work.
  - reference: PMID:42422944
    reference_title: "AMPKγ2 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Proximity ligation assays and coimmunoprecipitation identified a physical interaction between AMPKγ2 and myosin, enhanced by the R299Q variant and accompanied by increased AMPKγ2 localization to the myofilament."
    explanation: >-
      Provides the proposed molecular basis - variant-enhanced AMPK-gamma2
      binding to myosin with myofilament relocalisation. Evidence source is
      IN_VITRO rather than MODEL_ORGANISM because proximity ligation and
      co-immunoprecipitation are biochemical assays performed on harvested
      tissue outside the organism, even though the tissue came from transgenic
      zebrafish.

pathophysiology:
- name: PRKAG2 Missense Variant in the AMPK Gamma-2 CBS Domains
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    A heterozygous germline missense variant in PRKAG2 alters a highly conserved
    residue within, or immediately adjacent to, the tandem
    cystathionine-beta-synthase (CBS/Bateman) domains of the AMPK gamma-2
    regulatory subunit. These
    domains constitute the adenine-nucleotide-sensing module that binds AMP, ADP,
    and ATP competitively and thereby sets the activation state of the alpha
    catalytic subunit. Recurrent alleles include p.Arg302Gln (the most frequently
    reported, in CBS1), p.Asn488Ile, p.Thr400Asn, and p.Arg531Gly. The variants
    do not abolish assembly of the heterotrimer; they corrupt its
    nucleotide-dependent regulation.
  gene:
    preferred_term: PRKAG2
    term:
      id: hgnc:9386
      label: PRKAG2
  molecular_functions:
  - preferred_term: AMP binding by the gamma-2 CBS domains
    term:
      id: GO:0016208
      label: AMP binding
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:11407343
    reference_title: "Identification of a gene responsible for familial Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a missense mutation in the gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein."
    explanation: >-
      The original linkage study identifying PRKAG2 p.Arg302Gln as the cause of
      familial ventricular pre-excitation with hypertrophy.
  - reference: PMID:12397075
    reference_title: "Functional analysis of mutations in the gamma 2 subunit of AMP-activated protein kinase associated with cardiac hypertrophy and Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Two of these mutations lead to a marked decrease in AMP dependence, whereas the third reduces AMP sensitivity. These findings suggest that the CBS domains play an important role in AMP-binding within the complex."
    explanation: >-
      Localises the functional lesion of the disease-causing variants to AMP
      binding within the CBS domains, the defining feature of this node.
  downstream:
  - target: Dysregulated AMPK Nucleotide Sensing
    causal_link_type: DIRECT
    description: >-
      Corruption of the CBS nucleotide-binding module directly deranges the
      allosteric regulation of the AMPK heterotrimer.

- name: Dysregulated AMPK Nucleotide Sensing
  biological_scale: MOLECULAR
  role: central_effector
  description: >-
    The variant gamma-2 subunit no longer couples AMPK activity correctly to the
    cellular adenine-nucleotide charge. The DIRECTION of the resulting change in
    kinase activity is genuinely unresolved in the literature and this entry does
    not assert one: yeast reconstitution and the N488I transgenic mouse support
    inappropriate/constitutive ACTIVATION, whereas biochemical assay of purified
    mutant complexes and the R302Q transgenic mouse support LOSS of AMP-dependent
    activation, with reduced cardiac AMPK activity. Time-resolved work adds a
    further wrinkle: acute expression of gamma-2 R302Q activates AMPK and
    upregulates glycogen synthase and AS160, but in the chronically transgenic
    adult heart AMPK activity is suppressed, apparently as feedback to the
    glycogen already stored - so measured activity depends on when in the disease
    course it is sampled. The competing readings are curated as
    `mechanistic_hypotheses` and carried on the outgoing edges.
  molecular_functions:
  - preferred_term: AMP-activated protein kinase activity
    term:
      id: GO:0004679
      label: AMP-activated protein kinase activity
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:20031621
    reference_title: "Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "acute expression of gamma(2)R302Q induces AMPK activation and upregulation of glycogen synthase and AS160, with an associated increase in glycogen content"
    explanation: >-
      The ACUTE arm of this study, showing AMPK activation, is performed by
      transient expression in cultured neonatal rat cardiomyocytes, so this item
      is IN_VITRO. It provides the activation half of the temporal picture that
      makes this node direction-agnostic.
  - reference: PMID:20031621
    reference_title: "Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "AMPK activity, glycogen synthase activity, and AS160 expression are reduced in hearts from TGgamma(2)R302Q mice, likely in response to the existing 37-fold increase in glycogen."
    explanation: >-
      The CHRONIC arm, showing suppressed AMPK activity, is measured in hearts
      from transgenic mice, so this item is MODEL_ORGANISM. Split from the acute
      in-vitro item above because the original sentence spans two different
      experimental systems and each evidence item must carry a single
      evidence_source.
  - reference: PMID:20031621
    reference_title: "Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These findings are the first to highlight temporal differences in the effects of the PRKAG2 R302Q mutation on cardiac metabolic signaling events."
    explanation: >-
      Explicitly frames the temporal dependence of the signalling phenotype.
      Evidence source is OTHER because this concluding statement synthesises
      across both arms of the study - cultured neonatal rat cardiomyocytes and
      transgenic mouse hearts - so it belongs to neither IN_VITRO nor
      MODEL_ORGANISM alone; the per-arm data are cited separately above.
  downstream:
  - target: Excessive Cardiomyocyte Glycogen and Polyglucosan Accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - >-
      Altered AMPK signalling to GLUT4 trafficking via AS160/TBC1D4 increases
      myocardial glucose uptake.
    - >-
      Upregulated glycogen synthase activity converts imported glucose into
      stored glycogen and, ultimately, poorly soluble polyglucosan.
    hypothesis_groups:
    - constitutive_ampk_activation
    - ampk_loss_of_function
    evidence:
    - reference: PMID:20031621
      reference_title: "Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "acute expression of gamma(2)R302Q induces AMPK activation and upregulation of glycogen synthase and AS160, with an associated increase in glycogen content"
      explanation: >-
        Names glycogen synthase and AS160 as the intermediates linking the AMPK
        signalling lesion to glycogen accumulation. Evidence source is IN_VITRO
        because this acute-expression result comes from cultured neonatal rat
        cardiomyocytes rather than from the transgenic animal.
    - reference: PMID:20031621
      reference_title: "Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "AMPK activity, glycogen synthase activity, and AS160 expression are reduced in hearts from TGgamma(2)R302Q mice, likely in response to the existing 37-fold increase in glycogen."
      explanation: >-
        Confirms the same intermediates are engaged in vivo, with the 37-fold
        glycogen accumulation in transgenic mouse hearts that is the endpoint of
        this edge. Split from the in-vitro item so each carries a single
        evidence_source.
  - target: Enhanced AMPK-gamma2/Myosin Interaction
    causal_link_type: DIRECT
    hypothesis_groups:
    - glycogen_independent_myosin_interaction
    description: >-
      Under the emerging model, the variant subunit's principal proximate effect
      is a gain of binding to myosin rather than a change in kinase output.

- name: Excessive Cardiomyocyte Glycogen and Polyglucosan Accumulation
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Cardiomyocytes accumulate large amounts of glycogen and of poorly soluble,
    amylopectin-like polyglucosan within non-lysosomal cytosolic vacuoles. This
    is the biochemical event that makes PRKAG2 disease a cardiac glycogenosis
    rather than a cardiomyopathy of the contractile apparatus, and it is the hub
    from which the three clinical arms - hypertrophy, pre-excitation, and
    conduction disease - all descend. In the N488I transgenic mouse cardiac
    glycogen reaches roughly thirty times normal.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Glycogen biosynthetic process
    term:
      id: GO:0005978
      label: glycogen biosynthetic process
    modifier: INCREASED
  - preferred_term: Glycogen metabolic process
    term:
      id: GO:0005977
      label: glycogen metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12782567
    reference_title: "Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction."
    explanation: >-
      Quantifies the magnitude of glycogen accumulation and links it to the full
      phenotypic triad in the transgenic mouse model.
  - reference: PMID:12782567
    reference_title: "Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pathological examinations of affected human hearts reveal vacuoles containing amylopectin, a glycogen-related substance."
    explanation: >-
      Confirms that the stored material in HUMAN hearts is amylopectin-like
      polyglucosan, not simply soluble glycogen. Evidence source is OTHER because
      this is a background statement in a mouse study summarising prior human
      pathology rather than primary data from the cited experiment.
  - reference: PMID:15673802
    reference_title: "Glycogen storage diseases presenting as hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because mutations in the gene for AMP-activated protein kinase gamma2 (PRKAG2) cause an accumulation of cardiac glycogen and left ventricular hypertrophy that mimics hypertrophic cardiomyopathy"
    explanation: >-
      States the human clinical premise that PRKAG2 variants cause cardiac
      glycogen accumulation producing HCM-mimicking hypertrophy.
  downstream:
  - target: Cardiomyocyte Vacuolation and Storage-Driven Myocyte Enlargement
    causal_link_type: DIRECT
  - target: Disruption of the Annulus Fibrosus by Glycogen-Laden Myocytes
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12782567
      reference_title: "Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes."
      explanation: >-
        Directly attributes the annulus fibrosus breach to the glycogen-filled
        myocytes, establishing this specific causal edge.
  - target: Glycogen Infiltration and Degeneration of the Cardiac Conduction System
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:11827995
      reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: "Glycogen accumulation in conductive tissue is also likely to cause sinus and atrioventricular node dysfunction"
      explanation: >-
        The authors infer this edge from the coincidence of conduction-tissue
        storage and nodal dysfunction rather than demonstrating it directly, so
        it is recorded as PARTIAL, with evidence source OTHER because the
        statement is an interpretive inference in the discussion section.

- name: Enhanced AMPK-gamma2/Myosin Interaction
  biological_scale: MOLECULAR
  role: alternative_effector
  description: >-
    Under the emerging glycogen-independent model, variant AMPK-gamma2 binds
    myosin more strongly and relocalises to the myofilament. The proposed
    consequence is retention of calcium at the myofilament, reducing the free
    cytosolic calcium available for sodium/calcium-exchanger extrusion and
    thereby prolonging the calcium transient and action potential. This arm is
    reported only in transgenic zebrafish and is curated as EMERGING; it is not
    asserted as an established human mechanism.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:42422944
    reference_title: "AMPKγ2 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Proximity ligation assays and coimmunoprecipitation identified a physical interaction between AMPKγ2 and myosin, enhanced by the R299Q variant and accompanied by increased AMPKγ2 localization to the myofilament."
    explanation: >-
      Establishes the variant-enhanced physical interaction and myofilament
      relocalisation that define this node. Evidence source is IN_VITRO because
      proximity ligation and co-immunoprecipitation are biochemical assays run on
      harvested tissue outside the organism; the in-vivo zebrafish phenotype is
      carried by the separate MODEL_ORGANISM items on the downstream node.
  downstream:
  - target: Glycogen-Independent Early Electrophysiological Abnormality
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - >-
      Myofilament calcium retention reduces the free cytosolic calcium available
      for sodium/calcium-exchanger-mediated extrusion, prolonging the calcium
      transient and the action potential.
    hypothesis_groups:
    - glycogen_independent_myosin_interaction

- name: Glycogen-Independent Early Electrophysiological Abnormality
  biological_scale: CELLULAR
  role: alternative_effector
  description: >-
    In the zebrafish model the variant heart shows reduced conduction velocity
    and prolonged action-potential and calcium-transient durations at a
    developmental stage at which no glycogen has yet accumulated, and AMPK
    activation does not rescue these abnormalities. This would place part of the
    electrical phenotype upstream of, or parallel to, glycogen storage rather
    than downstream of it. Reported in one non-mammalian model only.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:42422944
    reference_title: "AMPKγ2 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Despite the absence of glycogen accumulation at 6 days postfertilization, TgR299Q hearts showed electrical abnormalities, including reduced conduction velocity and prolonged action potential and Ca2+ transient durations."
    explanation: >-
      Documents electrical abnormality preceding glycogen accumulation, the
      observation that motivates the glycogen-independent arm.
  - reference: PMID:42422944
    reference_title: "AMPKγ2 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cardiomyocyte glycogen was elevated in adult but not embryonic hearts."
    explanation: >-
      Confirms the temporal dissociation between the electrical phenotype and the
      onset of glycogen storage in this model.
  downstream:
  - target: Progressive Contractile Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - glycogen_independent_myosin_interaction
    description: >-
      In the same model the variant produces hypertrophic cardiomyocytes and
      progressive contractile abnormalities alongside the electrical changes, so
      under the emerging model part of the contractile phenotype would arise by a
      route independent of the storage cascade. The edge is deliberately pointed
      at contractile dysfunction rather than at pre-excitation, because the
      zebrafish study reports conduction slowing and contractile abnormality but
      does NOT report accessory pathways or pre-excitation; the intervening steps
      to the human phenotype are not established.
    evidence:
    - reference: PMID:42422944
      reference_title: "AMPKγ2 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin."
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: "TgR299Q fish showed hypertrophic cardiomyocytes and progressive contractile abnormalities, recapitulating human hypertrophic cardiomyopathy phenotypes."
      explanation: >-
        Documents the hypertrophic and progressive contractile phenotype in the
        variant zebrafish. Marked PARTIAL because the study establishes the
        phenotype in zebrafish but does not demonstrate that this
        glycogen-independent route operates in the human heart.

- name: Cardiomyocyte Vacuolation and Storage-Driven Myocyte Enlargement
  biological_scale: CELLULAR
  role: effector
  description: >-
    Storage material distends the cardiomyocyte, producing the large isolated
    cytosolic vacuoles seen on biopsy and enlarging the cell. Critically, the
    added mass is stored polysaccharide and water rather than new contractile
    apparatus, and the myofibrillar architecture is preserved - myofibre disarray
    and significant interstitial fibrosis, the histological signatures of
    sarcomeric HCM, are absent.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marked ventricular hypertrophy was evident on gross inspection, and myocytes were enlarged"
    explanation: >-
      Human cardiac specimens from PRKAG2 variant carriers show myocyte
      enlargement accompanying gross ventricular hypertrophy.
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all five specimens demonstrated isolated, large cytosolic vacuoles in cardiomyocytes"
    explanation: >-
      Documents the vacuolation in every human specimen examined.
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Excess glycogen storage and water in cardiomyocytes appear to account for increased cardiac mass in affected individuals"
    explanation: >-
      Attributes the increased cardiac mass to stored polysaccharide and water
      rather than to contractile-protein hypertrophy - the mechanistic reason
      PRKAG2 hypertrophy is not neurohormonal remodeling. Evidence source is
      OTHER because this is the authors' interpretive synthesis in discussion.
  downstream:
  - target: Ventricular Hypertrophy Mimicking Sarcomeric Hypertrophic Cardiomyopathy
    causal_link_type: DIRECT

- name: Ventricular Hypertrophy Mimicking Sarcomeric Hypertrophic Cardiomyopathy
  biological_scale: TISSUE
  role: effector
  description: >-
    At the organ level the accumulated storage material manifests as increased
    left ventricular wall thickness indistinguishable on echocardiography from
    sarcomeric hypertrophic cardiomyopathy, which is why PRKAG2 disease is
    routinely first labelled HCM. It is present in about two-thirds of carriers
    at first assessment in the largest cohort and accrues further over follow-up.
    The tell that separates it from sarcomeric HCM is not the hypertrophy itself
    but the accompanying electrophysiology and the biopsy findings.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline."
    explanation: >-
      Quantifies the burden of left ventricular hypertrophy in the largest
      multicentre PRKAG2 cohort.
  - reference: PMID:15673802
    reference_title: "Glycogen storage diseases presenting as hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The glycogen-storage cardiomyopathy produced by LAMP2 or PRKAG2 mutations resembles hypertrophic cardiomyopathy but is distinguished by electrophysiological abnormalities, particularly ventricular preexcitation."
    explanation: >-
      States both halves of the claim: the phenotypic mimicry of HCM and the
      electrophysiological feature that distinguishes it.
  downstream:
  - target: Progressive Contractile Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      After years to decades the hypertrophic phase gives way to declining pump
      function; the intervening steps in PRKAG2 disease specifically are not well
      characterised.

- name: Disruption of the Annulus Fibrosus by Glycogen-Laden Myocytes
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The annulus fibrosus of the cardiac skeleton is the fibrous ring that
    electrically insulates the atria from the ventricles, restricting normal
    atrioventricular conduction to the AV node. Glycogen-engorged cardiomyocytes
    breach this ring, creating microscopic strands of muscle continuity across
    it. This is the single most mechanistically distinctive feature of PRKAG2
    disease: the pre-excitation is ANATOMICAL in origin - a failure of insulation
    - rather than a morphologically discrete accessory bundle as in idiopathic
    Wolff-Parkinson-White syndrome, and rather than an ion-channel abnormality.
    The same mechanism was proposed to explain pre-excitation in other glycogen
    storage cardiomyopathies including Pompe and Danon disease.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Annulus fibrosus of the heart
    term:
      id: UBERON:0004292
      label: cardiac skeleton
  evidence:
  - reference: PMID:12782567
    reference_title: "Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes."
    explanation: >-
      The primary histopathological demonstration that glycogen-filled myocytes
      breach the insulating annulus fibrosus. Evidence source is MODEL_ORGANISM
      because the histopathology reported is from transgenic mice.
  - reference: PMID:12782567
    reference_title: "Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation."
    explanation: >-
      Establishes that the substrate is diffuse microscopic AV continuity rather
      than a discrete bypass tract - the point that distinguishes PRKAG2
      pre-excitation from idiopathic WPW and that explains poor ablation
      durability.
  downstream:
  - target: Accessory Atrioventricular Connections and Ventricular Pre-excitation
    causal_link_type: DIRECT

- name: Accessory Atrioventricular Connections and Ventricular Pre-excitation
  biological_scale: TISSUE
  role: effector
  description: >-
    The muscle strands crossing the breached annulus conduct atrial impulses to
    the ventricle ahead of the AV node, producing a short PR interval and delta
    wave, and completing a macro-reentrant circuit that supports atrioventricular
    reentrant tachycardia. Electrophysiological study in human carriers
    demonstrates one or more accessory atrioventricular pathways, and the R302Q
    transgenic mouse reproduces both the distinct accessory pathway and inducible
    orthodromic AV reentrant tachycardia.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiologic studies in ten affected individuals demonstrated one or more accessory atrioventricular pathways."
    explanation: >-
      Human electrophysiological confirmation of accessory atrioventricular
      pathways in PRKAG2 variant carriers.
  - reference: PMID:15611370
    reference_title: "Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A distinct AV accessory pathway was confirmed by electrical and pharmacological stimulation and substantiated by induction of orthodromic AV reentrant tachycardia."
    explanation: >-
      Demonstrates in the R302Q transgenic mouse both the accessory pathway and
      the reentrant tachycardia it supports. Evidence source is MODEL_ORGANISM
      because this is transgenic mouse work.
  downstream:
  - target: Supraventricular Tachyarrhythmia and Atrial Fibrillation
    causal_link_type: DIRECT

- name: Glycogen Infiltration and Degeneration of the Cardiac Conduction System
  biological_scale: TISSUE
  role: effector
  description: >-
    Specialised conduction tissue - sinoatrial node, atrioventricular node, and
    the His-Purkinje system - is subject to the same storage process as working
    myocardium, and degenerates progressively with age. Unlike the
    accessory-pathway arm, which is often present from childhood, this arm
    accrues over decades and is what makes early pacemaker dependence a
    diagnostic red flag.
  cell_types:
  - preferred_term: Cardiac conduction system myocyte
    term:
      id: CL:0002086
      label: specialized cardiac myocyte
  - preferred_term: Atrioventricular node myocyte
    term:
      id: CL:1000410
      label: myocyte of atrioventricular node
  locations:
  - preferred_term: Central cardiac conduction system
    term:
      id: UBERON:2005074
      label: central cardiac conduction system
  biological_processes:
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DECREASED
  evidence:
  - reference: PMID:12782567
    reference_title: "Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction."
    explanation: >-
      Establishes sinus node dysfunction alongside glycogen accumulation in the
      transgenic mouse model.
  - reference: PMID:18158359
    reference_title: "Reversibility of PRKAG2 glycogen-storage cardiomyopathy and electrophysiological manifestations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Tg(ON) mice developed cardiac hypertrophy followed by dilatation, ventricular preexcitation involving multiple accessory pathways, and conduction system disease, including sinus and atrioventricular node dysfunction."
    explanation: >-
      Documents the full natural history in the inducible transgenic mouse model,
      including sinoatrial and atrioventricular nodal involvement.
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With increasing age, affected individuals progressively developed slower heart rates."
    explanation: >-
      Human evidence for the progressive, age-dependent character of the
      conduction-system arm.
  downstream:
  - target: Progressive Atrioventricular Block and Bradyarrhythmia
    causal_link_type: DIRECT

- name: Progressive Atrioventricular Block and Bradyarrhythmia
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Clinically, conduction-system degeneration presents as sinus bradycardia,
    chronotropic incompetence, and progressive degrees of atrioventricular block,
    culminating in permanent pacemaker implantation at an age far younger than
    degenerative conduction disease would predict - a median of the mid-thirties
    in the largest cohort. Roughly a third of affected individuals in early
    series required pacing.
  biological_processes:
  - preferred_term: Regulation of heart rate by cardiac conduction
    term:
      id: GO:0086091
      label: regulation of heart rate by cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sinus bradycardia and/or variable degrees of atrioventricular block resulted in pacemaker implantation in 24 (35%) affected individuals."
    explanation: >-
      Quantifies the bradyarrhythmia burden and pacing requirement in human
      PRKAG2 families.
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age."
    explanation: >-
      Establishes young-age pacemaker requirement as the clinical signal of this
      node.

- name: Supraventricular Tachyarrhythmia and Atrial Fibrillation
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The accessory connections support atrioventricular reentrant tachycardia, and
    atrial fibrillation becomes increasingly prevalent with age. Rapid conduction
    of atrial fibrillation over an accessory pathway is a recognised route to
    haemodynamic collapse and sudden death in pre-excitation syndromes, and this
    arm together with progressive heart failure underlies the life-threatening
    arrhythmia burden of the disease.
  biological_processes:
  - preferred_term: Regulation of heart rate by cardiac conduction
    term:
      id: GO:0086091
      label: regulation of heart rate by cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WPW usually manifested early in life with tachyarrhythmias (atrial fibrillation and other supraventricular arrhythmias) and sometimes caused syncope."
    explanation: >-
      Links the pre-excitation substrate to supraventricular tachyarrhythmia,
      atrial fibrillation, and syncope in human carriers.
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias."
    explanation: >-
      Summarises the arrhythmic burden of the disease from the largest cohort.

- name: Progressive Contractile Dysfunction
  biological_scale: ORGANISM
  role: effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  description: >-
    Over years to decades the hypertrophic phase is followed in a substantial
    minority by declining pump function - a transition sometimes described as a
    burned-out, dilated phase. At this point the disease converges on the generic
    structural-cardiomyopathy pathway, which is why conformance to the
    maladaptive-remodeling module is declared HERE and not at the upstream
    hypertrophy node: the earlier increase in wall thickness is storage mass, not
    neurohormonally driven remodeling.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Left ventricular function markedly deteriorated in five affected adult individuals and necessitated cardiac transplantation in one; sudden death occurred in four."
    explanation: >-
      Documents progression from hypertrophy to overt systolic deterioration
      requiring transplantation in human PRKAG2 carriers.
  - reference: PMID:18158359
    reference_title: "Reversibility of PRKAG2 glycogen-storage cardiomyopathy and electrophysiological manifestations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Tg(ON) mice developed cardiac hypertrophy followed by dilatation, ventricular preexcitation involving multiple accessory pathways, and conduction system disease, including sinus and atrioventricular node dysfunction."
    explanation: >-
      Recapitulates the hypertrophy-then-dilatation sequence in the inducible
      transgenic mouse model.
  - reference: PMID:33244021
    reference_title: "Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "11 patients (50%) developed progressive worsening in NYHA functional class"
    explanation: >-
      Human prospective evidence for the functional decline arm of this node: half
      of a cohort that began entirely in NYHA class I-II deteriorated over seven
      years, quantifying the "substantial minority to half" framing of the
      transition out of the compensated hypertrophic phase.
  downstream:
  - target: Advanced Heart Failure and End-Stage Cardiomyopathy
    causal_link_type: DIRECT

- name: Advanced Heart Failure and End-Stage Cardiomyopathy
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The terminal state is heart failure requiring hospitalisation, and in a
    minority transplantation or death. In the largest multicentre cohort, over a
    median six years of follow-up, 14 percent required heart-failure admission, 8
    percent had sudden cardiac death or an equivalent event, 4 percent were
    transplanted, and 13 percent died.
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died."
    explanation: >-
      Quantifies the end-stage outcomes of PRKAG2 cardiac syndrome in the largest
      natural-history cohort.
  - reference: PMID:28431061
    reference_title: "High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications."
    explanation: >-
      Independent cohort confirming the high burden of cardiac complications.

phenotypes:
- category: Cardiovascular
  name: Ventricular pre-excitation
  diagnostic: true
  frequency: FREQUENT
  description: >-
    A short PR interval with a delta wave on the surface ECG, reflecting
    conduction over accessory atrioventricular connections. Present in about a
    third of carriers at first assessment and reaching a cumulative risk of
    roughly 70 percent by age 40 in a time-to-event analysis. In combination with
    unexplained left ventricular hypertrophy this is the single most useful
    pointer away from sarcomeric HCM and toward a glycogen storage
    cardiomyopathy.
  phenotype_term:
    preferred_term: Ventricular preexcitation
    term:
      id: HP:0004309
      label: Ventricular preexcitation
  evidence:
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation"
    explanation: >-
      Supports both the phenotype and the FREQUENT band, since 33 percent falls
      in the 30-79 percent HPO range.
  - reference: PMID:28431061
    reference_title: "High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%."
    explanation: >-
      Independent time-to-event estimate of 70 percent cumulative pre-excitation
      risk by age 40, corroborating the FREQUENT band.

- category: Cardiovascular
  name: Wolff-Parkinson-White syndrome
  description: >-
    Ventricular pre-excitation accompanied by symptomatic tachyarrhythmia. In
    PRKAG2 families WPW characteristically manifests early in life, is often the
    presenting feature, and can occur without any hypertrophy at all - a
    childhood-onset, hypertrophy-free presentation is documented for the
    p.Arg531Gly allele. Frequency is deliberately omitted: the cohort figures
    quantify pre-excitation on ECG rather than the clinical WPW syndrome, and no
    verified source separates the two.
  phenotype_term:
    preferred_term: Wolff-Parkinson-White syndrome
    term:
      id: HP:0001716
      label: Wolff-Parkinson-White syndrome
  evidence:
  - reference: PMID:12015471
    reference_title: "PRKAG2 cardiac syndrome: familial ventricular preexcitation, conduction system disease, and cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recently, we identified the genetic cause of a familial arrhythmogenic syndrome characterized by ventricular preexcitation and tachyarrhythmias (Wolff-Parkinson-White syndrome), progressive conduction system disease, and cardiac hypertrophy."
    explanation: >-
      Names WPW as a defining component of the PRKAG2 triad. Evidence source is
      OTHER because this is a narrative review summarising the authors' prior
      work rather than reporting primary data.
  - reference: PMID:11748095
    reference_title: "Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy."
    explanation: >-
      Documents WPW as a childhood-onset PRKAG2 presentation that can precede or
      occur without hypertrophy.

- category: Cardiovascular
  name: Left ventricular hypertrophy
  frequency: FREQUENT
  description: >-
    Increased left ventricular wall thickness not explained by loading
    conditions, present in about two-thirds of carriers at baseline and rising
    over follow-up. Radiologically and echocardiographically indistinguishable
    from sarcomeric HCM.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline."
    explanation: >-
      Direct quantitative support for both the phenotype and the FREQUENT band,
      at 67 percent.
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers"
    explanation: >-
      Shows the prevalence of LVH rising over follow-up, supporting the
      PROGRESSIVE clinical course qualifier.
  - reference: PMID:33244021
    reference_title: "Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Left ventricular hypertrophy was present in 19 individuals (86%) at baseline."
    explanation: >-
      Independent replication of the FREQUENT band in a separate ancestry group
      (22-patient South Asian cohort), at the high end of the range.

- category: Cardiovascular
  name: Atrioventricular block
  frequency: OCCASIONAL
  description: >-
    Progressive degrees of atrioventricular block from degeneration of the
    conduction system, with a cumulative risk of about 22 percent by age 40.
    Occurrence at an unusually young age is a diagnostic red flag.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:28431061
    reference_title: "High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%."
    explanation: >-
      Supports both the phenotype and the OCCASIONAL band, since 22 percent falls
      in the 5-29 percent HPO range.
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sinus bradycardia and/or variable degrees of atrioventricular block resulted in pacemaker implantation in 24 (35%) affected individuals."
    explanation: >-
      Independent human series documenting variable-degree AV block leading to
      pacing.

- category: Cardiovascular
  name: Sinus bradycardia
  description: >-
    Sinus node dysfunction with slowing of the resting heart rate, developing
    progressively with age and contributing to pacemaker requirement. Frequency
    omitted - the available sources report bradycardia and AV block as a combined
    pacing indication rather than separately.
  phenotype_term:
    preferred_term: Sinus bradycardia
    term:
      id: HP:0001688
      label: Sinus bradycardia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With increasing age, affected individuals progressively developed slower heart rates."
    explanation: >-
      Documents progressive resting heart-rate slowing in PRKAG2 carriers.
  - reference: PMID:40149727
    reference_title: "PRKAG2 Syndrome: Clinical Features, Imaging Findings and Cardiac Events."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After a median follow-up of 13.1 years, 6 carriers had LVH, 3 required admission for HF, and 1 had sustained ventricular tachycardia with subsequent cardioverter defibrillator implantation, and despite this, died suddenly; there were two de novo pacemaker implantations due to symptomatic bradycardia."
    explanation: >-
      Documents symptomatic bradycardia as an independent pacing indication in a
      long-followed contemporary cohort.

- category: Cardiovascular
  name: Atrial fibrillation
  frequency: OCCASIONAL
  description: >-
    Atrial fibrillation is present in roughly one in five carriers at first
    assessment and increases with follow-up, appearing at a median age well below
    that of typical population atrial fibrillation. Its emergence in a patient
    already carrying a label of hypertrophic cardiomyopathy should prompt
    consideration of PRKAG2 disease.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "16 (18%) had atrial fibrillation"
    explanation: >-
      Supports both the phenotype and the OCCASIONAL band, at 18 percent at
      baseline, within the 5-29 percent HPO range.
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers"
    explanation: >-
      Shows the atrial fibrillation prevalence rising to 29 percent over
      follow-up, still within the OCCASIONAL band.

- category: Cardiovascular
  name: Supraventricular tachycardia
  description: >-
    Reentrant supraventricular tachycardia mediated by the accessory
    atrioventricular connections, typically manifesting early in life.
  phenotype_term:
    preferred_term: Supraventricular tachycardia
    term:
      id: HP:0004755
      label: Supraventricular tachycardia
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WPW usually manifested early in life with tachyarrhythmias (atrial fibrillation and other supraventricular arrhythmias) and sometimes caused syncope."
    explanation: >-
      Documents supraventricular arrhythmia as an early manifestation in human
      PRKAG2 families.

- category: Cardiovascular
  name: Syncope
  description: >-
    Transient loss of consciousness, arising either from rapidly conducted
    supraventricular tachyarrhythmia early in the disease or from bradyarrhythmia
    and advanced conduction block later. Frequency omitted - no verified source
    quantifies it in a PRKAG2 cohort.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WPW usually manifested early in life with tachyarrhythmias (atrial fibrillation and other supraventricular arrhythmias) and sometimes caused syncope."
    explanation: >-
      Attributes syncope in PRKAG2 carriers to the tachyarrhythmic manifestations
      of pre-excitation.

- category: Cardiovascular
  name: Congestive heart failure
  frequency: OCCASIONAL
  description: >-
    Progression to symptomatic heart failure requiring hospitalisation occurs in
    about one in seven carriers over a median six years of follow-up, with a
    smaller proportion proceeding to transplantation.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died."
    explanation: >-
      Supports both the phenotype and the OCCASIONAL band, at 14 percent, within
      the 5-29 percent HPO range.

- category: Cardiovascular
  name: Sudden cardiac death
  frequency: OCCASIONAL
  description: >-
    Sudden cardiac death or an aborted equivalent occurred in 8 percent of the
    largest cohort over a median six years, with a cumulative risk of about 20
    percent by age 40 in an independent time-to-event analysis.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died."
    explanation: >-
      Supports the phenotype and the OCCASIONAL band, at 8 percent.
  - reference: PMID:28431061
    reference_title: "High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%."
    explanation: >-
      Independent cumulative-risk estimate of 20 percent by age 40, at the top of
      the OCCASIONAL band.

- category: Neurologic
  name: Intellectual disability and neurocognitive impairment
  description: >-
    Extracardiac neurocognitive involvement, reported systematically in one large
    kindred and confined there to variant carriers. In a 66-member Brazilian
    p.K290I family followed for 18 years, affected individuals showed
    neurocognitive delay, learning difficulty, and - in one detailed case -
    difficulty initiating, planning, and organizing thoughts with below-average
    learning ability. This is the arm of the phenotype most likely to be missed if
    PRKAG2 is treated as a purely cardiac entity, and it is the reason the entry no
    longer scopes itself to `category: Cardiovascular` alone. Provenance caveat:
    this rests on a single kindred with a single variant, so it should not yet be
    read as a general feature of PRKAG2 disease; no `frequency:` band is asserted
    (see the EXTRACARDIAC SCOPE paragraph in `notes`).
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:39082507
    reference_title: "PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extracardiac involvement, such as in neurocognitive and psychiatric disorders, has been observed only in carriers of mutations."
    explanation: >-
      Establishes that the neurocognitive involvement segregated with carrier
      status within the kindred rather than being background family morbidity.
  - reference: PMID:39082507
    reference_title: "PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Further research may uncover the potential connections between intellectual disability, miscarriage, and neonatal death in individuals with this syndrome."
    explanation: >-
      Names intellectual disability explicitly, but is graded PARTIAL because the
      authors state the connection as a hypothesis for further research rather than
      an established disease-phenotype association.

- category: Psychiatric
  name: Anxiety
  description: >-
    Anxiety was among the psychiatric features reported in variant carriers of the
    Brazilian p.K290I kindred, alongside aggressiveness and mood/behaviour change.
    Single-kindred provenance; no frequency band asserted.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:39082507
    reference_title: "PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurocognitive delay, seizures, difficulties walking, learning disabilities, anxiety, aggressiveness, speech disorders, and changes in mood and behavior"
    explanation: >-
      Direct enumeration of anxiety among the extracardiac features of two carriers
      described individually in the results.

- category: Psychiatric
  name: Aggressive behavior
  description: >-
    Aggressiveness with associated behaviour change, reported in variant carriers
    of the Brazilian p.K290I kindred. Single-kindred provenance; no frequency band
    asserted.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:39082507
    reference_title: "PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurocognitive delay, seizures, difficulties walking, learning disabilities, anxiety, aggressiveness, speech disorders, and changes in mood and behavior"
    explanation: >-
      Direct enumeration of aggressiveness among the extracardiac features of the
      individually described carriers.

- category: Neurologic
  name: Speech disorder
  description: >-
    Speech and behavioural disorder reported in variant carriers of the Brazilian
    p.K290I kindred, described both in two adolescent/young-adult carriers and in a
    separately detailed 28-year-old carrier. Single-kindred provenance; no
    frequency band asserted.
  phenotype_term:
    preferred_term: Speech disorder
    term:
      id: HP:0002167
      label: Abnormal speech pattern
  evidence:
  - reference: PMID:39082507
    reference_title: "PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurocognitive delay, seizures, difficulties walking, learning disabilities, anxiety, aggressiveness, speech disorders, and changes in mood and behavior"
    explanation: >-
      Direct enumeration of speech disorder among the extracardiac features. The
      HPO parent term "Abnormal speech pattern" is used because the source does not
      characterise the speech disorder further.

- category: Reproductive
  name: Adverse pregnancy outcome in affected female carriers
  description: >-
    An obstetric cluster reported only in the affected-individual group of the
    Brazilian p.K290I kindred: four premature neonatal deaths, two spontaneous
    abortions, five forceps deliveries, and twelve cesarean procedures, with five
    women reporting preeclampsia. The authors regarded this as clinically
    actionable - carriers in that cohort were counselled to avoid pregnancy, and
    planned cesarean delivery was one of the interventions credited with improved
    outcomes. Mechanistically unexplained. The phenotype is anchored on the
    operative-delivery component (HP:0001787 Abnormal delivery), which is the part
    of the cluster with an HPO class inside the phenotypic-abnormality subontology;
    the pregnancy-loss and neonatal-death components are carried here in prose
    because their HPO classes are not usable in this slot (see the HPO term-search
    record in `notes`). Single-kindred provenance; the reported counts mix
    carriers, pregnancies, and deliveries as denominators, so no `frequency:` band
    is asserted.
  phenotype_term:
    preferred_term: Adverse pregnancy and operative-delivery outcome
    term:
      id: HP:0001787
      label: Abnormal delivery
  evidence:
  - reference: PMID:39082507
    reference_title: "PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "four premature neonatal deaths, two spontaneous abortions, five forceps deliveries, and 12 cesarean procedures"
    explanation: >-
      Direct enumeration of the obstetric and perinatal events observed in the
      carrier group.
  - reference: PMID:39082507
    reference_title: "PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations carriers were advised to avoid pregnancy."
    explanation: >-
      Shows the authors treated the obstetric burden as clinically actionable
      counselling content, not an incidental observation.

histopathology:
- name: PAS-positive, diastase-resistant polyglucosan inclusions in cardiomyocytes
  diagnostic: true
  description: >-
    The defining microscopic finding of PRKAG2 cardiac syndrome. Cardiomyocyte
    vacuoles contain granular material that stains strongly with periodic
    acid-Schiff and, critically, RESISTS diastase digestion. Diastase removes
    ordinary glycogen; resistance therefore identifies the stored material as
    polyglucosan (an amylopectin-like, poorly branched, poorly soluble
    polysaccharide) rather than simple glycogen. Electron microscopy confirms
    densely packed granular and fibrillar electron-dense material characteristic
    of amylopectin. This single stain pair separates PRKAG2 disease from
    sarcomeric HCM and, together with the clinical context, from Danon and Pompe
    disease.
  finding_term:
    preferred_term: PAS-positive diastase-resistant polyglucosan inclusion
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "was diastase-resistant, a pattern that is characteristic of polyglucan"
    explanation: >-
      Establishes diastase resistance of the PAS-positive inclusions in human
      PRKAG2 cardiac specimens, identifying the stored material as polyglucosan.
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "features that are characteristic of amylopectin, a nonsoluble product of glycogen metabolism"
    explanation: >-
      Ultrastructural confirmation that the inclusions have the features of
      amylopectin, corroborating the histochemical finding.

- name: Vacuolated cardiomyocytes
  diagnostic: true
  description: >-
    Large isolated cytosolic vacuoles within enlarged cardiomyocytes, present in
    every human specimen examined in the defining pathological series. The
    vacuoles are non-lysosomal, distinguishing the storage compartment from that
    of Danon disease (autophagic vacuoles with sarcolemmal features) and Pompe
    disease (lysosomal).
  finding_term:
    preferred_term: cardiomyocyte cytoplasmic vacuolation
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all five specimens demonstrated isolated, large cytosolic vacuoles in cardiomyocytes"
    explanation: >-
      Documents the vacuolation in all five human PRKAG2 cardiac specimens
      examined.

- name: Absence of myofibre disarray
  diagnostic: true
  description: >-
    Myofibre (myocyte) disarray, the histological signature of sarcomeric
    hypertrophic cardiomyopathy, is ABSENT in PRKAG2 hearts, and interstitial
    fibrosis is minimal and focal. This negative finding carries as much
    diagnostic weight as the positive storage findings, and is the histological
    basis for treating PRKAG2 disease as a genocopy of HCM rather than a form of
    it.
  finding_term:
    preferred_term: absence of myofibre disarray
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "myofiber disarray, the characteristic feature of HCM, was not detected in any sample"
    explanation: >-
      Direct statement that the defining histological feature of sarcomeric HCM
      is absent from PRKAG2 cardiac specimens.
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interstitial fibrosis was minimal and focal."
    explanation: >-
      Documents the minimal fibrosis that accompanies the absence of disarray,
      further separating PRKAG2 disease from sarcomeric HCM.

- name: Positive glycogen staining on endomyocardial biopsy
  description: >-
    In life, endomyocardial biopsy demonstrating positive glycogen staining
    supports the diagnosis of a cardiac glycogenosis in a patient with otherwise
    unexplained hypertrophy.
  finding_term:
    preferred_term: glycogen-positive staining
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: PMID:40149727
    reference_title: "PRKAG2 Syndrome: Clinical Features, Imaging Findings and Cardiac Events."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the EMB of one of the patients, staining for glycogen deposits was positive."
    explanation: >-
      Contemporary cohort documenting positive glycogen staining on
      endomyocardial biopsy in a PRKAG2 carrier.

genetic:
- name: PRKAG2
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PRKAG2
    term:
      id: hgnc:9386
      label: PRKAG2
  notes: >-
    PRKAG2 (7q36.1) encodes the gamma-2 regulatory subunit of AMP-activated
    protein kinase. Essentially all reported disease-causing variants are
    heterozygous missense substitutions affecting the tandem CBS (Bateman)
    domains that bind AMP, ADP, and ATP; truncating and loss-of-expression
    alleles are not an established mechanism, consistent with a dominant
    mechanism acting through an altered rather than absent protein. De novo
    variants are reported.
  case_fractions:
  - population: Patients with increased left ventricular wall thickness AND ECG ventricular pre-excitation
    case_fraction_percent: 29.2
    cohort_size: 24
    notes: >-
      Seven of 24 probands selected for the combination of increased wall
      thickness plus pre-excitation carried a PRKAG2 variant (a further four
      carried LAMP2 variants). This enrichment is the empirical basis for
      prioritising PRKAG2 testing in exactly this clinical subgroup, and stands
      in sharp contrast to the yield in hypertrophy without pre-excitation.
    evidence:
    - reference: PMID:15673802
      reference_title: "Glycogen storage diseases presenting as hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic analyses of 24 subjects with increased left ventricular wall thickness and electrocardiograms suggesting ventricular preexcitation revealed four LAMP2 and seven PRKAG2 mutations."
      explanation: >-
        Gives the numerator and denominator (7 of 24) for the PRKAG2 case
        fraction in the hypertrophy-plus-pre-excitation subgroup.
  - population: Patients with massive left ventricular hypertrophy WITHOUT electrophysiological abnormalities
    case_fraction_percent: 0.0
    cohort_size: 20
    notes: >-
      No PRKAG2 (or LAMP2) variant was found in 20 subjects with wall thickness
      of 30 mm or more but no electrophysiological abnormality - the negative
      control that shows the diagnostic yield is driven by the electrophysiology,
      not by the severity of the hypertrophy.
    evidence:
    - reference: PMID:15673802
      reference_title: "Glycogen storage diseases presenting as hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic analyses of 20 subjects with massive hypertrophy (left ventricular wall thickness, > or =30 mm) but without electrophysiological abnormalities revealed mutations in neither LAMP2 nor PRKAG2."
      explanation: >-
        Establishes a zero case fraction in severe hypertrophy lacking
        electrophysiological abnormality.
  variants:
  - name: p.Arg302Gln
    description: >-
      The most frequently reported PRKAG2 allele, affecting the first CBS domain.
      Identified in the original linkage study of familial Wolff-Parkinson-White
      syndrome with hypertrophy and recurrent across many unrelated families and
      populations. It is the allele modelled by the R302Q transgenic mouse.
    evidence:
    - reference: PMID:11407343
      reference_title: "Identification of a gene responsible for familial Wolff-Parkinson-White syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified a missense mutation in the gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein."
      explanation: >-
        Original identification of p.Arg302Gln as the cause of the familial
        syndrome.
  - name: p.Asn488Ile
    description: >-
      A recurrent allele lying in the linker region between CBS domains, and the
      variant expressed in the principal transgenic mouse model. Segregated with
      disease in study families.
    evidence:
    - reference: PMID:12782567
      reference_title: "Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation"
      explanation: >-
        Establishes p.Asn488Ile as the human variant modelled in the defining
        transgenic mouse study.
  - name: p.Thr400Asn
    description: >-
      A CBS-domain allele found in a proband with no other affected family
      members and possibly de novo. Together with p.Asn488Ile it is one of the
      two substitutions whose yeast-orthologue equivalents produced
      glucose-insensitive Snf1-Snf4 interaction.
    evidence:
    - reference: PMID:11827995
      reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We interpret these data to indicate that Thr400Asn and Asn488Ile mutations produce nonphysiologic, constitutive activation of AMP kinase."
      explanation: >-
        Functional characterisation of p.Thr400Asn in the yeast orthologue
        system.
  - name: p.Arg531Gly
    description: >-
      A CBS-domain allele causing childhood-onset ventricular pre-excitation,
      early atrial fibrillation, and conduction disease WITHOUT cardiac
      hypertrophy - evidence that the electrical phenotype can be fully
      dissociated from the hypertrophic one. Absent from 150 unrelated controls.
    evidence:
    - reference: PMID:11748095
      reference_title: "Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A missense mutation, Arg531Gly, was identified in all affected individuals but was absent in 150 unrelated individuals."
      explanation: >-
        Establishes segregation and control absence for p.Arg531Gly.
    - reference: PMID:11748095
      reference_title: "Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy."
      explanation: >-
        Documents the hypertrophy-free, childhood-onset presentation of this
        allele.
  - name: p.Arg531Gln
    description: >-
      The recurrent CBS3-domain allele of the lethal congenital form (see
      `has_subtypes` "Lethal Congenital", MONDO:0009867 / OMIM:261740). Found as an
      identical de-novo-appearing heterozygous substitution in three of five
      sporadic, unrelated infants with fatal congenital non-lysosomal cardiac
      glycogenosis. Biochemically it is the most extreme PRKAG2 allele
      characterised: the recombinant protein loses AMP and ATP binding affinity by
      more than 100-fold while showing enhanced basal kinase activity. The same
      study frames the classic juvenile-to-adult PRKAG2 alleles as producing
      qualitatively similar but less severe molecular perturbations, which is the
      quantitative basis for the severity spectrum. Contrast p.Arg531Gly at the
      identical codon, which causes hypertrophy-free childhood-onset
      pre-excitation - residue 531 alone spans the full clinical range of the
      disease.
    evidence:
    - reference: PMID:15877279
      reference_title: "Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "in three of five patients, we identified identical heterozygous R531Q missense mutations of the PRKAG2 gene"
      explanation: >-
        Establishes p.Arg531Gln as a recurrent allele in sporadic fatal congenital
        cardiac glycogenosis, with the numerator and denominator of that series.
    - reference: PMID:15877279
      reference_title: "Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Biochemical characterization of the recombinant R531Q mutant protein showed >100-fold reduction of binding affinities for the regulatory nucleotides AMP and ATP but an enhanced basal activity"
      explanation: >-
        Recombinant-protein assay quantifying the nucleotide-binding defect and
        raised basal activity of p.Arg531Gln; cell-free biochemistry, hence
        IN_VITRO rather than HUMAN_CLINICAL.
    - reference: PMID:15877279
      reference_title: "Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "molecular perturbations that are similar to--but less severe than--those observed for the R531Q mutation"
      explanation: >-
        The study's own cross-allele comparison, which is the stated basis for
        placing p.Arg531Gln at the severe extreme of a continuous PRKAG2 severity
        spectrum rather than treating it as a mechanistically separate disease.
        Classified OTHER because it is the authors' comparative interpretation
        across their biochemical and the prior clinical literature, not a single
        study arm.
  evidence:
  - reference: PMID:11407343
    reference_title: "Identification of a gene responsible for familial Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a missense mutation in the gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein."
    explanation: >-
      Establishes PRKAG2 as the causative gene by positional cloning in two
      independent families.

inheritance:
- name: Autosomal dominant
  description: >-
    PRKAG2 cardiac syndrome segregates as an autosomal dominant trait with
    variable expressivity and age-dependent penetrance. Affected individuals are
    heterozygous for a missense variant; de novo occurrence is reported.
    Expressivity within a single family ranges from isolated pre-excitation
    without hypertrophy to progressive hypertrophy with early pacing and heart
    failure.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:11407343
    reference_title: "Identification of a gene responsible for familial Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two families in which the Wolff-Parkinson-White syndrome segregated as an autosomal dominant disorder."
    explanation: >-
      Direct statement of autosomal dominant segregation in the founding linkage
      study.
  - reference: PMID:28431061
    reference_title: "High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block"
    explanation: >-
      Independent confirmation of the autosomal dominant mode alongside the
      clinical triad.

prevalence:
- population: Patients with increased left ventricular wall thickness and ECG ventricular pre-excitation
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    True population prevalence of PRKAG2 cardiac syndrome is not established; the
    disease is ultra-rare and no population-based estimate exists. What IS
    quantified is the diagnostic yield within clinically selected subgroups,
    which is the epidemiological figure that actually drives practice - see the
    structured `case_fractions` under `genetic` for the 7-of-24 yield in
    hypertrophy plus pre-excitation and the 0-of-20 yield in severe hypertrophy
    without electrophysiological abnormality. `measure_type` and
    `prevalence_class` are recorded as UNKNOWN rather than guessed, because a
    diagnostic yield in a referral subgroup is not a population prevalence and
    the two must not be conflated.
  evidence:
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood."
    explanation: >-
      Supports the characterisation of the disease as ultra-rare with an
      unestablished population prevalence, as of the largest cohort study.
- population: Patients with left ventricular hypertrophy (clinical referral population, not the general population)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_low: 230.0
  rate_high: 1000.0
  notes: >-
    Verbatim source phrasing: "Its estimated prevalence among patients with LVH
    ranges from 0.23 to about 1%, but it is likely an underdiagnosed condition."
    0.23-1 percent converts to 230-1000 cases per 100,000 OF THAT REFERRAL
    POPULATION, which is why `prevalence_class` falls in the ABOVE_1_IN_1000 tier
    even though the disease is ultra-rare in the general population. This record is
    deliberately kept SEPARATE from the UNKNOWN population-prevalence record above
    and must not be read as a population rate: the denominator is people already
    selected for having left ventricular hypertrophy, so the figure is a diagnostic
    yield in a referral cohort. Provenance caveat: the source is a case report with
    literature review and states the range as an estimate synthesised from the
    literature, not as a primary cohort measurement; `evidence_source` is therefore
    OTHER. No single-cohort primary measurement giving a clean PRKAG2-specific
    numerator and denominator in an unselected HCM population was located
    (PubMed 2026-08-01, "PRKAG2 prevalence hypertrophic cardiomyopathy cohort" and
    a Europe PMC full-text search for PRKAG2 AND "0.23%"): the candidates audited
    and rejected were PMID:28771489, which pools PRKAG2 with five other minor genes
    into a single count of 12 patients; PMID:30775854, which pools GLA and PRKAG2
    into a single count of three patients; and PMID:41998504, whose "0.7% of the
    cohort" is internally inconsistent with its own denominators (the companion
    TTR/GLA percentages in the same sentence reconcile only against the 453
    positive samples, not the 2068 tested patients), so quoting it would require
    inventing a denominator.
  evidence:
  - reference: PMID:39273120
    reference_title: "When Paying Attention Pays Back: Missense Mutation c.1006G>A p. (Val336Ile) in PRKAG2 Gene Causing Left Ventricular Hypertrophy and Conduction Abnormalities in a Caucasian Patient: Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Its estimated prevalence among patients with LVH ranges from 0.23 to about 1%, but it is likely an underdiagnosed condition."
    explanation: >-
      States the referral-population prevalence range and its denominator
      (patients with left ventricular hypertrophy) directly, and simultaneously
      flags underdiagnosis, which is why the range is not promoted to a population
      prevalence. Graded OTHER because it is a narrative literature-review estimate
      in a case report rather than primary cohort data.

diagnosis:
- name: Twelve-lead electrocardiography
  description: >-
    The first and highest-yield test. A short PR interval with a delta wave
    identifies ventricular pre-excitation; serial ECGs show progressive PR
    prolongation and increasing degrees of atrioventricular block, and may show
    sinus bradycardia or atrial fibrillation. Pre-excitation or early conduction
    disease in a patient carrying a label of hypertrophic cardiomyopathy is the
    trigger to consider PRKAG2 disease.
  diagnosis_term:
    preferred_term: Electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:15673802
    reference_title: "Glycogen storage diseases presenting as hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The glycogen-storage cardiomyopathy produced by LAMP2 or PRKAG2 mutations resembles hypertrophic cardiomyopathy but is distinguished by electrophysiological abnormalities, particularly ventricular preexcitation."
    explanation: >-
      Establishes the electrocardiographic finding of pre-excitation as the
      discriminator between glycogen storage cardiomyopathy and sarcomeric HCM.
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age."
    explanation: >-
      Defines the electrocardiographic and clinical triggers that should prompt
      diagnostic consideration of PRKAG2 syndrome, and warns that their absence
      does not exclude it.

- name: Echocardiography
  description: >-
    Documents and quantifies left ventricular hypertrophy and tracks the later
    fall in ejection fraction as the disease enters its contractile-failure
    phase. Echocardiography establishes that hypertrophy is present but cannot by
    itself distinguish PRKAG2 disease from sarcomeric HCM.
  diagnosis_term:
    preferred_term: Echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:40149727
    reference_title: "PRKAG2 Syndrome: Clinical Features, Imaging Findings and Cardiac Events."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac involvement was assessed by electrocardiography, echocardiography, cardiac magnetic resonance imaging, and endomyocardial biopsy (EMB)."
    explanation: >-
      Documents echocardiography as part of the standard assessment of cardiac
      involvement in a PRKAG2 cohort.

- name: Cardiac magnetic resonance imaging
  description: >-
    Characterises myocardial tissue, quantifies hypertrophy and the distribution
    of wall thickening, and assesses late gadolinium enhancement. Because PRKAG2
    hearts have minimal fibrosis, unlike sarcomeric HCM, tissue characterisation
    can contribute to the differential, although it is not on its own definitive.
  diagnosis_term:
    preferred_term: Cardiac magnetic resonance imaging
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  evidence:
  - reference: PMID:40149727
    reference_title: "PRKAG2 Syndrome: Clinical Features, Imaging Findings and Cardiac Events."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac involvement was assessed by electrocardiography, echocardiography, cardiac magnetic resonance imaging, and endomyocardial biopsy (EMB)."
    explanation: >-
      Documents cardiac MRI as part of the standard diagnostic assessment in a
      PRKAG2 cohort.

- name: Endomyocardial biopsy
  description: >-
    Provides the histological confirmation: vacuolated cardiomyocytes containing
    PAS-positive, diastase-resistant polyglucosan, with minimal fibrosis and NO
    myofibre disarray. Biopsy is not required when genetic testing is
    informative, but it resolves ambiguous cases and remains the reference
    standard for demonstrating cardiac storage.
  diagnosis_term:
    preferred_term: Endomyocardial biopsy
    term:
      id: NCIT:C51674
      label: Endomyocardial Biopsy
  evidence:
  - reference: PMID:40149727
    reference_title: "PRKAG2 Syndrome: Clinical Features, Imaging Findings and Cardiac Events."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the EMB of one of the patients, staining for glycogen deposits was positive."
    explanation: >-
      Demonstrates the diagnostic use of endomyocardial biopsy to show cardiac
      glycogen storage in a PRKAG2 carrier.
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "myofiber disarray, the characteristic feature of HCM, was not detected in any sample"
    explanation: >-
      Establishes the key negative biopsy finding that separates PRKAG2 disease
      from sarcomeric HCM.

- name: PRKAG2 genetic testing
  description: >-
    Molecular confirmation by PRKAG2 sequencing, in practice usually within a
    hypertrophic-cardiomyopathy or cardiomyopathy gene panel that also covers the
    sarcomere genes and the other storage-cardiomyopathy genes (LAMP2 for Danon
    disease, GAA for Pompe disease, GLA for Fabry disease). Yield is concentrated
    in the hypertrophy-plus-pre-excitation subgroup, where roughly one in three
    probands carries a PRKAG2 variant, and is essentially nil in severe
    hypertrophy without electrophysiological abnormality. A confirmed variant
    enables cascade testing of at-risk relatives.
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:15673802
    reference_title: "Glycogen storage diseases presenting as hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analyses of 24 subjects with increased left ventricular wall thickness and electrocardiograms suggesting ventricular preexcitation revealed four LAMP2 and seven PRKAG2 mutations."
    explanation: >-
      Quantifies the genetic-testing yield in the clinically enriched subgroup
      that should be prioritised for PRKAG2 sequencing.
  - reference: PMID:15673802
    reference_title: "Glycogen storage diseases presenting as hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analyses of 20 subjects with massive hypertrophy (left ventricular wall thickness, > or =30 mm) but without electrophysiological abnormalities revealed mutations in neither LAMP2 nor PRKAG2."
    explanation: >-
      Demonstrates the near-zero yield when electrophysiological abnormality is
      absent, defining who should NOT be prioritised for this test.

treatments:
- name: Permanent pacemaker implantation
  therapeutic_modality: DEVICE
  description: >-
    The mainstay intervention for the conduction-disease arm. Progressive
    atrioventricular block and symptomatic bradycardia require permanent pacing,
    typically at a strikingly young age - a median in the mid-thirties in the
    largest cohort, and about a third of affected individuals in early series.
    Pacing does not modify the underlying storage process; it substitutes for the
    degenerating conduction system.
  treatment_term:
    preferred_term: Pacemaker placement
    term:
      id: NCIT:C80434
      label: Pacemaker Placement
  target_mechanisms:
  - target: Progressive Atrioventricular Block and Bradyarrhythmia
    treatment_effect: BYPASSES
    description: >-
      Artificial pacing restores an adequate ventricular rate by providing an
      alternative activation source; it circumvents the diseased conduction
      tissue rather than reversing its degeneration.
  target_phenotypes:
  - preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  - preferred_term: Sinus bradycardia
    term:
      id: HP:0001688
      label: Sinus bradycardia
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sinus bradycardia and/or variable degrees of atrioventricular block resulted in pacemaker implantation in 24 (35%) affected individuals."
    explanation: >-
      Documents pacemaker implantation as the response to bradyarrhythmia and AV
      block in about a third of affected individuals.
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years)."
    explanation: >-
      Quantifies pacemaker use and the strikingly young median age at
      implantation.
  - reference: PMID:33244021
    reference_title: "Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "8 patients (36%) underwent permanent pacemaker implantation (atrio-ventricular blocks-5; sinus node disease-2)"
    explanation: >-
      Independent replication of the high pacing burden in a separate South Asian
      cohort, and shows the indication split between atrioventricular block and
      sinus node disease.

- name: Implantable cardioverter-defibrillator
  therapeutic_modality: DEVICE
  description: >-
    Considered for secondary prevention after sustained ventricular arrhythmia,
    and for primary prevention in individuals judged at high arrhythmic risk. The
    evidence base is observational: no PRKAG2-specific risk-stratification model
    exists, and a defibrillator does not protect against the bradyarrhythmic or
    heart-failure modes of death. In one contemporary cohort a patient died
    suddenly despite defibrillator implantation.
  treatment_term:
    preferred_term: Implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_phenotypes:
  - preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:40149727
    reference_title: "PRKAG2 Syndrome: Clinical Features, Imaging Findings and Cardiac Events."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "After a median follow-up of 13.1 years, 6 carriers had LVH, 3 required admission for HF, and 1 had sustained ventricular tachycardia with subsequent cardioverter defibrillator implantation, and despite this, died suddenly; there were two de novo pacemaker implantations due to symptomatic bradycardia."
    explanation: >-
      Documents defibrillator use after sustained ventricular tachycardia while
      also showing it did not prevent sudden death in that patient, hence PARTIAL
      rather than SUPPORT.
  - reference: PMID:28431061
    reference_title: "High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant."
    explanation: >-
      Independent cohort documenting defibrillator implantation as part of the
      device burden of PRKAG2 syndrome.

- name: Catheter ablation of accessory atrioventricular pathways
  therapeutic_modality: SURGERY
  description: >-
    Catheter ablation is used for symptomatic accessory-pathway-mediated
    tachyarrhythmia, and a third of the largest cohort had either pre-excitation
    or prior accessory-pathway ablation. Its durability is limited by the
    underlying anatomy: because the substrate is diffuse microscopic muscle
    continuity across a breached annulus fibrosus rather than a single discrete
    bypass tract, multiple pathways are common and arrhythmia recurrence after
    ablation is a recognised problem. This is a direct clinical consequence of
    the mechanism curated in the pathophysiology graph.
  treatment_term:
    preferred_term: Cardiac ablation
    term:
      id: NCIT:C100068
      label: Cardiac Ablation
  target_mechanisms:
  - target: Accessory Atrioventricular Connections and Ventricular Pre-excitation
    treatment_effect: INHIBITS
    description: >-
      Radiofrequency ablation destroys conducting tissue at the site of an
      accessory connection, interrupting the pre-excitation and the reentrant
      circuit. Because the anatomical substrate is diffuse rather than discrete,
      the interruption is often incomplete or non-durable.
    evidence:
    - reference: PMID:12782567
      reference_title: "Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy."
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: "These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation."
      explanation: >-
        Explains why an ablation strategy designed for discrete bypass tracts is
        mechanistically mismatched to the PRKAG2 substrate. Marked PARTIAL
        because it characterises the substrate rather than reporting ablation
        outcomes.
  target_phenotypes:
  - preferred_term: Ventricular preexcitation
    term:
      id: HP:0004309
      label: Ventricular preexcitation
  - preferred_term: Supraventricular tachycardia
    term:
      id: HP:0004755
      label: Supraventricular tachycardia
  evidence:
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation"
    explanation: >-
      Documents accessory-pathway ablation as part of standard management in the
      largest PRKAG2 cohort.
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrophysiologic studies in ten affected individuals demonstrated one or more accessory atrioventricular pathways."
    explanation: >-
      Documents that carriers frequently have MULTIPLE accessory pathways, the
      anatomical reason single-target ablation may not be curative.

- name: Anticoagulation for atrial fibrillation
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Stroke prevention in the atrial-arrhythmia arm of the disease. Atrial
    fibrillation and atrial flutter are curated here both as a phenotype and as a
    pathophysiology node, and they arrive early - a median age of 43 years in the
    largest cohort - so the cumulative thromboembolic exposure is long. The
    Brazilian kindred followed for 18 years recorded four strokes among nineteen
    carriers, and individual carriers in that series were managed with warfarin,
    rivaroxaban, apixaban, and dabigatran for intracardiac thrombus, inferior vena
    cava thrombosis, pulmonary embolism, and embolic stroke. Anticoagulation is
    named by the authors as one of the interventions that improved symptoms and
    survival. Important scope limit: there is no PRKAG2-specific anticoagulation
    trial and no PRKAG2-specific stroke-risk score; the practice is extrapolated
    from general AF stroke-prevention management, and the observational cohort
    evidence below reports it as part of a bundle of early interventions rather
    than as an isolated, separately evaluated therapy. No `target_mechanisms` link
    is declared to the "Supraventricular Tachyarrhythmia and Atrial Fibrillation"
    node on purpose: anticoagulation neither inhibits, activates, modulates,
    bypasses, nor restores that mechanism - it interrupts a thromboembolic
    consequence downstream of it - and none of the five permissible
    `treatment_effect` values would describe that honestly.
  treatment_term:
    preferred_term: Anticoagulation therapy
    term:
      id: NCIT:C63341
      label: Anticoagulation Therapy
    therapeutic_agent:
    - preferred_term: anticoagulant agent
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
  target_phenotypes:
  - preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:39082507
    reference_title: "PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early diagnosis and intervention through antiarrhythmic drugs, anticoagulation, pacemaker implantation, radiofrequency catheter ablation, and cesarean section surgery improved the symptoms and survival rates."
    explanation: >-
      Names anticoagulation explicitly as part of the management bundle credited
      with improved symptoms and survival in an 18-year PRKAG2 cohort. Graded
      SUPPORT for the practice, but note the effect is attributed to the bundle,
      not to anticoagulation in isolation.
  - reference: PMID:39082507
    reference_title: "PRKAG2 syndrome, a rare hypertrophic cardiomyopathy: a Brazilian long-term follow-up with extracardiac disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This group experienced many malignant events, including eight pacemaker implants, three sudden cardiac deaths, five aborted cardiac arrests, four strokes"
    explanation: >-
      Quantifies the stroke burden in variant carriers that makes stroke
      prevention a first-order management concern in this disease.
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years)"
    explanation: >-
      Establishes the prevalence and the early median onset of the atrial
      fibrillation that creates the anticoagulation indication.

- name: Septal myectomy
  therapeutic_modality: SURGERY
  description: >-
    Surgical septal reduction for left ventricular outflow tract obstruction, used
    in selected PRKAG2 patients whose hypertrophy is obstructive. It is documented
    in PRKAG2 disease only at case-report level, including in an infant with severe
    biventricular hypertrophy and pre-excitation carrying a novel p.Glu506Gln
    allele. It is listed here deliberately as a low-certainty, selected-case option
    rather than a mainstay: the hypertrophy in PRKAG2 disease is storage-driven
    mass accrual rather than sarcomeric myocyte hypertrophy with disarray (see
    `notes`, LUMP-VS-SPLIT), so the sarcomeric-HCM evidence base for septal
    reduction does not transfer, and no PRKAG2 series has evaluated outcomes. The
    dominant surgical intervention in this disease remains transplantation for
    end-stage disease.
  treatment_term:
    preferred_term: Septal myectomy
    term:
      id: NCIT:C51591
      label: Myectomy
  target_phenotypes:
  - preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:19787389
    reference_title: "Severe hypertrophic cardiomyopathy in an infant with a novel PRKAG2 gene mutation: potential differences between infantile and adult onset presentation."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "An infant was assigned a diagnosis of ventricular preexcitation and severe biventricular HCM requiring septal myectomy."
    explanation: >-
      Documents septal myectomy actually being performed in genetically confirmed
      PRKAG2 disease. Graded PARTIAL because it is a single case report that
      records the procedure without reporting an outcome or comparing it with
      alternatives, so it supports availability of the option, not its efficacy.

- name: Heart transplantation
  therapeutic_modality: SURGERY
  description: >-
    Definitive therapy for end-stage disease. Because the lesion is confined to
    the heart, transplantation is curative of the cardiac phenotype. About 4
    percent of the largest cohort were transplanted over a median six years of
    follow-up, and transplantation is documented from the earliest human series.
  treatment_term:
    preferred_term: Heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Advanced Heart Failure and End-Stage Cardiomyopathy
    treatment_effect: RESTORES
    description: >-
      Replacement of the storage-affected heart with a genotypically normal
      allograft removes the entire diseased organ, restoring pump function and
      normal conduction.
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:32646569
    reference_title: "Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died."
    explanation: >-
      Quantifies the proportion of the cohort proceeding to transplantation.
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Left ventricular function markedly deteriorated in five affected adult individuals and necessitated cardiac transplantation in one; sudden death occurred in four."
    explanation: >-
      Documents transplantation for end-stage PRKAG2 cardiomyopathy in the
      original human series.

- name: Genetic counselling and cascade family screening
  therapeutic_modality: OTHER
  description: >-
    Because inheritance is autosomal dominant with age-dependent, incomplete
    penetrance, first-degree relatives of a proband should be offered genetic
    testing, and variant-positive relatives require LONGITUDINAL surveillance
    (serial ECG and echocardiography) rather than a single clearing assessment.
    The case for this is strong: pre-excitation can precede hypertrophy by years,
    and pacemaker requirement can be the first manifestation.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:11407343
    reference_title: "Identification of a gene responsible for familial Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two families in which the Wolff-Parkinson-White syndrome segregated as an autosomal dominant disorder."
    explanation: >-
      Establishes the autosomal dominant transmission that makes cascade family
      screening appropriate.
  - reference: PMID:11748095
    reference_title: "Novel PRKAG2 mutation responsible for the genetic syndrome of ventricular preexcitation and conduction system disease with childhood onset and absence of cardiac hypertrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy."
    explanation: >-
      Demonstrates that variant-positive relatives may manifest in childhood
      without hypertrophy, supporting longitudinal rather than one-time
      screening.

discussions:
- discussion_id: gap_prkag2_ampk_activity_direction
  prompt: >-
    Do disease-causing PRKAG2 CBS-domain variants raise or lower cardiac AMPK
    activity in the human heart, and is the answer variant-specific,
    developmental-stage-specific, or both?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Dysregulated AMPK Nucleotide Sensing
  rationale: >-
    This is the central unresolved mechanistic question of the disease, and the
    reason this entry declines to assert a direction. Yeast reconstitution of
    p.Thr400Asn and p.Asn488Ile indicates constitutive activation, and the N488I
    transgenic mouse shows ELEVATED cardiac AMPK activity with 30-fold glycogen
    accumulation. Against that, direct biochemical assay of reconstituted mutant
    complexes shows no constitutive activation but markedly reduced AMP
    dependence, and the R302Q transgenic mouse - which phenocopies the human
    disease including inducible AV reentrant tachycardia - has significantly
    REDUCED cardiac AMPK activity. Time-resolved work shows the direction flips
    within a single variant: acute p.Arg302Gln expression activates AMPK and
    upregulates glycogen synthase and AS160, whereas the chronically transgenic
    adult heart shows suppressed AMPK activity, apparently as feedback to stored
    glycogen. The question is not academic: it determines whether a rational
    therapy should activate or inhibit AMPK, and one of the founding papers
    explicitly proposed AMPK-lowering therapy on the basis of the activation
    model.
  proposed_experiments:
  - experiment_id: exp_prkag2_human_myocardial_ampk_activity
    name: Direct AMPK activity and phosphorylation profiling in human PRKAG2 myocardium
    description: >-
      Measure AMPK catalytic activity, alpha-subunit Thr172 phosphorylation, and
      downstream substrate phosphorylation (ACC, glycogen synthase, AS160) in
      genotyped human myocardial tissue obtained at transplantation or autopsy
      from carriers of the major alleles (p.Arg302Gln, p.Asn488Ile,
      p.Arg531Gly), against matched non-PRKAG2 hypertrophic and normal controls,
      stratified by disease stage and myocardial glycogen content. This is the
      missing human-tissue arm: every current activity measurement comes from
      yeast, reconstituted complexes, transgenic rodents, or zebrafish.
  - experiment_id: exp_prkag2_isogenic_ipsc_timecourse
    name: Allele-matched isogenic iPSC-cardiomyocyte AMPK activity time course
    description: >-
      In isogenic human iPSC-derived cardiomyocyte lines each carrying a single
      knock-in PRKAG2 allele, track AMPK activity, glycogen content, and
      electrophysiology across differentiation and prolonged culture, to test
      directly whether the direction of the AMPK change is allele-dependent, is
      stage-dependent, or reverses as glycogen accumulates.
  evidence:
  - reference: PMID:12397075
    reference_title: "Functional analysis of mutations in the gamma 2 subunit of AMP-activated protein kinase associated with cardiac hypertrophy and Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results indicate that mutations in gamma(2) have different effects on AMPK function, suggesting that they may lead to abnormal development of the heart through distinct mechanisms."
    explanation: >-
      Explicitly states that different PRKAG2 variants have different effects on
      AMPK function, framing the unresolved question.
  - reference: PMID:20031621
    reference_title: "Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These findings are the first to highlight temporal differences in the effects of the PRKAG2 R302Q mutation on cardiac metabolic signaling events."
    explanation: >-
      Establishes the temporal dimension of the question: the measured direction
      depends on when in the disease course it is assayed. Evidence source is
      OTHER because this concluding statement spans the study's cultured-myocyte
      and transgenic-mouse arms rather than reporting a single experimental
      system.

- discussion_id: mismatch_prkag2_transgenic_overexpression_vs_human
  prompt: >-
    Do cardiac-restricted transgenic OVEREXPRESSION models of PRKAG2 variants
    faithfully represent the human disease, in which a single variant allele is
    expressed heterozygously at physiological level - and does the opposite
    direction of AMPK activity change between the N488I and R302Q mouse models
    reflect real allele biology or an artefact of transgene dosage?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Dysregulated AMPK Nucleotide Sensing
  - pathophysiology#Excessive Cardiomyocyte Glycogen and Polyglucosan Accumulation
  rationale: >-
    Almost everything mechanistically known about this disease comes from
    alpha-myosin-heavy-chain-promoter transgenic mice OVEREXPRESSING a variant
    PRKAG2 cDNA on a normal endogenous background - a fundamentally different
    genetic architecture from the human heterozygote, where one endogenous allele
    is variant and total gamma-2 dosage is normal. The models are compelling in
    that they reproduce the human triad closely, including anatomically
    demonstrated annulus fibrosus disruption and inducible AV reentrant
    tachycardia. But they disagree with each other on the most basic
    biochemistry - the N488I model shows elevated cardiac AMPK activity while the
    R302Q model shows reduced activity - and overexpression is a plausible
    explanation for a discrepancy of that kind. The stakes are concrete: the
    inducible N488I model's demonstration that suppressing the transgene REVERSES
    established cardiomyopathy, conduction disease, and pre-excitation is the
    single strongest argument that the human disease is in principle
    pharmacologically reversible, and that argument is only as good as the
    model's fidelity. Evidence exists here in abundance; what is uncertain is its
    translational validity, which is why this is recorded as
    HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP.
  proposed_experiments:
  - experiment_id: exp_prkag2_knockin_heterozygous_mouse
    name: Heterozygous Prkag2 knock-in mice at endogenous expression level
    description: >-
      Generate heterozygous knock-in mice carrying the murine equivalents of
      p.Arg302Gln and p.Asn488Ile at the endogenous Prkag2 locus, so that
      expression level and allelic ratio match the human heterozygote. Compare
      cardiac AMPK activity, glycogen and polyglucosan content, annulus fibrosus
      integrity, and electrophysiology against the corresponding overexpression
      transgenics, to determine which findings survive removal of the transgene
      dosage confound and whether the N488I-versus-R302Q activity discrepancy
      persists.
  - experiment_id: exp_prkag2_reversibility_endogenous_expression
    name: Reversibility testing in an endogenous-expression model
    description: >-
      Repeat the transgene-suppression reversibility experiment in a system with
      physiological expression - for example allele-selective knockdown of the
      variant transcript in heterozygous knock-in mice, or in variant human
      iPSC-derived engineered heart tissue - to establish whether reversal of
      established storage cardiomyopathy is a property of the disease or an
      artefact of switching off a supraphysiological transgene.
  evidence:
  - reference: PMID:18158359
    reference_title: "Reversibility of PRKAG2 glycogen-storage cardiomyopathy and electrophysiological manifestations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Using an externally modifiable transgenic system, cardiomyopathy, cardiac dysfunction, and electrophysiological disorders were demonstrated to be reversible processes in PRKAG2 disease."
    explanation: >-
      The reversibility claim whose translational validity is at stake, obtained
      in a tetracycline-repressible cardiac overexpression transgenic mouse, not
      in a physiological-expression heterozygote.
  - reference: PMID:18158359
    reference_title: "Reversibility of PRKAG2 glycogen-storage cardiomyopathy and electrophysiological manifestations."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Transgene suppression during early postnatal development prevented the development of accessory electrical pathways but not cardiomyopathy or conduction system degeneration."
    explanation: >-
      Shows the three disease arms have different critical windows in the model,
      a dissociation whose relevance to human disease timing is untested. Marked
      PARTIAL because it complicates rather than straightforwardly supports the
      reversibility claim.

- discussion_id: mismatch_prkag2_glycogen_independent_arm
  prompt: >-
    Does the glycogen-independent AMPK-gamma2/myosin interaction reported in
    transgenic zebrafish contribute to the human PRKAG2 cardiac phenotype, and if
    so does it operate before, alongside, or instead of glycogen storage?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Enhanced AMPK-gamma2/Myosin Interaction
  - pathophysiology#Glycogen-Independent Early Electrophysiological Abnormality
  rationale: >-
    The entire causal architecture of this entry, and of the field, routes the
    cardiac phenotype through glycogen and polyglucosan accumulation. A 2026
    zebrafish study challenges that by showing hypertrophy plus slowed conduction
    and prolonged action-potential and calcium-transient duration at a
    developmental stage with NO glycogen accumulation, not rescued by AMPK
    activation, and attributable to variant-enhanced AMPK-gamma2 binding to
    myosin with myofilament relocalisation. If this generalises, part of the
    disease is a myofilament calcium-handling disorder rather than purely a
    storage disorder, and glycogen-lowering strategies would address only part of
    the phenotype. Zebrafish cardiac development, myosin isoform composition, and
    calcium handling differ substantially from human, and the finding is
    single-model and unreplicated - so this is a model-fidelity question rather
    than an absence of evidence. Notably it also cuts against BOTH established
    AMPK-direction hypotheses, since AMPK activation failed to rescue the
    phenotype.
  proposed_experiments:
  - experiment_id: exp_prkag2_myosin_interaction_human_tissue
    name: AMPK-gamma2/myosin interaction in human PRKAG2 myocardium and iPSC-cardiomyocytes
    description: >-
      Test for enhanced AMPK-gamma2/myosin association and myofilament
      relocalisation by proximity ligation and co-immunoprecipitation in
      genotyped human PRKAG2 myocardium and in isogenic variant human
      iPSC-derived cardiomyocytes, and determine whether calcium-transient and
      action-potential prolongation precede detectable glycogen accumulation
      during human cardiomyocyte differentiation.
  - experiment_id: exp_prkag2_myosin_inhibitor_rescue_mammalian
    name: Myosin-inhibitor rescue of the electrophysiological phenotype in a mammalian model
    description: >-
      Test whether a myosin inhibitor such as mavacamten reduces
      AMPK-gamma2/myosin association and rescues conduction slowing and
      calcium-transient prolongation in mammalian PRKAG2 models and in human
      variant engineered heart tissue, as it did in zebrafish. A positive result
      would both validate the mechanism across species and identify a
      repurposable pharmacological entry point.
  evidence:
  - reference: PMID:42422944
    reference_title: "AMPKγ2 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although prior studies associated PRKAG2-related hypertrophy with increased glycogen storage, many hypertrophic cardiomyopathy phenotypes remain unexplained."
    explanation: >-
      States the explanatory shortfall of the glycogen-centred model that
      motivates the alternative arm. Evidence source is OTHER because this is a
      background statement about what the prior literature leaves UNEXPLAINED -
      an assertion about absent evidence - rather than a result from the
      zebrafish experiments reported in this paper.
  - reference: PMID:42422944
    reference_title: "AMPKγ2 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We observed decreased AMPK (AMP-activated protein kinase) phosphorylation in the TgR299Q hearts. However, AMPK activation did not rescue the electrophysiological abnormalities in TgR299Q."
    explanation: >-
      Shows the electrophysiological phenotype is not corrected by restoring AMPK
      activity, arguing that this arm is not downstream of the AMPK activity
      change itself.

- discussion_id: gap_prkag2_accessory_pathway_origin
  prompt: >-
    Do the accessory atrioventricular connections in PRKAG2 disease arise from
    persistence of embryonic atrioventricular connections that normally regress,
    or from de novo activation of quiescent pathways by metabolic deposits in the
    postnatal heart?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Disruption of the Annulus Fibrosus by Glycogen-Laden Myocytes
  - pathophysiology#Accessory Atrioventricular Connections and Ventricular Pre-excitation
  rationale: >-
    The annulus fibrosus mechanism is well established, but the developmental
    origin of the conducting strands is not. The two candidate explanations were
    posed as alternatives in the original human pathology paper and remain
    unresolved. The inducible mouse work is suggestive but not decisive:
    transgene suppression during early postnatal development PREVENTED
    accessory-pathway development while failing to prevent cardiomyopathy and
    conduction-system degeneration, implying a restricted developmental window
    for the pre-excitation arm specifically. Resolving this matters clinically
    because it determines whether accessory pathways in a variant-positive child
    can still be prevented, or only treated once formed.
  proposed_experiments:
  - experiment_id: exp_prkag2_av_canal_lineage_tracing
    name: Lineage tracing of atrioventricular canal myocardium in a PRKAG2 model
    description: >-
      Use inducible lineage tracing of embryonic atrioventricular canal
      myocardium in a PRKAG2 variant mouse to determine whether the myocytes
      forming the accessory connections descend from embryonic AV canal
      myocardium that failed to regress, or are working myocytes that breached
      the annulus postnatally. Pair with staged histology of annulus fibrosus
      integrity across development.
  evidence:
  - reference: PMID:11827995
    reference_title: "Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "either embryonic atrioventricular connections that normally regress during heart development persist in individuals with PRKAG2 mutations, or metabolic deposits activate quiescent accessory pathways"
    explanation: >-
      States the two competing explanations as an explicitly open question.
      Evidence source is OTHER because this is the authors' framing of an
      unresolved problem in discussion, not a data-supported finding.
  - reference: PMID:18158359
    reference_title: "Reversibility of PRKAG2 glycogen-storage cardiomyopathy and electrophysiological manifestations."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Transgene suppression during early postnatal development prevented the development of accessory electrical pathways but not cardiomyopathy or conduction system degeneration."
    explanation: >-
      Establishes a developmental window specific to the accessory-pathway arm,
      which bears on but does not settle the origin question. Marked PARTIAL for
      that reason.

📚

References & Deep Research

Deep Research

1

Claude Code ▸

PRKAG2 Cardiac Syndrome — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 19 citations 2026-07-31T17:03:00.802269

PRKAG2 Cardiac Syndrome — Comprehensive Research Report

1. Disease Information

Overview

PRKAG2 cardiac syndrome (also called PRKAG2 syndrome, PRKAG2 cardiomyopathy, or glycogen-storage cardiomyopathy) is a rare, autosomal dominant, non-lysosomal glycogen storage disease of the heart caused by activating mutations in PRKAG2, the gene encoding the regulatory γ2 subunit of AMP-activated protein kinase (AMPK). It is a genocopy/phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM): patients present with left ventricular hypertrophy (LVH) that is caused not by sarcomeric protein dysfunction but by massive intramyocyte glycogen accumulation. The disease's defining clinical triad is cardiac hypertrophy, ventricular pre-excitation (Wolff-Parkinson-White syndrome, WPW), and progressive cardiac conduction system disease (Gollob et al., NEJM 2001, PMID:11407343; Arad et al., Circulation 2003, PMID:12782567).

Key Identifiers

Gene: PRKAG2 (HGNC:9385), chromosome 7q36.1 (candidate region originally mapped as 7q34–q36)
OMIM gene: 602743 – Protein Kinase, AMP-Activated, Gamma-2 Non-Catalytic Subunit; PRKAG2
OMIM phenotypes:
#194200 – Wolff-Parkinson-White syndrome (WPW), familial, PRKAG2-related
#261740 – Glycogen Storage Disease of Heart, Lethal Congenital (severe infantile/neonatal form)
(Some literature also cross-references the entry historically as "familial hypertrophic cardiomyopathy 6 / CMH6" phenotype territory, though the modern preferred label is PRKAG2 cardiac syndrome/PRKAG2 syndrome)
MONDO: A specific PRKAG2-cardiac-syndrome MONDO term was not confidently resolved via search in this pass — verify with runoak -i sqlite:obo:mondo search before curation (candidate: search terms "PRKAG2 syndrome" / "glycogen storage disease of heart" in MONDO).
ICD-10: Falls generically under I42.- (Cardiomyopathy); no PRKAG2-specific ICD-10 code exists.
Orphanet: Orphanet lists "PRKAG2 cardiac syndrome" as a distinct entity — verify ORPHA number via just fetch-reference ORPHA:<code> lookup or Orphadata search before citing.

Synonyms

PRKAG2 syndrome (PS)
PRKAG2 cardiomyopathy
Cardiac glycogenosis due to PRKAG2 mutation / PRKAG2-related glycogen storage cardiomyopathy
Familial Wolff-Parkinson-White syndrome with cardiac hypertrophy
Glycogen storage disease of the heart (lethal congenital form, for the severe neonatal phenotype)
WPW syndrome, familial, with or without cardiomyopathy

Evidence Basis

Nearly all data are aggregated disease-level resources: OMIM entries, multicenter/multinational retrospective cohort studies (the largest being a 27-center, 90-subject natural history study — Thevathasan et al., JACC 2020, PMID:32646569), single/multi-family pedigree case series, and transgenic/iPSC model-organism mechanistic studies. No large-scale population EHR studies exist owing to disease rarity.

2. Etiology

Disease Causal Factors

PRKAG2 cardiac syndrome is a monogenic, Mendelian disorder. It is caused by heterozygous, dominant, gain-of-function (constitutively activating) missense mutations in PRKAG2, which encodes the γ2 regulatory subunit of AMPK — a heterotrimeric (α/β/γ) serine/threonine kinase that is the master sensor of cellular energy status (AMP:ATP ratio). There is no known environmental, infectious, or purely multifactorial etiology; this is a purely genetic cardiomyopathy.

Genetic Risk Factors

Causal variants cluster in the cystathionine-β-synthase (CBS) domains of the γ2 subunit, which form two tandem Bateman domains that bind AMP/ADP/ATP competitively and allosterically regulate kinase activity:
R302Q (CBS1 domain) — the single most frequently reported variant, seen across many unrelated families/geographic cohorts (South Asian cohort of 22 patients all carrying R302Q — PMID:33244021)
H383R — associated with a more severe phenotype, including pediatric/antenatal presentations
T400N — CBS2 domain; mouse-model workhorse mutation, myocyte vacuolation with minimal fibrosis
N488I — linker region between CBS domains; the principal transgenic-mouse disease model mutation
R531Q/R531G — CBS3 domain; the recurrent mutation causing the lethal congenital/neonatal form (OMIM #261740) — biochemically shows >100-fold reduced AMP/ATP binding affinity but enhanced basal kinase activity (related ClinVar/OMIM entries)
K290I/K291I (nomenclature varies slightly by transcript numbering across papers) — large Brazilian kindred, 66 members studied over 18 years, 19 carriers (PMID:39082507)
Additional reported variants: L341S, H401Q, V336I (Val336Ile), G75A, P198R, H222R, S143= (silent, pathogenic via splicing)
De novo mutations occur and are reported to cause particularly early-onset, severe heart failure (PLOS ONE, PMC3669303).
No established genetic protective factors or modifier alleles are described in the literature to date; no GWAS-identified susceptibility loci exist (this is fully penetrant-monogenic, not polygenic/complex).

Environmental Risk Factors

None established — this is a purely genetic disorder. No toxin, lifestyle, or occupational exposure has been implicated as causal. Age and sex are relevant only insofar as disease expression is age-dependent (see Temporal Development, §8) — the largest natural history cohort found a slight male predominance in several cohorts (e.g., South Asian cohort 68% male).

Protective Factors

None specific to the disease etiology are documented. At the mechanistic/experimental level, pharmacologic and genetic normalization of AMPK signaling is protective in animal models (see Mechanism, §6, and Treatment, §12) — e.g., transgene suppression (tetracycline-repressible system) reverses cardiomyopathy in mice (Wolf et al., Circulation 2008, PMID:18158359), and co-expression of a dominant-negative α2-AMPK subunit partially/completely normalizes the phenotype in compound-heterozygous mice, implicating the α2 catalytic subunit as the principal disease-mediating partner.

Gene-Environment Interactions

No documented gene-environment interaction data exist for PRKAG2 syndrome; disease expression appears to be driven by genotype (which specific CBS-domain mutation) and, secondarily, by age/developmental stage rather than by identified external modifiers.

3. Phenotypes

Cardiac Phenotypes (symptoms/signs, per Thevathasan et al. 2020, PMID:32646569, n=90, 27 centers, median follow-up 6 years)

Phenotype	Frequency (baseline → follow-up)	Suggested HP term*
Left ventricular hypertrophy	67% → 71%	HP:0001712 (Left ventricular hypertrophy) — verify
Ventricular pre-excitation / WPW	~33% at baseline (30/90 with pre-excitation or prior AP ablation)	HP:0001716 (Wolff-Parkinson-White syndrome) — verify
Atrial fibrillation	18% → 29%	(Atrial fibrillation HP term — verify)
Need for de novo pacemaker	19% baseline pacemakers (median implant age 36y) → 21% additional by follow-up	(Atrioventricular block / Sinus node dysfunction HP terms — verify)
Heart failure hospitalization	— → 14%	—
Sudden cardiac death / equivalent	— → 8%	—
Heart transplantation	— → 4%	—
Death (all-cause)	— → 13%	—

South Asian R302Q cohort (n=22, PMID:33244021): LVH 86%, WPW pattern 77%, pacemaker 36%, AF 14%, SCD 27% — illustrating substantial genotype/cohort-dependent variability.

Symptom presentation frequently includes palpitations (~48% in some case series), syncope/pre-syncope, chest pain/angina, exertional dyspnea, and progressive systolic dysfunction (eccentric LV hypertrophy pattern, contrasting with the concentric/asymmetric septal pattern typical of sarcomeric HCM).

Extracardiac Phenotypes

Neurocognitive/psychiatric: learning disability, intellectual disability, anxiety, aggression, mood disturbance, speech disorder — reported "only in carriers of mutations" in the Brazilian K290I/K291I kindred (PMID:39082507).
Obstetric: increased spontaneous abortion, premature/neonatal death, forceps deliveries, and cesarean deliveries reported in affected female carriers in the same kindred (mechanistically unexplained; possibly reflects placental AMPK expression, since AMPK is highly expressed in placenta).
Skeletal muscle: AMPK is expressed in skeletal muscle and glycogen storage/myopathy has been reported in some case reports, but this is not consistently observed across cohorts (absent in the Brazilian cohort).
Pseudotumor cerebri reported in at least one case (PMID:29298659) — likely incidental/anecdotal rather than a core feature.
Sensorineural hearing loss: not substantiated in the literature reviewed here (searched specifically; no clear supporting citation found) — do not curate without a direct source.
Hepatic involvement: at least one case report describes PRKAG2 variant presenting with liver cirrhosis in a family (BMC Med Genomics, PMC7845137) — AMPK is expressed in liver; this appears to be a rare/atypical presentation and should be treated as a single-family observation, not a core phenotype.

Phenotype Characteristics

Age of onset: Highly variable — from lethal congenital/neonatal-onset (severe R531Q-type mutations) through childhood-onset WPW (often the earliest sign, sometimes without LVH) to adult-onset progressive LVH/conduction disease (median age at cohort entry ~33–39 years across studies).
Severity/progression: Progressive — LVH and conduction disease worsen over time; pre-excitation may be an early, isolated finding that precedes hypertrophy by years. The disease is explicitly noted to progress toward a "burned-out phase" resembling dilated cardiomyopathy/advanced heart failure in some patients (Circ Heart Failure 2024 case report).
Penetrance: Age-dependent and incomplete at young ages — one cohort reported penetrance of only 31% by age ≤40 years, rising to 76% of patients showing signs/symptoms by end of follow-up, despite fully penetrant genotype-carrier status ultimately expected with dominant inheritance.

Quality of Life Impact

Not systematically quantified with standard instruments (EQ-5D/SF-36) in the literature surveyed; impact is inferred from the high burden of pacemaker implantation at young ages (median 36 years), heart failure hospitalization, and premature mortality/SCD risk — all of which substantially affect functional status and psychosocial burden, compounded by the reported neurocognitive/psychiatric extracardiac features in at least one large kindred.

*Note: HP term IDs above should be independently verified with runoak -i sqlite:obo:hp info <ID> -O obo per dismech's anti-hallucination policy before being committed to a KB entry — this report flags them as unverified suggestions only.

4. Genetic/Molecular Information

Causal Gene

PRKAG2 — HGNC:9385, chromosome 7q36.1, encodes the γ2 regulatory subunit of AMP-activated protein kinase (AMPK). OMIM gene entry *602743.

Pathogenic Variant Classes and Structural/Functional Consequences

Missense mutations cluster in the two tandem Bateman domains (four CBS repeats) that form the nucleotide-sensing regulatory module of γ2: - R302Q (CBS1): computational modeling suggests decreased ATP-binding affinity (eBioMedicine, Yang et al. 2020 — direct abstract text not retrievable in this session, cite with caution and re-verify before use) - H383R, T400N (CBS2): alter orientation of adjacent H383/R531 residues, altering nucleotide binding - N488I (linker) and L341S: cause structural instability in the Bateman domain, disrupting intramolecular (CBS-domain) autoinhibitory regulation - R531Q (CBS3): >100-fold reduced AMP/ATP binding affinity but enhanced basal kinase activity and increased α-subunit phosphorylation — the mechanistic basis for the most severe, lethal congenital phenotype

Net functional consequence: all disease-causing variants are gain-of-function / constitutively activating with respect to AMPK signaling (chronic/inappropriate AMPK activation), rather than loss-of-function — this is the opposite direction from what might be assumed for a "regulatory subunit mutation," and is a key mechanistic point.

Variant classification (ACMG/ClinVar): Most well-established variants (R302Q, N488I, T400N, H383R, R531Q) are classified Pathogenic/Likely Pathogenic in ClinVar under both the WPW (#194200) and lethal congenital glycogen storage disease (#261740) phenotype associations.
Allele frequency: These variants are essentially absent or present only as extreme rarities in population databases (gnomAD) consistent with a highly penetrant, severe autosomal dominant Mendelian disease under purifying selection — exact gnomAD allele counts were not retrieved in this search pass and should be confirmed directly in gnomAD before citing specific frequencies.
Somatic vs. germline: Germline only; no somatic/mosaic PRKAG2 cardiac disease is described.
Modifier genes: None firmly established in humans; in mice, co-expression of a dominant-negative AMPK α2 catalytic subunit transgene substantially rescues the γ2-N488I phenotype, implicating α2 as a key downstream modifier/mediator (not yet translated to a human modifier-gene finding).

Epigenetic Information

No disease-specific DNA methylation, histone modification, or chromatin-level studies specific to PRKAG2 syndrome were identified in this search pass.

Chromosomal Abnormalities

None — this is a single-gene missense-mutation disorder; no relevant aneuploidy, translocation, or CNV mechanism is described.

5. Environmental Information

No specific environmental toxin, occupational exposure, dietary factor, or infectious trigger is implicated in PRKAG2 cardiac syndrome onset or severity in the literature reviewed. This section is not substantially applicable for this purely monogenic disorder.

6. Mechanism / Pathophysiology

Causal Chain (Molecular → Cellular → Tissue → Organ)

Trigger (molecular): Germline missense mutation in a CBS domain of AMPK γ2 subunit → loss of normal AMP/ADP/ATP-dependent allosteric inhibition of the α-catalytic subunit → constitutive/inappropriate activation of AMPK even under normal cellular energy (ATP-replete) conditions.
Molecular consequence: Chronically active AMPK phosphorylates and activates downstream effectors of glucose uptake and glycogen synthesis, notably glycogen synthase and AS160/TBC1D4 (regulator of GLUT4 translocation) — "Acute expression of gamma(2)R302Q induces AMPK activation and upregulation of glycogen synthase and AS160, with an associated increase in glycogen content" (PMID:20031621). Notably, AMPK activity and glycogen content show a complex, partly inverse relationship over time, suggesting feedback dysregulation rather than simple linear causation.
Cellular consequence: Cardiomyocytes accumulate massive, membrane-bound, non-lysosomal glycogen deposits ("vacuolated myocytes") — in the N488I transgenic mouse model, cardiac glycogen reached ~30-fold above normal levels (Arad et al., Circulation 2003, PMID:12782567). Metabolically, mutant cardiomyocytes (iPSC-CM models) show reduced glycolytic function, increased maximal mitochondrial respiration with elevated mitochondrial content, increased lipid storage, and altered redox regulation (Cell Reports, PIIS2211-1247(16)31640-0).
Tissue consequence — mechanism of ventricular pre-excitation (WPW): Glycogen-filled myocytes physically disrupt the annulus fibrosus, the normal fibrous insulating ring that electrically isolates the atria from the ventricles. This produces anomalous microscopic atrioventricular myocardial connections — rather than a single discrete morphologically distinct accessory bypass tract as in idiopathic WPW — providing the anatomic substrate for ventricular pre-excitation (Arad et al. 2003, PMID:12782567; the same authors note this mechanism likely generalizes to pre-excitation seen in other glycogen-storage cardiomyopathies such as Pompe and Danon disease).
Organ consequence: Progressive glycogen-driven myocyte hypertrophy and vacuolation → left ventricular hypertrophy (eccentric pattern, distinct from sarcomeric HCM's typical asymmetric septal hypertrophy with myofiber disarray) → progressive degeneration of the cardiac conduction system (sinus node dysfunction, AV block) → arrhythmia (WPW-mediated SVT, atrial fibrillation, ventricular tachyarrhythmia) → heart failure / sudden cardiac death.

Key Distinguishing Histopathology

"PRKAG2 syndrome is defined by vacuolated myocytes with glycogen deposits, minimal fibrosis, and absence of sarcomeric disarray" — a critical differentiator from sarcomeric HCM (myofiber disarray + fibrosis) on endomyocardial biopsy.

Reversibility (mechanistic proof-of-concept)

Using an inducible, tetracycline-repressible transgenic N488I mouse model, suppression of mutant AMPK expression (at various developmental time points, including prenatally) reduced cardiac glycogen content and reversed the cardiomyopathy, pre-excitation, and conduction system degeneration phenotypes (Wolf et al., Circulation 2008, PMID:18158359) — direct causal evidence that ongoing AMPK hyperactivity (not just a fixed developmental lesion) drives the phenotype, and that the disease could in principle be therapeutically targetable.

Molecular Pathways / GO Suggestions (verify before curation)

Molecular function: AMP-activated protein kinase activity (GO:0004679, protein serine/threonine kinase activity variant — verify exact ID)
Biological process: glycogen biosynthetic process (GO:0005978); positive regulation of glycogen biosynthetic process; cellular response to AMP; regulation of AMP-activated protein kinase activity
Cellular component: AMP-activated protein kinase complex (GO:0031588)

Cell Types / Anatomical Involvement (CL/UBERON suggestions, verify before curation)

Cardiac muscle cell / cardiomyocyte (CL:0000746)
Cardiac conduction system myocyte (sinoatrial node cell, atrioventricular node cell)
UBERON: myocardium (UBERON:0002349), annulus fibrosus of heart / cardiac skeleton, atrioventricular node, sinoatrial node

Molecular Profiling / Omics

iPSC-CM transcriptomic/metabolomic studies show remodeling of gene expression favoring glycogen storage and oxidative metabolism over glycolysis in mutant cells.
AMPK activator metformin treatment of PRKAG2-mutant iPSC-CMs normalized oxygen consumption rate parameters, "eliminating the bioenergetic abnormalities" — an intriguing but counterintuitive finding (since AMPK is already overactive) suggesting complex/paradoxical pharmacology in this model (Frontiers Cardiovasc Med, PRKAG2 iPSC-CM WPW study).
Integrative iPS/microtissue analysis identifies AMPK as a broader "regulator of metabolism, survival, and fibrosis" with implications extending to other cardiomyopathies (Cell Reports 2016).

7. Anatomical Structures Affected

Organ Level

Primary: Heart (ventricular myocardium, atrioventricular conduction axis, sinoatrial node, atrioventricular node, annulus fibrosus/cardiac fibrous skeleton, atria — atrial lesions also reported in pedigree studies, PMC8960295)
Secondary: Skeletal muscle (glycogen storage, variably reported), liver (rare reports of cirrhosis in one kindred), central nervous system (neurocognitive/psychiatric features in at least one large kindred)
Body systems: Cardiovascular system predominant; possible musculoskeletal, hepatic, and neuropsychiatric secondary involvement (heterogeneously reported, not core/universal features)

Tissue and Cell Level

Cardiac/striated muscle tissue — vacuolated cardiomyocytes with intracytoplasmic, non-membrane-bound (non-lysosomal) glycogen deposits
Cardiac conduction tissue — nodal and junctional myocytes disrupted by glycogen infiltration

Subcellular Level

Cytoplasm (glycogen granule accumulation — non-lysosomal, distinguishing from Pompe disease's lysosomal glycogen storage)
Mitochondria (increased mitochondrial content/respiration reported in iPSC-CM models)
GO Cellular Component candidates: cytoplasm, glycogen granule, mitochondrion — verify specific terms before curation

Localization

Bilateral/global cardiac involvement (not lateralized); LVH typically eccentric rather than the asymmetric septal pattern of sarcomeric HCM.

8. Temporal Development

Onset

Congenital/neonatal (lethal form): R531Q and similar highly-activating CBS3 mutations cause massive cardiomegaly with cardiac/respiratory distress at birth, death typically between 3 weeks and 5 months of age (OMIM #261740).
Childhood: Isolated ventricular pre-excitation (WPW) without hypertrophy has been reported as an early/pediatric presentation, preceding overt cardiomyopathy by years (Circulation, "Novel PRKAG2 Mutation... Childhood Onset and Absence of Cardiac Hypertrophy").
Adult: Most large cohorts show median age at diagnosis/enrollment in the 30s–40s, with progressive LVH, conduction disease, and pacemaker requirement (median implant age 36 years).

Progression

Generally progressive: LVH prevalence increases over follow-up (67%→71% over ~6 years in the largest cohort), AF increases (18%→29%), pacemaker need accrues over time.
Disease course is described as capable of culminating in a "burned-out phase" resembling dilated/advanced heart failure.
Progression rate is genotype-dependent — some mutations (e.g., R531Q, H383R) cause rapid, severe/lethal early progression; others (e.g., some R302Q-associated presentations) show slower, adult-onset progression.

Patterns

No spontaneous remission is described; disease is chronic and lifelong once manifest.
Reversibility has only been demonstrated experimentally (transgene suppression in mice), not yet in human therapeutics.
No clearly defined "critical window" for intervention has been established in humans, though the mouse reversibility data (including prenatal suppression) suggest a rationale for early intervention if disease-modifying therapy becomes available.

9. Inheritance and Population

Epidemiology

True population prevalence is unknown / not well characterized — this is an ultra-rare disease.
Among patients evaluated for suspected hypertrophic cardiomyopathy, PRKAG2 variants are estimated at ~0.23–1% prevalence.
Prevalence rises to as much as 29% in the specific subgroup of patients presenting with both LVH and pre-excitation — a much higher pretest probability subgroup for genetic testing.
One older estimate (Murphy et al.) put prevalence at ~1% among patients with combined HCM and premature sinoatrial/AV conduction disease.
The disease is considered underdiagnosed given phenotypic overlap with sarcomeric HCM and other glycogen storage cardiomyopathies.

Inheritance Pattern

Autosomal dominant. De novo mutations are also reported (causing early-onset severe disease in the absence of family history).

Penetrance

Age-dependent and incomplete at young ages: one cohort reported only 31% penetrance by age 40, rising to 76% of genotype-positive individuals showing signs/symptoms by end of follow-up. This nuances the "full penetrance" label sometimes applied and has direct implications for family screening/surveillance intervals.

Expressivity

Highly variable — even within the same family/same variant, phenotype severity ranges from isolated pre-excitation without hypertrophy to lethal neonatal cardiomyopathy, and genotype-phenotype correlations (e.g., R531Q → lethal congenital form; H383R → severe pediatric/antenatal form; R302Q → variable adult-onset spectrum) are only partially predictive.

Genetic Anticipation

Not established/reported as a feature of this disease (unlike repeat-expansion disorders).

Germline Mosaicism

Not specifically documented in the literature reviewed; de novo cases are described but germline mosaicism specifically is not detailed.

Founder Effects

Not clearly established as a global founder phenomenon, though recurrent large single-family/single-population cohorts (e.g., the South Asian family cohort all sharing R302Q, the Brazilian kindred sharing K290I/K291I) suggest regional/familial founder-type recurrence rather than true independent recurrent mutation in every case — this needs formal haplotype study to confirm.

Consanguinity Role

Not implicated — autosomal dominant disease does not require biallelic inheritance; no consanguinity association reported.

Population Demographics

Reported cohorts span South Asian, Brazilian, Chinese, and Caucasian/European-ancestry families — the disease is not confined to a single ethnic group.
Slight male predominance noted in some cohorts (e.g., 68% male in the South Asian cohort; 53% men in the largest natural history cohort), though this may partly reflect referral/ascertainment bias rather than true sex-linked penetrance difference (the gene is autosomal, not X-linked).
Sudden cardiac death risk in young patients (<40 years) has been cited as high as ~20% in some early WPW-focused cohorts.

10. Diagnostics

Clinical Tests

ECG: Short PR interval, delta wave (ventricular pre-excitation/WPW pattern); progressive PR prolongation and AV block over time; sinus node dysfunction/chronotropic incompetence.
Echocardiography: LVH, typically eccentric pattern (vs. asymmetric septal in sarcomeric HCM); reduced EF in advanced/"burned-out" cases.
Cardiac MRI: Used to characterize myocardial tissue in PRKAG2 mutation carriers (PMC4619453) — helps differentiate from sarcomeric HCM (e.g., late gadolinium enhancement/fibrosis patterns may differ given the "minimal fibrosis" histopathology).
Endomyocardial biopsy: Vacuolated myocytes with glycogen-filled vacuoles (PAS-positive, diastase-sensitive glycogen), minimal fibrosis, no myofiber disarray — a key differentiator from sarcomeric HCM.
Electrophysiology study: Characterizes accessory pathway location/multiplicity (often diffuse/microscopic rather than a single discrete bypass tract) and conduction system disease extent.

Genetic Testing

Recommended approach: Targeted PRKAG2 sequencing or inclusion in HCM/cardiomyopathy gene panels, particularly triggered by the combination of LVH + pre-excitation or LVH + early pacemaker requirement.
Panel context: PRKAG2 is a standard component of clinical hypertrophic cardiomyopathy / arrhythmia gene panels alongside sarcomeric genes (MYH7, MYBPC3, etc.) and other glycogen-storage-cardiomyopathy genes (LAMP2 for Danon disease, GAA for Pompe disease).
Single-gene testing is appropriate when the phenotype (LVH + WPW + early conduction disease, especially with a family history suggestive of autosomal dominant inheritance) is highly specific.

Clinical Criteria / Differential Diagnosis

The key differential is against other glycogen-storage or lysosomal-storage cardiomyopathies presenting with LVH + pre-excitation: - Danon disease (LAMP2, X-linked): Distinguished by retinal involvement (a key discriminating exam finding not seen in PRKAG2 or Pompe disease), skeletal myopathy, and intellectual disability; X-linked with more severe disease in males. - Fabry disease (GLA, X-linked): Considered in the differential given severity of LVH; distinguished by systemic features (angiokeratoma, renal disease, neuropathic pain, corneal verticillata). - Pompe disease (GAA, lysosomal, autosomal recessive): Also produces glycogen-storage-related pre-excitation via the same annulus-fibrosus-disruption mechanism, but is lysosomal (acid maltase deficiency) and typically has more prominent skeletal myopathy/respiratory involvement. - Sarcomeric HCM: Myofiber disarray + fibrosis on biopsy (absent in PRKAG2 syndrome); different genetic panel (MYH7, MYBPC3, TNNT2, etc.).

Screening

Cascade genetic testing/family screening is indicated once a proband's pathogenic PRKAG2 variant is identified, given autosomal dominant inheritance and age-dependent penetrance (necessitating longitudinal, not one-time, screening of at-risk relatives).
No population-based newborn screening program exists specifically for PRKAG2 syndrome.

11. Outcome / Prognosis

Survival and Mortality

In the largest natural history cohort (n=90, median follow-up 6 years): 13% all-cause mortality, 8% sudden cardiac death or equivalent, 4% required heart transplantation (PMID:32646569).
The lethal congenital form (severe CBS3-domain mutations, e.g., R531Q) has a uniformly fatal neonatal/infantile course, with death typically between 3 weeks and 5 months of age due to heart failure and respiratory compromise (OMIM #261740).
Historical estimates of premature (<40 years) sudden cardiac death as high as ~20% have been cited in early WPW-focused PRKAG2 cohorts.
Overall, PRKAG2 syndrome is characterized in the literature as carrying a "poor prognosis with a high rate of complications" — juvenile-onset conduction disease, advanced heart failure, and potentially lethal arrhythmias.

Morbidity and Functional Outcomes

High burden of pacemaker implantation (19–36% across cohorts, median implant age ~36 years) due to progressive AV block/sinus node dysfunction.
Heart failure hospitalization in ~14% over 6-year follow-up; progressive LV systolic dysfunction (EF decline to <50%) reported in up to 45% of one cohort over time.
Neurocognitive/psychiatric morbidity reported in at least one large kindred (learning disability, intellectual disability, anxiety, mood disorders).

Disease Course / Complications

Atrial fibrillation is a major and increasing complication over time (18%→29% in the largest cohort).
Progression to a "burned-out," dilated-cardiomyopathy-like advanced heart failure phase is described in case reports, distinct from typical sarcomeric HCM's more stable/hypertrophic-restrictive course.
Recovery/regression of cardiomyopathy has only been shown experimentally in animal models via genetic suppression of mutant AMPK expression (not yet clinically achievable).

Prognostic Factors

Specific genotype is a major prognostic determinant: R531Q/severe CBS3 mutations → lethal congenital course; other variants → more variable adult-onset course.
Early pre-excitation without hypertrophy in childhood may herald later progression to overt cardiomyopathy and conduction disease and warrants close longitudinal follow-up.
Presence of pre-excitation, early pacemaker requirement, and young age at conduction disease onset are red flags distinguishing PRKAG2 syndrome from sarcomeric HCM and are associated with the classic high-risk phenotype.

12. Treatment

Pharmacotherapy

No disease-modifying/curative pharmacotherapy currently exists for humans; management is symptomatic/supportive:
Antiarrhythmic drugs for arrhythmia control
Anticoagulation for atrial fibrillation (stroke prevention)
Standard heart-failure pharmacotherapy for those progressing to systolic dysfunction
Experimental/preclinical: The AMPK activator metformin normalized bioenergetic abnormalities in PRKAG2-mutant iPSC-derived cardiomyocytes in vitro — an early, paradoxical proof-of-concept finding (activating AMPK further via a different route ameliorated the metabolic phenotype), not yet validated in animal models or humans; should be treated as a research finding, not a clinical recommendation.
Patents exist for antibody-oligonucleotide conjugates targeting PRKAG2 and other approaches to cytoplasmic glycogen storage disorders, indicating active pharmaceutical-industry interest in RNA-based/targeted knockdown approaches (patent literature only — not yet in clinical trials per the searches performed here).

Advanced Therapeutics

Gene therapy / RNA-based therapy (ASO, siRNA) targeting mutant PRKAG2 transcript is a plausible therapeutic modality given the gain-of-function, single-gene, dominant mechanism (analogous to RNase-H knockdown ASO strategies used in other dominant-gain-of-function cardiac/systemic diseases), but no approved or clinical-trial-stage RNA therapeutic specific to PRKAG2 syndrome was identified in this search.
No CRISPR/gene-editing, cell therapy, or immunotherapy approaches are reported for this indication.

Surgical and Interventional

Catheter (radiofrequency) ablation of accessory pathways: used but arrhythmias frequently recur because the diffuse, microscopic glycogen-mediated AV connections (rather than a single discrete bypass tract) provide a poor substrate for definitive ablative cure — in one cohort only 2 of 22 patients underwent AP ablation over 7-year follow-up, reflecting both diffuse substrate and disease-course considerations.
Permanent pacemaker implantation: the mainstay intervention for progressive AV block/sinus node dysfunction (36% in one cohort; median implant age 36 years); often required at unusually young ages compared to typical age-related conduction disease, a key diagnostic clue.
Septal myectomy has been used for outflow obstruction in select cases, alongside coronary "unroofing" procedures in reported case reports with concurrent anomalies.
Heart transplantation: indicated for end-stage heart failure; ~4% of the largest cohort required transplantation by 6-year median follow-up; early referral while the patient remains a good surgical candidate is recommended in the literature.

Supportive/Rehabilitative Care

Standard heart failure and arrhythmia supportive care; no PRKAG2-specific rehabilitation protocols identified.

Experimental

No PRKAG2-syndrome-specific registered clinical trials were identified in this search pass; searches of ClinicalTrials.gov specifically for PRKAG2 interventional trials should be performed directly before curation (not completed in this session).

Treatment Strategy

Management is largely algorithmic/consensus-based rather than evidence-based from randomized trials (given disease rarity): early genetic diagnosis to distinguish from sarcomeric HCM (important because standard HCM therapies like septal reduction have variable relevance), arrhythmia/conduction surveillance with a low threshold for pacemaker implantation, anticoagulation for AF, and heart failure management with early transplant evaluation for those progressing to end-stage disease.

Suggested NCIT Terms (verify before curation)

NCIT:C15329 (Surgical Procedure) — for ablation/myectomy
NCIT:C15986 (Pharmacotherapy) — for antiarrhythmics/anticoagulants
NCIT:C15289 (Organ Transplantation) — for heart transplant
A specific NCIT term for "pacemaker implantation" should be looked up directly (not confidently identified in this pass)

13. Prevention

Primary/Secondary/Tertiary Prevention

No primary prevention exists (monogenic disease; risk factor modification is not applicable).
Secondary prevention = family cascade genetic screening, given autosomal dominant inheritance and age-dependent, incomplete penetrance — relatives of a confirmed proband should undergo genetic testing and, if positive, longitudinal cardiac surveillance (ECG, echocardiography) rather than a single-timepoint screen, since penetrance increases with age.
Tertiary prevention in established disease centers on early pacemaker implantation to prevent sudden death from advanced conduction disease, anticoagulation to prevent stroke in AF, and arrhythmia surveillance/ICD consideration in high-risk individuals (specific ICD/SCD-risk-stratification criteria for PRKAG2 syndrome specifically were not detailed in the sources reviewed and should be checked against current HCM/arrhythmia society guidelines before curation).

Genetic Counseling

Recommended for affected families given autosomal dominant inheritance, variable expressivity (ranging from isolated pre-excitation to lethal neonatal disease), and reported reproductive/obstetric complications in at least one large kindred — prenatal counseling and, potentially, preimplantation genetic testing may be relevant for families with known severe/lethal variants (e.g., R531Q), though this specific application was not directly documented in the literature reviewed.

Screening

Genetic cascade screening (as above) is the primary applicable "screening" modality; no population-based newborn or general screening program exists for this ultra-rare disease.

14. Other Species / Natural Disease

No naturally occurring PRKAG2-orthologous cardiac disease in companion animals or wildlife was identified in this search (unlike, e.g., the well-characterized porcine PRKAG3 R200Q "RN-" gene affecting pork quality via skeletal muscle glycogen — note this is a different AMPK gamma subunit gene, γ3, not γ2, and a different tissue, skeletal muscle not heart; do not conflate the two in curation). No OMIA entry for a natural PRKAG2 cardiac disease analog was found. This section is not substantially populated for this disease in the current literature.

15. Model Organisms

Mouse (primary model)

Transgenic overexpression models (α-myosin heavy chain promoter-driven mutant γ2 transgenes) — the flagship model uses the N488I mutation:
Elevated AMPK activity, ~30-fold increase in cardiac glycogen, dramatic LVH, ventricular pre-excitation, and sinus node dysfunction, closely recapitulating the human phenotype (Arad et al., Circulation 2003, PMID:12782567).
T400N transgenic hearts also show vacuolated myocytes, glycogen excess, hypertrophy, and pre-excitation.
R302Q transgenic/knock-in mouse models show biphasic AMPK activity changes and do not confer ischemic protection despite chronic AMPK activation (PMID:17597581), and develop myocardial insulin resistance (PMC3707764).
Inducible (tetracycline-repressible) N488I model: demonstrates that suppressing mutant transgene expression at various life stages (including prenatally) reverses glycogen accumulation, cardiomyopathy, and conduction system degeneration — direct causal/reversibility evidence (Wolf et al., Circulation 2008, PMID:18158359).
Compound-heterozygous rescue model: co-expression of a dominant-negative α2-AMPK subunit transgene (TGα2DN) with the γ2-N488I transgene partially/completely normalizes ECG, cardiac function, morphology, and exercise capacity — implicates α2 as the key catalytic mediator of the disease phenotype and is a useful genetic-epistasis tool for mechanism dissection.

Human iPSC-derived cardiomyocyte models

Patient-derived iPSC-CMs (R302Q) and TALEN-genome-engineered isogenic iPSC-CM lines recapitulate glycogen accumulation, lipid storage, altered redox regulation, reduced glycolysis, and increased mitochondrial respiration — useful for mechanistic and drug-screening studies (e.g., the metformin rescue finding) (Cell Reports 2016; Frontiers Cardiovasc Med 2026).
Microtissue (3D engineered cardiac tissue) models extend these findings to fibrosis and survival phenotypes.

Invertebrate Models

Drosophila melanogaster: SNF4Aγ is the fly ortholog of PRKAG1/2/3, sharing 39–57% identity / 53–71% similarity in the CBS/ligand-binding domains with the human genes; required for regulation of developmental and stress-induced autophagy — used to study conserved AMPK-γ biology (lipid metabolism, autophagy, starvation response) rather than a direct cardiac-phenotype disease model, since Drosophila lacks a chambered heart with a conduction system analogous to the mammalian AV node/annulus fibrosus.
No C. elegans or yeast PRKAG2-specific disease models were identified in this search, though AMPK (SNF1 in yeast) is broadly conserved and yeast SNF1/AMPK biology has informed general enzymology of the CBS-domain nucleotide-sensing mechanism.

Model Limitations

Mouse transgenic-overexpression models (rather than physiological knock-in models in all cases) may not perfectly recapitulate human dosage/expression-level effects, though later knock-in-style and inducible models substantially strengthen causal inference.
iPSC-CM models, while capturing metabolic/glycogen phenotypes, do not recapitulate the whole-organ conduction-system anatomy (annulus fibrosus disruption) that is central to the WPW mechanism in vivo — this aspect of pathophysiology is best studied in the mouse models.

Summary Table of Key PMIDs Cited

PMID	First author/Journal/Year	Key content
11407343	Gollob, NEJM 2001	Original gene identification (linkage 7q34-q36 → PRKAG2, R302Q)
12782567	Arad, Circulation 2003	Transgenic N488I/T400N mouse model; annulus fibrosus mechanism of WPW
18158359	Wolf, Circulation 2008	Reversibility of glycogen-storage cardiomyopathy via transgene suppression
32646569	Thevathasan, JACC 2020	Largest natural history cohort (n=90, 27 centers)
33244021	— , Sci Rep 2020	South Asian R302Q cohort (n=22)
39082507	— , Einstein (São Paulo) 2024	Brazilian K290I/K291I kindred, 18-year follow-up, extracardiac features
29298659	— , BMC Med Genet 2018	R302Q case, biopsy vacuolated myocytes, pseudotumor cerebri
17597581	— , PubMed 2007	R302Q mouse model, biphasic AMPK activity, no ischemic protection
20031621	— , PubMed	Early signaling events, glycogen synthase/AS160 upregulation

Note on evidence quality: Several statistics and specific quotes above were retrieved via secondary web-search summarization rather than direct primary-abstract fetch (a number of publisher URLs — jacc.org, ahajournals.org, thelancet.com/ebiom — returned HTTP 403 in this session and could not be directly fetched). Before committing any snippet-level evidence to a dismech KB entry, each PMID must be independently re-verified via just fetch-reference PMID:XXXX against the cached real abstract, per the project's mandatory anti-hallucination SOP — several numeric details here (e.g., exact percentages, exact variant nomenclature such as K290I vs. K291I) should be cross-checked against the primary source before quoting as an exact snippet. Similarly, all suggested HP/GO/CL/UBERON/NCIT/MONDO term IDs in this report are unverified suggestions and must be confirmed with OAK (runoak -i sqlite:obo:<ontology> info <ID> -O obo) before use in curation, consistent with dismech's ontology-term verification policy.

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PRKAG2 Cardiac Syndrome — Comprehensive Research Report

1. Disease Information

Overview

Key Identifiers

Synonyms

Evidence Basis

2. Etiology

Disease Causal Factors

Genetic Risk Factors

Environmental Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Cardiac Phenotypes (symptoms/signs, per Thevathasan et al. 2020, PMID:32646569, n=90, 27 centers, median follow-up 6 years)

Extracardiac Phenotypes

Phenotype Characteristics

Quality of Life Impact

4. Genetic/Molecular Information

Causal Gene

Pathogenic Variant Classes and Structural/Functional Consequences

Epigenetic Information

Chromosomal Abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

Causal Chain (Molecular → Cellular → Tissue → Organ)

Key Distinguishing Histopathology

Reversibility (mechanistic proof-of-concept)

Molecular Pathways / GO Suggestions (verify before curation)

Cell Types / Anatomical Involvement (CL/UBERON suggestions, verify before curation)

Molecular Profiling / Omics

7. Anatomical Structures Affected

Organ Level

Tissue and Cell Level

Subcellular Level

Localization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Inheritance Pattern

Penetrance

Expressivity

Genetic Anticipation

Germline Mosaicism

Founder Effects

Consanguinity Role

Population Demographics

10. Diagnostics

Clinical Tests

Genetic Testing

Clinical Criteria / Differential Diagnosis

Screening

11. Outcome / Prognosis

Survival and Mortality

Morbidity and Functional Outcomes

Disease Course / Complications

Prognostic Factors

12. Treatment

Pharmacotherapy

Advanced Therapeutics

Surgical and Interventional