CAPOS Syndrome

Mendelian MONDO:0011038 Pathograph 12 Show in embeddings browser ATP1A3-related disorder channelopathy hereditary ataxia neurogenetic disorder

CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) is an ultra-rare autosomal dominant neurological disorder caused, in essentially every reported patient, by the single recurrent ATP1A3 missense variant c.2452G>A (p.Glu818Lys). ATP1A3 encodes the neuron-specific alpha-3 subunit of the Na+/K+-ATPase; the p.Glu818Lys substitution cripples sodium handling at the pump's third (sodium-specific) ion-binding site so that the pump cannot be properly activated under physiological conditions. The clinical hallmark is a small number (typically one to three) of febrile-illness-triggered episodes of acute cerebellar ataxia and encephalopathy in infancy or early childhood, each followed by considerable but incomplete recovery, leaving a stepwise-accrued residuum of ataxia, areflexia, optic atrophy, auditory-neuropathy-type hearing loss and pes cavus.

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1
Definitions
1
Inheritance
7
Pathophys.
25
Phenotypes
1
Hypotheses
3
Gaps
12
Pathograph
1
Genes
5
Medical Actions
4
Differentials
1
References
1
Deep Research
🏷

Classifications

Harrison's Chapter
NEUROLOGIC GENETICS_ENVIRONMENT_DISEASE DISORDER_OF_EAR
Channelopathy
neurological channelopathy
📘

Definitions

1
Fever-associated acute ataxia case-finding query for undiagnosed CAPOS
EHR/OMOP case-finding query: identify children with an acute ataxia or acute encephalopathy encounter occurring during or immediately after a documented febrile illness, who subsequently acquire codes for optic atrophy, sensorineural hearing loss or areflexia, as candidates for undiagnosed ATP1A3 p.Glu818Lys CAPOS warranting targeted sequencing. The discriminating feature versus the far commoner acute post-infectious cerebellar ataxia is the later accrual of fixed sensory-organ deficits rather than full recovery. Directly analogous in structure to the Brugada_Syndrome fever-unmasking query, but with derivation_basis MECHANISTIC_HYPOTHESIS rather than ESTABLISHED_CRITERIA because the fever-to-decompensation mechanism in CAPOS is hypothesised (pump reserve failure) rather than demonstrated.
PHENOTYPE_ALGORITHM EHR/OMOP case-finding for undiagnosed CAPOS/ATP1A3-spectrum carriers; predicated on the unvalidated fever_triggered_pump_reserve_failure hypothesis.
Fever-locked acute ataxia with later fixed sensory-organ deficit
An acute ataxia or acute encephalopathy encounter in a child aged roughly 6 months to 5 years, temporally coincident with a documented febrile illness, followed at any later time by a code for optic atrophy, sensorineural hearing loss or areflexia.
Inclusion criteria
  • Documented febrile illness Fever or febrile-illness diagnosis code serving as the index exposure.
  • Acute ataxia or acute encephalopathy encounter Acute-onset ataxia or encephalopathy coded during or within days of the febrile episode.
  • Later fixed sensory-organ or reflex deficit A subsequent code for optic atrophy, sensorineural hearing loss, or areflexia, marking incomplete recovery rather than the monophasic full recovery of post-infectious cerebellar ataxia.
Exclusion criteria
  • Established alternative cause of acute ataxia Posterior fossa tumour, stroke, acute disseminated encephalomyelitis, intoxication, or an already-established ATP1A3 or other genetic diagnosis.
Show evidence (2 references)
PMID:27091223 SUPPORT Human Clinical
"Targeted sequencing of the ATP1A3 gene is recommended in children exhibiting paroxysmal, fever-induced ataxia and in adults with a more or less stationary or slowly progressive cerebellar syndrome since childhood accompanied by mixed combinations of areflexia, pes cavus, profound visual..."
Supplies the clinical logic the query operationalises: fever-induced ataxia plus fixed sensory-organ deficits should trigger ATP1A3 testing.
PMID:28483396 SUPPORT Human Clinical
"The acute symptoms improve within days, but most patients show slow progression afterward."
Supports the discriminating element of the query - incomplete recovery with later accrual of deficit - versus monophasic post-infectious ataxia.
Notes: Counterpart to the Brugada_Syndrome fever-unmasking query (ESTABLISHED_CRITERIA) and the Timothy_Syndrome fever_exacerbated_cav1.2 query (MECHANISTIC_HYPOTHESIS). CAPOS sits with Timothy: the fever association is clinically certain but the mechanism by which fever precipitates decompensation is hypothesised, and the computable phenotype itself is untested. See docs/hypothesis-based-phenotype-algorithms.md.
👪

Inheritance

1
Autosomal dominant, roughly half de novo and half inherited HP:0000006
CAPOS is inherited in an autosomal dominant manner. Unlike the more severe allelic phenotype alternating hemiplegia of childhood, in which the variant is usually de novo, roughly half of individuals with CAPOS inherit the p.Glu818Lys variant from an affected (sometimes mildly or belatedly recognised) parent, and roughly half have an apparently de novo variant. Multigenerational transmission was central to the original gene discovery, which found the identical variant segregating in three independent families.
Autosomal dominant inheritance De novo rate: About half of individuals with CAPOS
Show evidence (3 references)
PMID:20301294 SUPPORT Human Clinical
"ATP1A3-related disorder – including the four historically defined phenotypes of AHC, CAPOS syndrome, RECA/FIPWE, and RDP – is inherited in an autosomal dominant manner."
GeneReviews states autosomal dominant inheritance explicitly for the CAPOS phenotype within the ATP1A3-related disorder spectrum.
PMID:20301294 SUPPORT Human Clinical
"About half of individuals with a relatively less severe ATP1A3-related phenotype (e.g., CAPOS syndrome or RDP) have the disorder as the result of a pathogenic variant inherited from an affected parent; about half of individuals have an apparently de novo pathogenic variant."
Directly supports the roughly 50/50 inherited-versus-de-novo split that distinguishes CAPOS counselling from AHC counselling.
PMID:24468074 SUPPORT Human Clinical
"We undertook genetic analysis of three affected families to identify the cause of dominantly-inherited CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) syndrome."
The gene-discovery study was built on dominantly inherited multiplex families, supporting familial autosomal dominant transmission.
◈

Mechanistic Hypotheses

1
Fever exhausts a marginal neuronal alpha-3 pump reserve
fever_triggered_pump_reserve_failure EMERGING
Evidence balance 2 partial
Hypothesis: in a heterozygous p.Glu818Lys carrier the residual wild-type alpha-3 Na+/K+-ATPase provides just enough pumping capacity for baseline neuronal activity, and febrile illness raises metabolic and firing demand past that margin in the most pump-dependent neurons, producing acute failure of ion-gradient restoration and hence the stereotyped febrile ataxia/encephalopathy episode. This would explain why fever is a near-obligate trigger, why episodes are self-limited once the fever resolves, and why some deficit is nonetheless retained. It predicts that aggressive antipyresis should reduce episode frequency or severity, and that mutant pump function measured at febrile temperature should be disproportionately impaired relative to wild type.
Pathograph links
Impaired Neuronal Transmembrane Ion Gradient Restoration -> Febrile Illness Unmasking of Pump Reserve Failure INDIRECT UNKNOWN INTERMEDIATES
Febrile Illness Unmasking of Pump Reserve Failure -> Acute Febrile Encephalopathy and Cerebellar Decompensation INDIRECT UNKNOWN INTERMEDIATES
Show evidence (2 references)
PMID:30409907 PARTIAL In Vitro
"which together with the reduced Na+ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions"
Establishes a marginal/failing pump at baseline physiological conditions, which is the premise of the reserve hypothesis; the study did not test febrile temperature, so this is PARTIAL support for the fever-specific claim.
PMID:27091223 PARTIAL Human Clinical
"that were consistently associated with febrile illness"
Consistent clinical fever association supports the trigger relationship but does not itself establish the pump-reserve mechanism, hence PARTIAL.
?

Discussions and Knowledge Gaps

3
Does the persistent deficit in CAPOS reflect actual neuronal loss (degeneration) or persistent functional impairment of surviving neurons?
KNOWLEDGE GAP capos_degeneration_vs_dysfunction
Attached to
pathophysiology#Incomplete Recovery and Stepwise Deficit Accrual
This is the central unresolved mechanistic question in CAPOS and it determines whether the disorder belongs with the neurodegenerations at all. The clinical picture - stepwise accrual of fixed deficit after discrete febrile events, with considerable interval recovery - is equally compatible with (a) each episode killing a tranche of vulnerable neurons, or (b) each episode leaving surviving neurons in a persistently deranged but living state. Neuroimaging does not settle it: MRI is frequently unremarkable and only mild cerebellar atrophy has been reported, in isolated cases. No neuropathological study of a CAPOS brain has been published, and no longitudinal quantitative imaging cohort exists. The answer has direct therapeutic consequences, because a functional lesion is in principle reversible while neuronal loss is not. This gap is also the reason CAPOS does not declare conformance to the cerebellar_purkinje_degeneration module.
Proposed experiments
Longitudinal cerebellar volumetry and retinal OCT around febrile episodes
capos_longitudinal_structural_imaging
Longitudinal volumetric MRI of the cerebellum and quantitative optical coherence tomography of the retinal nerve fibre layer in genotyped CAPOS patients, timed around febrile episodes, to test whether fixed structural loss accrues stepwise at each episode.
Would support
Stepwise loss of cerebellar volume and retinal nerve fibre layer thickness time-locked to episodes would support true neuronal loss.
Would refute
Stable structural measures despite accrued clinical deficit would support persistent functional impairment of surviving neurons.
Patient-derived iPSC neuron febrile-temperature challenge
capos_ipsc_febrile_challenge
Patient-derived iPSC neurons (cerebellar and sensory) carrying p.Glu818Lys, challenged at febrile temperature, assayed for both acute ion-gradient failure and subsequent cell death versus persistent functional derangement in survivors.
Would support
Measurable cell death after febrile-temperature challenge would support the degeneration model.
Would refute
Survival with persistent electrophysiological derangement and no excess death would support the functional-impairment model.
Show evidence (1 reference)
PMID:36484864 PARTIAL Human Clinical
"the brain MRI indicated mild cerebellar atrophy"
The only structural evidence bearing on the question is a single case with mild cerebellar atrophy, which is insufficient to establish or exclude neurodegeneration.
Why does the single recurrent p.Glu818Lys allele produce the specific CAPOS lesion set (cerebellum, auditory nerve, optic nerve, dorsal root ganglion) while other ATP1A3 alleles in the same gene produce entirely different lesion sets?
KNOWLEDGE GAP capos_allelic_lesion_selectivity
Attached to
pathophysiology#Impaired Neuronal Transmembrane Ion Gradient Restoration
ATP1A3 is expressed broadly across neurons, yet allelic variants partition into strikingly discrete syndromes: p.Glu818Lys gives CAPOS with sensory organ and peripheral involvement, Arg756 variants give RECA, and a different heterogeneous set gives AHC or rapid-onset dystonia-parkinsonism. The biophysical characterisation of E818K explains that the pump fails, but not why the failure selects cerebellar, auditory, optic and dorsal root ganglion neurons specifically. Candidate explanations - regional differences in alpha-3 dependence, in firing rate and metabolic load, in compensating alpha-1 expression, or in the specific kinetic parameter each variant perturbs - have not been tested against each other. Resolving this would turn ATP1A3 genotype-phenotype correlation from empirical pattern-matching into prediction.
Proposed experiments
Cell-type-resolved alpha-3 pump dependence profiling
capos_celltype_pump_dependence
Cell-type-resolved measurement of alpha-3 versus alpha-1 pump dependence and firing-rate-dependent sodium load across cerebellar Purkinje, spiral ganglion, retinal ganglion and dorsal root ganglion neurons, correlated with each variant's specific kinetic defect.
Would support
A match between the CAPOS lesion set and the neurons with highest alpha-3 dependence and lowest alpha-1 compensation would support a dependence-based selectivity model.
Head-to-head electrophysiology of E818K, R756H and AHC variants
capos_comparative_variant_electrophysiology
Comparative electrophysiological profiling of E818K, R756H and the common AHC variants in a single common expression system, testing whether the distinct clinical lesion sets track distinct kinetic signatures rather than overall pump activity.
Would support
Variant-specific kinetic signatures that predict the clinical lesion set would support parameter-specific rather than dose-dependent selectivity.
Show evidence (1 reference)
PMID:36192182 SUPPORT Human Clinical
"The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study."
Documents the variant-specific phenotype partitioning that this knowledge gap asks the mechanism for.
Do heterologous-expression measurements of E818K pump kinetics, made at standard assay temperature in oocytes and cell lines, predict alpha-3 pump behaviour in human neurons at febrile temperature?
HUMAN MODEL MISMATCH capos_invitro_febrile_translational_validity
Attached to
pathophysiology#Febrile Illness Unmasking of Pump Reserve Failure
The entire mechanistic case for CAPOS rests on heterologous-expression electrophysiology and biochemistry: reduced sodium affinity, accelerated E1P-to-E2P transition, weakened voltage dependence, and failure of pump activation under "physiological conditions". But those conditions are the assay's physiological conditions, not a febrile human neuron's. The fever-trigger phenomenon - the single most characteristic clinical fact about CAPOS - has never been reproduced in any model system, and no study has measured mutant pump function across the normothermic-to-febrile temperature range. This is not an absence of evidence but a translational validity gap: strong in-vitro evidence exists, and its applicability to the defining in-vivo phenomenon is the open question.
Proposed experiments
E818K pump characterisation across the febrile temperature range
capos_temperature_ramp_electrophysiology
Repeat the E818K two-electrode voltage-clamp and biochemical characterisation across a 37 to 41 degrees Celsius range to test whether the mutant pump's deficit is disproportionately temperature-sensitive relative to wild type.
Would support
Disproportionate loss of mutant pump activity as temperature rises would support the fever-unmasking reserve-failure hypothesis.
Would refute
Parallel temperature responses in mutant and wild type would argue the fever trigger acts through some other route, such as systemic metabolic or inflammatory demand.
E818K knock-in animal model fever challenge
capos_knockin_fever_challenge
Establish a knock-in animal model carrying the orthologous E818K allele and test whether experimentally induced fever provokes an acute ataxic episode with incomplete recovery, which would be the first in-vivo recapitulation of the CAPOS trigger.
Would support
Fever-provoked ataxia with incomplete recovery in the knock-in would establish in-vivo validity of the mechanism.
Would refute
Absence of any fever-provoked phenotype despite the orthologous allele would indicate a human-specific determinant not captured by the model.
Show evidence (1 reference)
PMID:30409907 PARTIAL In Vitro
"Here, using biochemical and electrophysiological approaches, we examined the functional characteristics of E818K, as well as of E818Q and E818A mutants."
Confirms the mechanistic evidence base is biochemical and heterologous-expression electrophysiology, establishing the model system whose translational validity at febrile temperature is unresolved.
⚙

Pathophysiology

7
ATP1A3 p.Glu818Lys Na+/K+-ATPase Alpha-3 Pump Dysfunction
The heterozygous ATP1A3 p.Glu818Lys substitution acts on the alpha-3 catalytic subunit of the Na+/K+-ATPase, the isoform expressed selectively in neurons. Glu818 participates in a hydrogen-bonding and salt-bridge network that positions the residues coordinating Na+ at ion-binding site III, the sodium-specific site. The charge-reversing substitution lowers apparent Na+ affinity at both the cytoplasmic-facing and (far more markedly) the extracellular-facing sites, accelerates the E1P-to-E2P phosphoenzyme transition, flattens the voltage dependence of pumping and increases inhibition by cytoplasmic K+. The K+ arm of the cycle and the ATP/E1-E2 equilibrium are spared, and proton-leak currents are not increased, so this is a specific sodium-handling defect rather than a generalised loss of pump protein or a leak channelopathy.
neuron CL:0000540
ATP1A3 hgnc:801
sodium:potassium-exchanging ATPase activity GO:0005391 ↓ DECREASED
Downstream
Impaired Neuronal Transmembrane Ion Gradient Restoration
Show evidence (4 references)
PMID:29305691 SUPPORT Human Clinical
"is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase"
Identifies the affected protein as the neuron-specific alpha subunit of the Na+/K+-ATPase, establishing the molecular substrate of this node.
PMID:30409907 SUPPORT In Vitro
"We found that these amino acid substitutions reduce the apparent Na+ affinity at the cytoplasmic-facing sites of the pump protein"
Direct biochemical demonstration of reduced cytoplasmic Na+ affinity. Evidence source is IN_VITRO because the measurements are biochemical assays and heterologous-expression (Xenopus oocyte) electrophysiology, not in vivo animal work.
PMID:30409907 SUPPORT In Vitro
"However, the CAPOS mutation caused a weaker voltage dependence of the pumping rate and a stronger inhibition by cytoplasmic K+ than the WT enzyme, which together with the reduced Na+ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions."
The central functional finding: the mutant pump cannot be properly activated under physiological conditions. Evidence source is IN_VITRO because this is heterologous-expression electrophysiology in an expression system, not an in vivo animal model.
+ 1 more reference
Impaired Neuronal Transmembrane Ion Gradient Restoration
Because the alpha-3 pump can no longer be properly activated, neurons that depend on it fail to restore the Na+ and K+ gradients that were spent during activity. The alpha-3 isoform is the high-turnover, activity-recruited neuronal pump, so the deficit is expressed as an inability to reset the membrane after firing rather than as a resting-potential collapse. Neurons with high sustained firing rates and long, energetically expensive axons are disproportionately affected, which is the cell-biological basis of the otherwise puzzling CAPOS lesion distribution: cerebellar Purkinje and cerebellar circuit neurons, spiral ganglion neurons of the auditory nerve, retinal ganglion cells projecting through the optic nerve, and dorsal root ganglion sensory neurons.
Fever exhausts a marginal neuronal alpha-3 pump reserve
cerebellar Purkinje cell CL:0000121 spiral ganglion neuron CL:0011113 retinal ganglion cell CL:0000740 dorsal root ganglion sensory neuron CL:1001451
intracellular sodium ion homeostasis GO:0006883 ↕ DYSREGULATED intracellular potassium ion homeostasis GO:0030007 ↕ DYSREGULATED membrane repolarization GO:0086009 ↓ DECREASED
Downstream
Febrile Illness Unmasking of Pump Reserve Failure Fever exhausts a marginal neuronal alpha-3 pump reserve
Show evidence (2 references)
PMID:30409907 SUPPORT In Vitro
"which together with the reduced Na+ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions"
Failure of pump activation under physiological conditions is precisely the inability to restore ion gradients that this node asserts. Evidence source is IN_VITRO (heterologous expression electrophysiology).
PMID:29305691 SUPPORT Human Clinical
"we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons."
Human audiological evidence that the CAPOS lesion in the auditory system is impaired impulse propagation in spiral ganglion neurons, one of the vulnerable cell types named in this node.
Febrile Illness Unmasking of Pump Reserve Failure
The mechanistic signature of CAPOS is that neurological decompensation is provoked, essentially without exception, by febrile illness. The proposed mechanism is a reserve failure: a heterozygous carrier retains enough wild-type alpha-3 pump to meet baseline demand, but fever raises metabolic and firing demand on exactly the neurons whose pump reserve is already exhausted, tipping them into a state in which ion gradients cannot be maintained. This makes fever a mechanistically privileged trigger rather than a non-specific stressor, and it is the reason aggressive antipyresis is treated as disease-modifying rather than merely symptomatic. The trigger dependence also explains the episodic, punctuated natural history: patients typically have only one to three episodes in a lifetime, each aligned to a febrile illness.
Fever exhausts a marginal neuronal alpha-3 pump reserve
Downstream
Acute Febrile Encephalopathy and Cerebellar Decompensation Fever exhausts a marginal neuronal alpha-3 pump reserve
Show evidence (3 references)
PMID:20301294 SUPPORT Human Clinical
"CAPOS syndrome presents in infancy or childhood (usually ages 6 months to 5 years) with cerebellar ataxia during or after a fever."
GeneReviews defines the presentation as fever-associated cerebellar ataxia, establishing febrile illness as the defining trigger.
PMID:27091223 SUPPORT Human Clinical
"The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness."
Directly supports both the consistent febrile association and the characteristic low episode count.
PMID:28483396 SUPPORT Human Clinical
"Patients typically present at an early age with an acute-onset fever-induced episode of ataxia frequently associated with encephalopathy and weakness."
Systematic review confirms fever-induced onset as the typical CAPOS presentation.
Acute Febrile Encephalopathy and Cerebellar Decompensation
The acute episode is a combined encephalopathy and cerebellar syndrome: hypotonia and flaccidity, nystagmus and strabismus, ophthalmoparesis, dysarthria or anarthria, motor weakness, lethargy, and in severe cases loss of consciousness or coma. It is this acute phase, not a chronic degenerative process, that carries the clinical risk and that is the target of acute management. It is the node that generates the acute-episode phenotypes curated below (Encephalopathy, Hypotonia, Nystagmus, Strabismus, Ophthalmoparesis, Dysarthria, Lethargy, Episodic ataxia).
Downstream
Incomplete Recovery and Stepwise Deficit Accrual
Show evidence (1 reference)
PMID:20301294 SUPPORT Human Clinical
"The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
Enumerates the components of the acute decompensation event modelled by this node.
Incomplete Recovery and Stepwise Deficit Accrual
This is the node that makes CAPOS mechanistically distinctive. After each febrile episode the patient recovers considerably over days to weeks, but not completely: a residuum of ataxia and of the other cardinal deficits persists. Because episodes are few, the natural history is better described as stepwise than as a steady slope - though the cited sources establish incomplete recovery and slow subsequent progression rather than a formally quantified step function. Modelling this as its own node separates the reversible acute physiology (which antipyresis and trigger avoidance can address) from the irreversible accrued deficit (which they cannot).
Downstream
Persistent Multimodal Neurological Deficit
Auditory Neuropathy with Preserved Outer Hair Cell Function
Show evidence (2 references)
PMID:20301294 SUPPORT Human Clinical
"Usually, considerable recovery occurs within days to weeks; however, persistence of some degree of ataxia and other manifestations is typical."
Directly supports the incomplete-recovery pattern that defines this node.
PMID:28483396 SUPPORT Human Clinical
"They usually present one to three episodes. The acute symptoms improve within days, but most patients show slow progression afterward."
Supports both the small episode count and the residual slow progression that together produce the stepwise course.
Persistent Multimodal Neurological Deficit
The accrued residuum is the CAPOS acronym itself: persistent cerebellar ataxia, generalised areflexia, pes cavus foot deformity, optic atrophy with visual impairment, and auditory-neuropathy-type sensorineural hearing loss. The peripheral components (areflexia, pes cavus) reflect the dorsal root ganglion and peripheral sensory involvement that separates CAPOS from the purely central allelic ATP1A3 phenotypes. This node generates the persistent phenotypes curated below (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy).
Show evidence (2 references)
PMID:25895915 SUPPORT Human Clinical
"with permanent areflexia and optic nerve pallor"
Explicitly contrasts the episodic acute features with the permanent areflexia and optic nerve pallor that constitute the persistent deficit.
PMID:25895915 SUPPORT Human Clinical
"The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement."
Supports peripheral nervous system involvement as a distinguishing feature of the persistent CAPOS deficit relative to the allelic ATP1A3 disorders.
Auditory Neuropathy with Preserved Outer Hair Cell Function
The CAPOS hearing loss is mechanistically a neural, not a sensory, lesion. Cochlear outer hair cell activity is preserved, demonstrated by intact otoacoustic emissions and cochlear microphonic potentials, while auditory brainstem responses are grossly abnormal, indicating neural dyssynchrony in the cochlear nerve. Speech perception, especially in noise, is disproportionately poor relative to the pure-tone audiogram. This is the classic auditory neuropathy spectrum disorder profile and it is why conventional amplification performs badly and why cochlear implantation became the management question. This node generates the Sensorineural hearing impairment and Abnormal auditory evoked potentials phenotypes.
spiral ganglion neuron CL:0011113
Show evidence (3 references)
PMID:29305691 SUPPORT Human Clinical
"we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony."
The defining audiological demonstration that CAPOS hearing loss spares the hair cells and localises to the auditory nerve.
PMID:29305691 SUPPORT Human Clinical
"Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here."
Supports the auditory-neuropathy signature of speech perception worse than predicted by the pure-tone audiogram.
PMID:34692702 SUPPORT Human Clinical
"Four subjects with AN were identified to share a de novo variant, p.E818K in the ATP1A3 gene."
Independent cohort confirming the same variant as a cause of auditory neuropathy, including as the presenting phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CAPOS Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

25
Cardiovascular 1
Wolff-Parkinson-White syndrome Wolff-Parkinson-White syndrome HP:0001716
Show evidence (2 references)
PMID:24468074 PARTIAL Human Clinical
"He was treated for Wolff-Parkinson-White syndrome at age 24 years."
Narrative report of WPW in one genotyped CAPOS patient; PARTIAL because a single case does not establish a disease association.
PMID:24468074 PARTIAL Human Clinical
"Cardiac arrhythmia - - - + h -- - - - -"
Table 1 row: the authors tabulated cardiac arrhythmia as a clinical feature and marked 1 of the 10 patients present. No frequency band is assigned from n=1 with no asserted mechanism.
Ear 1
Sensorineural hearing impairment Sensorineural hearing impairment HP:0000407
Show evidence (2 references)
PMID:29305691 SUPPORT Human Clinical
"We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN)."
The largest genotype-confirmed CAPOS audiological series characterises the hearing impairment as auditory neuropathy.
PMID:34692702 SUPPORT Human Clinical
"During the 15 years follow-up of patient 1, we observed delayed neurological events and progressive bilateral sensorineural hearing loss in pure tone threshold (pure tone audiometry, PTA)."
Long-term follow-up documents progressive bilateral sensorineural hearing loss in a p.E818K carrier.
Eye 4
Optic atrophy Optic atrophy HP:0000648
Show evidence (2 references)
PMID:25895915 SUPPORT Human Clinical
"with permanent areflexia and optic nerve pallor"
Documents permanent optic nerve pallor in a CAPOS family.
PMID:28483396 SUPPORT Human Clinical
"The mother had been previously diagnosed with sensorineural hearing loss and optic nerve atrophy."
Shows optic atrophy as a recognised standing diagnosis in an affected parent, supporting it as a persistent trait feature.
Nystagmus Nystagmus HP:0000639
Show evidence (1 reference)
PMID:20301294 SUPPORT Human Clinical
"The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
Lists nystagmus among the acute CAPOS features.
Strabismus Strabismus HP:0000486
Show evidence (1 reference)
PMID:20301294 SUPPORT Human Clinical
"The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
Lists strabismus among the acute CAPOS features.
Visual impairment Visual impairment HP:0000505
Course: PROGRESSIVE
Show evidence (2 references)
PMID:27091223 SUPPORT Human Clinical
"by mixed combinations of areflexia, pes cavus, profound visual impairment, and/or sensorineural hearing loss"
Lists profound visual impairment among the persisting CAPOS features that should prompt ATP1A3 testing.
PMID:36484864 PARTIAL Human Clinical
"The initial symptom of the patient with CAPOS was ataxia followed by developmental regression, seizures, deafness, visual impairment, and dysarthria"
Independent documentation of visual impairment in the CAPOS patient of a mixed AHC/CAPOS/RECA cohort; PARTIAL because it is one patient.
Limbs 1
Pes cavus FREQUENT Pes cavus HP:0001761
Show evidence (3 references)
PMID:28483396 SUPPORT Human Clinical
"CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare disease"
Pes cavus is a definitional component of the CAPOS syndrome as expanded in the source.
PMID:24468074 SUPPORT Human Clinical
"Table 1 Clinical features of 10 patients from three families with CAPOS syndrome"
Establishes the denominator (10 patients) for the frequency band assigned from the Table 1 row quoted below.
PMID:24468074 SUPPORT Human Clinical
"Pes cavus + + - + - - - - - -"
Table 1 row: 3 of the 10 tabulated patients are marked present (+) for pes cavus. 3/10 = 30%, which sits at the lower boundary of the FREQUENT band (30-79%); the band is assigned conservatively at that boundary rather than rounded down. The denominator is read off the Table 1 title quoted above, not derived. No frequency band is assigned to the other four cardinal CAPOS features from this table: all are 10/10 there, but the cohort was ascertained on those very features, so 100% would report the case definition rather than a frequency.
Musculoskeletal 2
Hypotonia Hypotonia HP:0001252
Temporal: ACUTE
Show evidence (1 reference)
PMID:20301294 SUPPORT Human Clinical
"The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
Lists hypotonia among the acute febrile encephalopathy features.
Muscle weakness Muscle weakness HP:0001324
Temporal: ACUTE
Show evidence (2 references)
PMID:27091223 SUPPORT Human Clinical
"The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness."
Lists motor weakness among the manifestations of the paroxysmal fever-associated episodes in four genotyped CAPOS patients.
PMID:28483396 SUPPORT Human Clinical
"Patients typically present at an early age with an acute-onset fever-induced episode of ataxia frequently associated with encephalopathy and weakness."
A review of the published CAPOS literature reports weakness as a frequent accompaniment of the acute fever-induced episode.
Nervous System 13
Cerebellar ataxia Ataxia HP:0001251
Onset: INFANTILE
Show evidence (1 reference)
PMID:20301294 SUPPORT Human Clinical
"CAPOS syndrome presents in infancy or childhood (usually ages 6 months to 5 years) with cerebellar ataxia during or after a fever."
Supports both the ataxia phenotype and its infantile-to-early-childhood onset window.
Episodic ataxia Episodic ataxia HP:0002131
Temporal: RECURRENT
Show evidence (1 reference)
PMID:27091223 SUPPORT Human Clinical
"The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness."
Directly documents the paroxysmal, short-lasting, fever-associated episode pattern.
Areflexia Areflexia HP:0001284
Show evidence (2 references)
PMID:25895915 SUPPORT Human Clinical
"with permanent areflexia and optic nerve pallor"
Documents areflexia as a permanent rather than episodic CAPOS feature.
PMID:28483396 SUPPORT Human Clinical
"The second one developed generalized areflexia and mild instability without an acute episode."
Shows areflexia can be present before any acute febrile episode, i.e. it is a trait feature rather than only a post-episode sequela.
Encephalopathy Encephalopathy HP:0001298
Temporal: ACUTE
Show evidence (1 reference)
PMID:28483396 SUPPORT Human Clinical
"Patients typically present at an early age with an acute-onset fever-induced episode of ataxia frequently associated with encephalopathy and weakness."
Supports acute encephalopathy as a typical accompaniment of the febrile episode.
Dysarthria Dysarthria HP:0001260
Show evidence (1 reference)
PMID:20301294 SUPPORT Human Clinical
"The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
Lists dysarthria/anarthria among the acute CAPOS features.
Lethargy Lethargy HP:0001254
Temporal: ACUTE
Show evidence (1 reference)
PMID:27091223 SUPPORT Human Clinical
"motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness"
Documents lethargy as an acute febrile-episode feature.
Dystonia Dystonia HP:0001332
Show evidence (1 reference)
PMID:27091223 PARTIAL Human Clinical
"Besides the persisting CAPOS features, other possibly related sequelae included dystonia, myoclonus, and emotional and behavioral changes."
The source describes dystonia as a "possibly related" sequela rather than an established CAPOS feature, so support is recorded as PARTIAL.
Myoclonus Myoclonus HP:0001336
Show evidence (1 reference)
PMID:27091223 PARTIAL Human Clinical
"Besides the persisting CAPOS features, other possibly related sequelae included dystonia, myoclonus, and emotional and behavioral changes."
The source lists myoclonus as a "possibly related" sequela rather than an established CAPOS feature, so support is recorded as PARTIAL.
Developmental regression Developmental regression HP:0002376
Show evidence (1 reference)
PMID:36484864 PARTIAL Human Clinical
"The initial symptom of the patient with CAPOS was ataxia followed by developmental regression, seizures, deafness, visual impairment, and dysarthria"
The sentence describes the single CAPOS patient of this mixed AHC/CAPOS/RECA cohort, so the attribution is CAPOS-specific; support is PARTIAL because it is one patient.
Seizure OCCASIONAL Seizure HP:0001250
Show evidence (4 references)
PMID:36484864 PARTIAL Human Clinical
"The initial symptom of the patient with CAPOS was ataxia followed by developmental regression, seizures, deafness, visual impairment, and dysarthria"
Documents seizures in the single CAPOS patient of this mixed AHC/CAPOS/RECA cohort; support is PARTIAL because it is one patient.
PMID:24468074 SUPPORT Human Clinical
"Table 1 Clinical features of 10 patients from three families with CAPOS syndrome"
Establishes the denominator (10 patients) used for the frequency band assigned from the Table 1 rows quoted on this and other phenotypes.
PMID:24468074 SUPPORT Human Clinical
"Seizures - - - - + c -- - - -"
Table 1 row: 1 of the 10 tabulated patients is marked present (+) for seizures. 1/10 = 10%, which falls in the OCCASIONAL band (5-29%). The denominator is read off the Table 1 title quoted above, not derived.
+ 1 more reference
Cerebellar atrophy Cerebellar atrophy HP:0001272
Severity: MILD
Show evidence (1 reference)
PMID:36484864 PARTIAL Human Clinical
"the brain MRI indicated mild cerebellar atrophy"
The clause describes the single CAPOS patient of this mixed AHC/CAPOS/RECA cohort. Support is PARTIAL because it is one case and MRI findings across reported CAPOS patients are inconsistent.
Coma Coma HP:0001259
Temporal: ACUTE
Show evidence (2 references)
PMID:20301294 SUPPORT Human Clinical
"The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
GeneReviews places coma at the severe end of the CAPOS acute febrile encephalopathy spectrum.
PMID:24468074 SUPPORT Human Clinical
"The most severe episode occurred at age 4.5 years, when he was comatose for a week."
A genotyped CAPOS proband was comatose for a week during his most severe febrile episode, documenting that the coma can be prolonged.
Migraine Migraine HP:0002076
Show evidence (1 reference)
PMID:26453127 PARTIAL Human Clinical
"The ATP1A3 c.2452G>A mutation was identified in the affected members of the family, while one of the mutation carriers exhibited both CAPOS and hemiplegic migraine."
Anchors the migraine to a genotype-confirmed CAPOS carrier. Support is PARTIAL because it is a single patient and the same paper notes migraine had not previously been reported in ATP1A3 carriers.
Other 3
Abnormal auditory evoked potentials Abnormal auditory evoked potentials HP:0006958
Show evidence (1 reference)
PMID:29305691 SUPPORT Human Clinical
"the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony"
Directly documents grossly abnormal auditory brainstem responses in CAPOS.
Ophthalmoparesis Ophthalmoparesis HP:0000597
Temporal: ACUTE
Show evidence (1 reference)
PMID:27091223 SUPPORT Human Clinical
"hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness"
Documents ophthalmoparesis during the fever-associated episodes.
Abnormal EKG FREQUENT Abnormal EKG HP:0003115
Show evidence (2 references)
PMID:32913013 SUPPORT Human Clinical
"Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP."
Directly quantitative and CAPOS-specific: 2/3 = 67%, which falls in the FREQUENT band (30-79%). Both numerator and denominator are read off the sentence, not derived. The CAPOS arm of this multicentre cohort is only three patients, which is stated here rather than hidden behind the band.
PMID:32913013 SUPPORT Human Clinical
"We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies"
Establishes the clinical significance of the ECG findings across the ATP1A3 spectrum, which is what makes cardiac surveillance actionable. The claim is spectrum-level rather than CAPOS-specific.
🧬

Genetic Associations

1
ATP1A3
Gene: ATP1A3 hgnc:801 relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:24468074 SUPPORT Human Clinical
"This study shows that an allelic mutation in ATP1A3 produces CAPOS syndrome."
Establishes ATP1A3 as the causative gene for CAPOS, distinct from the previously known ATP1A3 phenotypes.
PMID:24468074 SUPPORT Human Clinical
"This mutation was not found in more than 3600 chromosomes from unaffected individuals."
Population-control data supporting pathogenicity of the recurrent c.2452G>A allele.
💊

Medical Actions

5
Aggressive fever management and febrile-trigger avoidance
Action: supportive care Ontology label: Supportive Care NCIT:C15747
Because febrile illness is the near-obligate trigger for the episodes that accrue permanent deficit, early and aggressive antipyresis during intercurrent illness, prompt treatment of infections, and general avoidance of the physical, environmental and metabolic stressors known to provoke ATP1A3-related episodes are treated as preventive rather than merely symptomatic measures. This is the one intervention that is directly mechanism-linked in CAPOS. Its efficacy in reducing episode frequency has not been formally trialled - the rationale is mechanistic plus the consistency of the fever association.
Mechanism Target:
INHIBITS Febrile Illness Unmasking of Pump Reserve Failure — Antipyresis and trigger avoidance act on the febrile-unmasking node itself, upstream of the acute decompensation and therefore upstream of the irreversible stepwise deficit accrual.
Show evidence (2 references)
PMID:20301294 SUPPORT Human Clinical
"individuals who are heterozygous for an ATP1A3 pathogenic variant should avoid the known triggers for manifestations and/or episodes"
The GeneReviews Agents/Circumstances to Avoid recommendation, the authoritative source for trigger avoidance in ATP1A3-related disorder.
PMID:28483396 PARTIAL Human Clinical
"The fact that both siblings were assessed before the first acute-onset episode contributes to the description of early symptoms and signs of the disease, which could aid early diagnosis and management before the onset of acute episodes."
Supports the value of pre-episode identification so that trigger management can be instituted; PARTIAL because the source describes the opportunity rather than demonstrating benefit.
Acetazolamide episode prophylaxis
Action: Pharmacotherapy NCIT:C15986
Agent: acetazolamide CHEBI:27690
Acetazolamide, borrowed from the episodic ataxias, has been tried as prophylaxis against CAPOS episodes. The evidence is genuinely conflicting and should not be presented as established: two patients in one series had no further episodes after starting acetazolamide, while a separate cohort reported no fluctuation benefit in its CAPOS patient. The originating authors themselves say further study is required.
Show evidence (3 references)
PMID:27091223 PARTIAL Human Clinical
"After initiation of acetazolamide in two patients, no further episodes occurred."
Uncontrolled observation in two patients; PARTIAL because episodes are naturally infrequent (one to three per lifetime) so absence of further episodes is weak evidence of benefit.
PMID:27091223 PARTIAL Human Clinical
"acetazolamide may be considered in patients with CAPOS syndrome to prevent or attenuate bouts of ataxia, but this requires further study."
The authors explicitly flag the recommendation as tentative and requiring further study.
PMID:36484864 REFUTE Human Clinical
"No fluctuation was noted after using Acetazolamide."
A separate cohort's CAPOS patient showed no response to acetazolamide, directly counterbalancing the positive series and justifying the conflicting-evidence framing.
Cochlear implantation for auditory neuropathy
Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329
Conventional hearing aids perform poorly in CAPOS because the lesion is neural dyssynchrony rather than loss of cochlear amplification. A cochlear implant is the rehabilitative option, but outcomes reported to date are inconsistent: one series reported preliminary speech-perception improvement and another reported a poor result in an implanted p.E818K patient. Counsel accordingly rather than promising benefit. therapeutic_modality is DEVICE because the therapy is an implanted prosthesis; the treatment_term records the surgical action by which it is delivered, since NCIT's Cochlear Implant concept (NCIT:C157820) is a Medical Device and is therefore not reachable from the Clinical Intervention or Procedure root that treatment_term is bound to.
Target Phenotypes: Sensorineural hearing impairment HP:0000407
Show evidence (3 references)
PMID:29305691 PARTIAL Human Clinical
"Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients."
Supports the poor performance of conventional amplification and offers preliminary, explicitly hedged support for cochlear implantation.
PMID:34692702 PARTIAL Human Clinical
"Patient 2 underwent CI on his left ear, and the result was poor."
Documents a poor cochlear implantation outcome in a genotype-confirmed p.E818K patient, the counterweight to the optimistic report.
PMID:34692702 PARTIAL Human Clinical
"Our study further demonstrates the significance of genetic testing for this specific mutation for identifying the special subtype of AN with somewhat favorable CI outcome"
The same study nonetheless concludes the genotype identifies an auditory neuropathy subtype with a somewhat favourable implantation outcome, capturing the genuine uncertainty in the field.
Multidisciplinary supportive and rehabilitative care
Action: physical therapy Ontology label: Physical Therapy NCIT:C15302
There is no disease-modifying therapy for CAPOS. Management is supportive and multidisciplinary: physical therapy and mobility support for ataxia and pes cavus, low-vision support for optic atrophy, speech and language therapy for dysarthria, and orthopaedic assessment of the foot deformity, coordinated across neurology, ophthalmology, audiology, rehabilitation and genetics.
Show evidence (2 references)
PMID:20301294 SUPPORT Human Clinical
"There is no cure for ATP1A3-related disorder. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended."
GeneReviews establishes supportive care as the standard of management for ATP1A3-related disorder including CAPOS.
PMID:20301294 SUPPORT Human Clinical
"This ideally involves multidisciplinary care by specialists in neurology, developmental pediatrics, orthopedics, physical medicine and rehabilitation, speech-language therapy, psychology, mental health, ophthalmology, social work, and medical genetics."
Specifies the multidisciplinary composition of supportive care recommended by GeneReviews.
Genetic counselling and predictive testing
Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240
Autosomal dominant transmission with a 50% recurrence risk per child, and a roughly even split between inherited and de novo variants, make genetic counselling central. Parental testing is important because a mildly affected parent may be recognised only after the child is diagnosed - several published families were ascertained this way. Once the familial variant is known, predictive and prenatal/preimplantation testing are possible.
Show evidence (2 references)
PMID:20301294 SUPPORT Human Clinical
"Each child of an individual with ATP1A3-related disorder has a 50% chance of inheriting the pathogenic variant. Once the ATP1A3 pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
Establishes the recurrence risk and the availability of predictive and prenatal testing that this counselling entry describes.
PMID:28483396 SUPPORT Human Clinical
"We describe three new patients, a woman and her two sons diagnosed with CAPOS syndrome."
Illustrates the multigenerational ascertainment pattern (affected mother plus two affected sons) that makes family-wide evaluation important.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from CAPOS Syndrome:

Alternating hemiplegia of childhood MONDO:0016241
Overlapping Features The best-known allelic ATP1A3 disorder and the most important entity to keep distinct from CAPOS. AHC is defined by recurrent paroxysmal hemiplegic episodes beginning before 18 months with remission during sleep, and it does not encompass the hearing or visual impairment that define CAPOS. AHC is also usually de novo and caused by a different, heterogeneous set of ATP1A3 variants (D801N, E815K, G947R predominating), not by p.Glu818Lys. Note the E815K/E818K near-collision in residue numbering - a named-entity-confusion trap when reading the ATP1A3 literature.
Show evidence (1 reference)
PMID:29305691 SUPPORT Human Clinical
"Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment."
States the discriminating feature: the allelic disorders lack the hearing and visual impairment that define CAPOS.
Rapid-onset dystonia-parkinsonism Not Yet Curated MONDO:0007496
Overlapping Features The third classical ATP1A3 phenotype (DYT12). Presents from 18 months to adulthood with abrupt-onset, usually stress-triggered, bulbar-predominant generalised dystonia and parkinsonism. Like AHC it lacks the CAPOS sensory-organ involvement, and the movement-disorder predominance is extrapyramidal rather than cerebellar.
Show evidence (1 reference)
PMID:25895915 SUPPORT Human Clinical
"The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement."
Explicitly contrasts CAPOS with rapid-onset dystonia-parkinsonism and AHC on age of onset, course, cerebellar-versus-extrapyramidal predominance and peripheral involvement.
Relapsing encephalopathy with cerebellar ataxia (RECA/FIPWE)
Overlapping Features The closest CAPOS mimic and the hardest differential, because RECA/FIPWE is also an ATP1A3 disorder defined by fever-induced episodes of ataxia and encephalopathy in early childhood. RECA is associated with variants at ATP1A3 residue Arg756, not Glu818, and lacks the fixed optic atrophy, auditory neuropathy, areflexia and pes cavus that make up the CAPOS residuum. Molecular testing, not the acute episode phenotype, separates them.
Show evidence (1 reference)
PMID:20301294 SUPPORT Human Clinical
"RECA/FIPWE primarily presents with fever-induced episodes (infancy to age 5 years); however, first episodes can occur occasionally in young adults during illnesses such as mononucleosis."
Establishes RECA/FIPWE as a separately named fever-induced ATP1A3 phenotype overlapping the CAPOS acute presentation window.
Acute post-infectious cerebellar ataxia Not Yet Curated MONDO:0850107
Overlapping Features The commonest cause of acute ataxia after a febrile illness in a young child, and the diagnosis CAPOS is most often mistaken for at first presentation. It is typically monophasic with full recovery and no accompanying optic atrophy, hearing loss, areflexia or pes cavus. The presence of any of the fixed CAPOS features, or a second episode, or an affected parent, should prompt ATP1A3 testing.
Show evidence (1 reference)
PMID:27091223 PARTIAL Human Clinical
"Targeted sequencing of the ATP1A3 gene is recommended in children exhibiting paroxysmal, fever-induced ataxia"
Supports the recommendation to test ATP1A3 in the fever-induced childhood ataxia population, i.e. the population that otherwise receives an acute post-infectious cerebellar ataxia label. Support is PARTIAL because the source does not itself contrast the two entities.
{ }

Source YAML

click to show 
name: CAPOS Syndrome
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
description: >-
  CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy and
  sensorineural hearing loss) is an ultra-rare autosomal dominant neurological
  disorder caused, in essentially every reported patient, by the single
  recurrent ATP1A3 missense variant c.2452G>A (p.Glu818Lys). ATP1A3 encodes the
  neuron-specific alpha-3 subunit of the Na+/K+-ATPase; the p.Glu818Lys
  substitution cripples sodium handling at the pump's third (sodium-specific)
  ion-binding site so that the pump cannot be properly activated under
  physiological conditions. The clinical hallmark is a small number (typically
  one to three) of febrile-illness-triggered episodes of acute cerebellar ataxia
  and encephalopathy in infancy or early childhood, each followed by
  considerable but incomplete recovery, leaving a stepwise-accrued residuum of
  ataxia, areflexia, optic atrophy, auditory-neuropathy-type hearing loss and
  pes cavus.
disease_term:
  preferred_term: CAPOS syndrome
  term:
    id: MONDO:0011038
    label: cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
parents:
- ATP1A3-related disorder
- channelopathy
- hereditary ataxia
- neurogenetic disorder
synonyms:
- CAPOS
- cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss syndrome
- CAOS syndrome
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:36192182
      reference_title: The Phenotypic Continuum of ATP1A3-Related Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome."
      explanation: >-
        Places CAPOS within the predominantly neurologic ATP1A3-related disorder
        spectrum, supporting the NEUROLOGIC Harrison's Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:25895915
      reference_title: "CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our findings substantiate this variant as the cause of a unique inherited autosomal dominant neurologic syndrome that constitutes a third allelic disease of the ATP1A3 gene."
      explanation: >-
        Establishes CAPOS as a Mendelian, autosomal dominant single-gene
        disorder, supporting the genetics Part alongside the neurologic Part.
  - classification_value: DISORDER_OF_EAR
    evidence:
    - reference: PMID:29305691
      reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons."
      explanation: >-
        A defining and management-relevant component of CAPOS is a specific
        cochlear-nerve (auditory neuropathy) hearing disorder, supporting the
        ear Part.
  channelopathy_category:
    classification_value: neurological channelopathy
    notes: >-
      ATP1A3 encodes an electrogenic ion pump (Na+/K+-ATPase alpha-3) rather than
      a classical ion channel, but dismech and the clinical literature both group
      ATP1A3-related disorders with the neurological channelopathies because the
      primary lesion is failure of neuronal transmembrane ion-gradient
      maintenance and excitability control. The allelic entry
      Alternating_Hemiplegia_of_Childhood is likewise classified as a
      channelopathy in this knowledge base.
inheritance:
- name: Autosomal dominant, roughly half de novo and half inherited
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: About half of individuals with CAPOS
  description: >-
    CAPOS is inherited in an autosomal dominant manner. Unlike the more severe
    allelic phenotype alternating hemiplegia of childhood, in which the variant
    is usually de novo, roughly half of individuals with CAPOS inherit the
    p.Glu818Lys variant from an affected (sometimes mildly or belatedly
    recognised) parent, and roughly half have an apparently de novo variant.
    Multigenerational transmission was central to the original gene discovery,
    which found the identical variant segregating in three independent families.
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ATP1A3-related disorder – including the four historically defined phenotypes of AHC, CAPOS syndrome, RECA/FIPWE, and RDP – is inherited in an autosomal dominant manner."
    explanation: >-
      GeneReviews states autosomal dominant inheritance explicitly for the
      CAPOS phenotype within the ATP1A3-related disorder spectrum.
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About half of individuals with a relatively less severe ATP1A3-related phenotype (e.g., CAPOS syndrome or RDP) have the disorder as the result of a pathogenic variant inherited from an affected parent; about half of individuals have an apparently de novo pathogenic variant."
    explanation: >-
      Directly supports the roughly 50/50 inherited-versus-de-novo split that
      distinguishes CAPOS counselling from AHC counselling.
  - reference: PMID:24468074
    reference_title: A novel recurrent mutation in ATP1A3 causes CAPOS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We undertook genetic analysis of three affected families to identify the cause of dominantly-inherited CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) syndrome."
    explanation: >-
      The gene-discovery study was built on dominantly inherited multiplex
      families, supporting familial autosomal dominant transmission.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence or incidence estimate exists for CAPOS. The
    literature is case-series only: 22 patients were reported by 2017, rising to
    25 with the addition of one Spanish family, and subsequent reports remain
    single families or small cohorts. A rate_per_100000 value is deliberately
    omitted rather than back-calculated from a case count, because the
    denominator is unknown and ascertainment is driven by targeted ATP1A3
    sequencing.
  evidence:
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare disease that has been reported in 22 patients so far."
    explanation: >-
      A systematic literature review quantifies the total reported case count,
      the only occurrence measure available for CAPOS.
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 25 Individuals with CAPOS syndrome have been reported, including our family."
    explanation: >-
      Confirms the cumulative published-case denominator, supporting the
      ULTRA_RARE prevalence class and the CASES_IN_LITERATURE measure type.
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present four patients from the seventh and eighth family identified worldwide, provide a critical review of all patients published thus far, and speculate about the pathophysiologic processes underlying the acute neurological manifestations."
    explanation: >-
      Reporting the seventh and eighth families worldwide independently
      corroborates that CAPOS is countable at the level of individual families.
genetic:
- name: ATP1A3
  gene_term:
    preferred_term: ATP1A3
    term:
      id: hgnc:801
      label: ATP1A3
  relationship_type: CAUSATIVE
  notes: >-
    ATP1A3 encodes the neuron-specific alpha-3 catalytic subunit of the
    Na+/K+-ATPase. CAPOS is genetically homogeneous to a degree that is unusual
    even among Mendelian disorders: essentially every reported patient carries
    the same heterozygous missense change, c.2452G>A (p.Glu818Lys). This is a
    striking genotype-phenotype restriction, because the same gene produces
    clinically distinct allelic disorders (alternating hemiplegia of childhood,
    rapid-onset dystonia-parkinsonism, RECA/FIPWE) through a large and
    heterogeneous set of other variants.
  evidence:
  - reference: PMID:24468074
    reference_title: A novel recurrent mutation in ATP1A3 causes CAPOS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study shows that an allelic mutation in ATP1A3 produces CAPOS syndrome."
    explanation: >-
      Establishes ATP1A3 as the causative gene for CAPOS, distinct from the
      previously known ATP1A3 phenotypes.
  - reference: PMID:24468074
    reference_title: A novel recurrent mutation in ATP1A3 causes CAPOS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation was not found in more than 3600 chromosomes from unaffected individuals."
    explanation: >-
      Population-control data supporting pathogenicity of the recurrent
      c.2452G>A allele.
  variants:
  - name: ATP1A3 c.2452G>A (p.Glu818Lys)
    type: MISSENSE
    clinical_significance: PATHOGENIC
    description: >-
      The recurrent, near-exclusive CAPOS allele. Glu818 lies in a
      hydrogen-bonding/salt-bridge network that positions residues coordinating
      sodium at the pump's third, sodium-specific ion-binding site; the
      glutamate-to-lysine charge reversal disrupts that network.
    gene:
      preferred_term: ATP1A3
      term:
        id: hgnc:801
        label: ATP1A3
    evidence:
    - reference: PMID:28483396
      reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In all cases, the mutation c.2452G>A (p.Glu818Lys) in the ATP1A3 gene was identified."
      explanation: >-
        A systematic review of every reported CAPOS patient found the identical
        variant in all of them, the strongest available statement of the
        near-exclusive genotype-phenotype restriction.
    - reference: PMID:27091223
      reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An underlying c.2452G>A mutation in the ATP1A3 gene was found in all four individuals."
      explanation: >-
        Independent replication of the same recurrent allele in a further family
        cohort.
    - reference: PMID:25895915
      reference_title: "CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Whole exome sequencing identified a deleterious heterozygous c.2452 G>A, p.(E818K) variant in the ATP1A3 gene and structural analysis predicted its protein-destabilizing effect."
      explanation: >-
        In-silico structural analysis predicted a destabilising effect for the
        recurrent variant; classified COMPUTATIONAL because this specific claim
        rests on structural prediction rather than wet-lab assay.
    - reference: PMID:30409907
      reference_title: "Functional consequences of the CAPOS mutation E818K of Na(+),K(+)-ATPase."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The functional deficiencies could be traced to the participation of Glu-818 in an intricate hydrogen-bonding/salt-bridge network, connecting it to key residues involved in Na+ interaction at site III."
      explanation: >-
        Biochemical and heterologous-expression electrophysiology localise the
        variant's effect to the sodium site III coordination network.
pathophysiology:
- name: ATP1A3 p.Glu818Lys Na+/K+-ATPase Alpha-3 Pump Dysfunction
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The heterozygous ATP1A3 p.Glu818Lys substitution acts on the alpha-3
    catalytic subunit of the Na+/K+-ATPase, the isoform expressed selectively in
    neurons. Glu818 participates in a hydrogen-bonding and salt-bridge network
    that positions the residues coordinating Na+ at ion-binding site III, the
    sodium-specific site. The charge-reversing substitution lowers apparent Na+
    affinity at both the cytoplasmic-facing and (far more markedly) the
    extracellular-facing sites, accelerates the E1P-to-E2P phosphoenzyme
    transition, flattens the voltage dependence of pumping and increases
    inhibition by cytoplasmic K+. The K+ arm of the cycle and the ATP/E1-E2
    equilibrium are spared, and proton-leak currents are not increased, so this
    is a specific sodium-handling defect rather than a generalised loss of pump
    protein or a leak channelopathy.
  genes:
  - preferred_term: ATP1A3
    term:
      id: hgnc:801
      label: ATP1A3
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  molecular_functions:
  - preferred_term: sodium:potassium-exchanging ATPase activity
    term:
      id: GO:0005391
      label: P-type sodium:potassium-exchanging transporter activity
    modifier: DECREASED
  evidence:
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase"
    explanation: >-
      Identifies the affected protein as the neuron-specific alpha subunit of
      the Na+/K+-ATPase, establishing the molecular substrate of this node.
  - reference: PMID:30409907
    reference_title: "Functional consequences of the CAPOS mutation E818K of Na(+),K(+)-ATPase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that these amino acid substitutions reduce the apparent Na+ affinity at the cytoplasmic-facing sites of the pump protein"
    explanation: >-
      Direct biochemical demonstration of reduced cytoplasmic Na+ affinity.
      Evidence source is IN_VITRO because the measurements are biochemical
      assays and heterologous-expression (Xenopus oocyte) electrophysiology,
      not in vivo animal work.
  - reference: PMID:30409907
    reference_title: "Functional consequences of the CAPOS mutation E818K of Na(+),K(+)-ATPase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, the CAPOS mutation caused a weaker voltage dependence of the pumping rate and a stronger inhibition by cytoplasmic K+ than the WT enzyme, which together with the reduced Na+ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions."
    explanation: >-
      The central functional finding: the mutant pump cannot be properly
      activated under physiological conditions. Evidence source is IN_VITRO
      because this is heterologous-expression electrophysiology in an
      expression system, not an in vivo animal model.
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site."
    explanation: >-
      Independent heterologous-expression study localising the defect to the
      sodium-specific third ion-binding site; IN_VITRO because the assay is a
      heterologous expression system.
  downstream:
  - target: Impaired Neuronal Transmembrane Ion Gradient Restoration
    causal_link_type: DIRECT
- name: Impaired Neuronal Transmembrane Ion Gradient Restoration
  role: amplifier
  biological_scale: CELLULAR
  description: >-
    Because the alpha-3 pump can no longer be properly activated, neurons that
    depend on it fail to restore the Na+ and K+ gradients that were spent during
    activity. The alpha-3 isoform is the high-turnover, activity-recruited
    neuronal pump, so the deficit is expressed as an inability to reset the
    membrane after firing rather than as a resting-potential collapse. Neurons
    with high sustained firing rates and long, energetically expensive axons are
    disproportionately affected, which is the cell-biological basis of the
    otherwise puzzling CAPOS lesion distribution: cerebellar Purkinje and
    cerebellar circuit neurons, spiral ganglion neurons of the auditory nerve,
    retinal ganglion cells projecting through the optic nerve, and dorsal root
    ganglion sensory neurons.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  - preferred_term: dorsal root ganglion sensory neuron
    term:
      id: CL:1001451
      label: sensory neuron of dorsal root ganglion
  biological_processes:
  - preferred_term: intracellular sodium ion homeostasis
    term:
      id: GO:0006883
      label: intracellular sodium ion homeostasis
    modifier: DYSREGULATED
  - preferred_term: intracellular potassium ion homeostasis
    term:
      id: GO:0030007
      label: intracellular potassium ion homeostasis
    modifier: DYSREGULATED
  - preferred_term: membrane repolarization
    term:
      id: GO:0086009
      label: membrane repolarization
    modifier: DECREASED
  evidence:
  - reference: PMID:30409907
    reference_title: "Functional consequences of the CAPOS mutation E818K of Na(+),K(+)-ATPase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "which together with the reduced Na+ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions"
    explanation: >-
      Failure of pump activation under physiological conditions is precisely the
      inability to restore ion gradients that this node asserts. Evidence source
      is IN_VITRO (heterologous expression electrophysiology).
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons."
    explanation: >-
      Human audiological evidence that the CAPOS lesion in the auditory system
      is impaired impulse propagation in spiral ganglion neurons, one of the
      vulnerable cell types named in this node.
  notes: >-
    The cerebellar Purkinje cell, spiral ganglion neuron, retinal ganglion cell
    and dorsal root ganglion neuron are listed here as the anatomically implied
    substrates of the CAPOS lesion distribution (cerebellar ataxia, auditory
    neuropathy, optic atrophy, areflexia). Direct human cell-type-resolved
    demonstration of alpha-3 pump failure exists only for the spiral ganglion
    arm (auditory neuropathy electrophysiology); the other three are inferred
    from the clinical lesion pattern. See the
    capos_allelic_lesion_selectivity KNOWLEDGE_GAP discussion entry.
  downstream:
  - target: Febrile Illness Unmasking of Pump Reserve Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - fever_triggered_pump_reserve_failure
- name: Febrile Illness Unmasking of Pump Reserve Failure
  role: trigger
  biological_scale: ORGANISM
  description: >-
    The mechanistic signature of CAPOS is that neurological decompensation is
    provoked, essentially without exception, by febrile illness. The proposed
    mechanism is a reserve failure: a heterozygous carrier retains enough
    wild-type alpha-3 pump to meet baseline demand, but fever raises metabolic
    and firing demand on exactly the neurons whose pump reserve is already
    exhausted, tipping them into a state in which ion gradients cannot be
    maintained. This makes fever a mechanistically privileged trigger rather
    than a non-specific stressor, and it is the reason aggressive antipyresis is
    treated as disease-modifying rather than merely symptomatic. The trigger
    dependence also explains the episodic, punctuated natural history: patients
    typically have only one to three episodes in a lifetime, each aligned to a
    febrile illness.
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CAPOS syndrome presents in infancy or childhood (usually ages 6 months to 5 years) with cerebellar ataxia during or after a fever."
    explanation: >-
      GeneReviews defines the presentation as fever-associated cerebellar
      ataxia, establishing febrile illness as the defining trigger.
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness."
    explanation: >-
      Directly supports both the consistent febrile association and the
      characteristic low episode count.
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients typically present at an early age with an acute-onset fever-induced episode of ataxia frequently associated with encephalopathy and weakness."
    explanation: >-
      Systematic review confirms fever-induced onset as the typical CAPOS
      presentation.
  notes: >-
    The reserve-failure interpretation of why fever specifically triggers CAPOS
    decompensation is a mechanistic hypothesis, not a demonstrated result; no
    study has measured alpha-3 pump function at febrile temperature in a
    patient-derived neuronal system. The clinical fever-episode association
    itself is well established. The hypothesis is registered under
    mechanistic_hypotheses as fever_triggered_pump_reserve_failure. This node is
    wired into the main pathograph (upstream: Impaired Neuronal Transmembrane
    Ion Gradient Restoration; downstream: Acute Febrile Encephalopathy and
    Cerebellar Decompensation) rather than left as a free-standing trigger.
  downstream:
  - target: Acute Febrile Encephalopathy and Cerebellar Decompensation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - fever_triggered_pump_reserve_failure
- name: Acute Febrile Encephalopathy and Cerebellar Decompensation
  role: effector
  biological_scale: ORGANISM
  description: >-
    The acute episode is a combined encephalopathy and cerebellar syndrome:
    hypotonia and flaccidity, nystagmus and strabismus, ophthalmoparesis,
    dysarthria or anarthria, motor weakness, lethargy, and in severe cases loss
    of consciousness or coma. It is this acute phase, not a chronic
    degenerative process, that carries the clinical risk and that is the target
    of acute management. It is the node that generates the acute-episode
    phenotypes curated below (Encephalopathy, Hypotonia, Nystagmus, Strabismus,
    Ophthalmoparesis, Dysarthria, Lethargy, Episodic ataxia).
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
    explanation: >-
      Enumerates the components of the acute decompensation event modelled by
      this node.
  downstream:
  - target: Incomplete Recovery and Stepwise Deficit Accrual
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Incomplete Recovery and Stepwise Deficit Accrual
  role: central_effector
  biological_scale: ORGANISM
  description: >-
    This is the node that makes CAPOS mechanistically distinctive. After each
    febrile episode the patient recovers considerably over days to weeks, but
    not completely: a residuum of ataxia and of the other cardinal deficits
    persists. Because episodes are few, the natural history is better described
    as stepwise than as a steady slope - though the cited sources establish
    incomplete recovery and slow subsequent progression rather than a formally
    quantified step function. Modelling this as its own node separates the
    reversible acute physiology (which antipyresis and trigger avoidance can
    address) from the irreversible accrued deficit (which they cannot).
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Usually, considerable recovery occurs within days to weeks; however, persistence of some degree of ataxia and other manifestations is typical."
    explanation: >-
      Directly supports the incomplete-recovery pattern that defines this node.
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They usually present one to three episodes. The acute symptoms improve within days, but most patients show slow progression afterward."
    explanation: >-
      Supports both the small episode count and the residual slow progression
      that together produce the stepwise course.
  downstream:
  - target: Persistent Multimodal Neurological Deficit
    causal_link_type: DIRECT
  - target: Auditory Neuropathy with Preserved Outer Hair Cell Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Persistent Multimodal Neurological Deficit
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The accrued residuum is the CAPOS acronym itself: persistent cerebellar
    ataxia, generalised areflexia, pes cavus foot deformity, optic atrophy with
    visual impairment, and auditory-neuropathy-type sensorineural hearing loss.
    The peripheral components (areflexia, pes cavus) reflect the dorsal root
    ganglion and peripheral sensory involvement that separates CAPOS from the
    purely central allelic ATP1A3 phenotypes. This node generates the persistent
    phenotypes curated below (Cerebellar ataxia, Areflexia, Pes cavus, Optic
    atrophy).
  evidence:
  - reference: PMID:25895915
    reference_title: "CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with permanent areflexia and optic nerve pallor"
    explanation: >-
      Explicitly contrasts the episodic acute features with the permanent
      areflexia and optic nerve pallor that constitute the persistent deficit.
  - reference: PMID:25895915
    reference_title: "CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement."
    explanation: >-
      Supports peripheral nervous system involvement as a distinguishing feature
      of the persistent CAPOS deficit relative to the allelic ATP1A3 disorders.
- name: Auditory Neuropathy with Preserved Outer Hair Cell Function
  role: effector
  biological_scale: TISSUE
  description: >-
    The CAPOS hearing loss is mechanistically a neural, not a sensory, lesion.
    Cochlear outer hair cell activity is preserved, demonstrated by intact
    otoacoustic emissions and cochlear microphonic potentials, while auditory
    brainstem responses are grossly abnormal, indicating neural dyssynchrony in
    the cochlear nerve. Speech perception, especially in noise, is
    disproportionately poor relative to the pure-tone audiogram. This is the
    classic auditory neuropathy spectrum disorder profile and it is why
    conventional amplification performs badly and why cochlear implantation
    became the management question. This node generates the Sensorineural
    hearing impairment and Abnormal auditory evoked potentials phenotypes.
  cell_types:
  - preferred_term: spiral ganglion neuron
    term:
      id: CL:0011113
      label: spiral ganglion neuron
  evidence:
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony."
    explanation: >-
      The defining audiological demonstration that CAPOS hearing loss spares the
      hair cells and localises to the auditory nerve.
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here."
    explanation: >-
      Supports the auditory-neuropathy signature of speech perception worse than
      predicted by the pure-tone audiogram.
  - reference: PMID:34692702
    reference_title: "Auditory Neuropathy as the Initial Phenotype for Patients With ATP1A3 c.2452 G > A: Genotype-Phenotype Study and CI Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four subjects with AN were identified to share a de novo variant, p.E818K in the ATP1A3 gene."
    explanation: >-
      Independent cohort confirming the same variant as a cause of auditory
      neuropathy, including as the presenting phenotype.
  notes: >-
    This node is the reason CAPOS does NOT declare conforms_to against
    kb/modules/sensorineural_hair_cell_loss.yaml. That module's central effector
    is "Hair Cell Mechanotransduction Failure and Death"; CAPOS demonstrably
    preserves outer hair cell function, so asserting conformance would invert
    the module's mechanism. See the top-level notes for the full lump/split and
    conformance reasoning.
mechanistic_hypotheses:
- hypothesis_group_id: fever_triggered_pump_reserve_failure
  hypothesis_label: Fever exhausts a marginal neuronal alpha-3 pump reserve
  status: EMERGING
  description: >-
    Hypothesis: in a heterozygous p.Glu818Lys carrier the residual wild-type
    alpha-3 Na+/K+-ATPase provides just enough pumping capacity for baseline
    neuronal activity, and febrile illness raises metabolic and firing demand
    past that margin in the most pump-dependent neurons, producing acute failure
    of ion-gradient restoration and hence the stereotyped febrile
    ataxia/encephalopathy episode. This would explain why fever is a
    near-obligate trigger, why episodes are self-limited once the fever resolves,
    and why some deficit is nonetheless retained. It predicts that aggressive
    antipyresis should reduce episode frequency or severity, and that mutant
    pump function measured at febrile temperature should be disproportionately
    impaired relative to wild type.
  evidence:
  - reference: PMID:30409907
    reference_title: "Functional consequences of the CAPOS mutation E818K of Na(+),K(+)-ATPase."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "which together with the reduced Na+ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions"
    explanation: >-
      Establishes a marginal/failing pump at baseline physiological conditions,
      which is the premise of the reserve hypothesis; the study did not test
      febrile temperature, so this is PARTIAL support for the fever-specific
      claim.
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "that were consistently associated with febrile illness"
    explanation: >-
      Consistent clinical fever association supports the trigger relationship
      but does not itself establish the pump-reserve mechanism, hence PARTIAL.
phenotypes:
- name: Cerebellar ataxia
  category: Neurologic
  diagnostic: true
  description: >-
    Acute fever-triggered cerebellar ataxia is the presenting event and, in
    residual form, the most consistent persisting deficit. Onset is usually
    between 6 months and 5 years. Generated by the Persistent Multimodal
    Neurological Deficit pathophysiology node. The HPO binding uses the general
    Ataxia term because the acute CAPOS episode is not adequately described by
    either the progressive or the nonprogressive cerebellar ataxia subterms -
    the course is stepwise.
  phenotype_term:
    preferred_term: cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
    onset:
      onset_category: INFANTILE
      notes: Usually ages 6 months to 5 years.
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CAPOS syndrome presents in infancy or childhood (usually ages 6 months to 5 years) with cerebellar ataxia during or after a fever."
    explanation: >-
      Supports both the ataxia phenotype and its infantile-to-early-childhood
      onset window.
- name: Episodic ataxia
  category: Neurologic
  description: >-
    The acute deterioration is paroxysmal and short-lasting, with typically one
    to three lifetime episodes, each tied to a febrile illness - a genuinely
    episodic pattern rather than continuous progression. Generated by the Acute
    Febrile Encephalopathy and Cerebellar Decompensation node.
  phenotype_term:
    preferred_term: Episodic ataxia
    term:
      id: HP:0002131
      label: Episodic ataxia
    temporality: RECURRENT
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness."
    explanation: >-
      Directly documents the paroxysmal, short-lasting, fever-associated episode
      pattern.
- name: Areflexia
  category: Neurologic
  diagnostic: true
  description: >-
    Generalised loss of deep tendon reflexes is one of the permanent CAPOS
    features and reflects peripheral sensory (dorsal root ganglion) involvement,
    a component absent from the allelic ATP1A3 phenotypes. Generated by the
    Persistent Multimodal Neurological Deficit node.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:25895915
    reference_title: "CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with permanent areflexia and optic nerve pallor"
    explanation: >-
      Documents areflexia as a permanent rather than episodic CAPOS feature.
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The second one developed generalized areflexia and mild instability without an acute episode."
    explanation: >-
      Shows areflexia can be present before any acute febrile episode, i.e. it
      is a trait feature rather than only a post-episode sequela.
- name: Pes cavus
  category: Skeletal
  diagnostic: true
  frequency: FREQUENT
  description: >-
    High-arched foot deformity, the "P" of CAPOS. Like areflexia, it is a marker
    of long-standing peripheral sensory-motor involvement, generated by the
    Persistent Multimodal Neurological Deficit node. Despite being one of the
    five letters of the acronym, it is the least consistent of the cardinal
    features: it was present in a minority of the tabulated Demos cohort, which
    is why its absence does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) is a rare disease"
    explanation: >-
      Pes cavus is a definitional component of the CAPOS syndrome as expanded in
      the source.
  - reference: PMID:24468074
    reference_title: "A novel recurrent mutation in ATP1A3 causes CAPOS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Table 1 Clinical features of 10 patients from three families with CAPOS syndrome"
    explanation: >-
      Establishes the denominator (10 patients) for the frequency band assigned
      from the Table 1 row quoted below.
  - reference: PMID:24468074
    reference_title: "A novel recurrent mutation in ATP1A3 causes CAPOS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pes cavus + + - + - - - - - -"
    explanation: >-
      Table 1 row: 3 of the 10 tabulated patients are marked present (+) for pes
      cavus. 3/10 = 30%, which sits at the lower boundary of the FREQUENT band
      (30-79%); the band is assigned conservatively at that boundary rather than
      rounded down. The denominator is read off the Table 1 title quoted above,
      not derived. No frequency band is assigned to the other four cardinal
      CAPOS features from this table: all are 10/10 there, but the cohort was
      ascertained on those very features, so 100% would report the case
      definition rather than a frequency.
- name: Optic atrophy
  category: Ophthalmologic
  diagnostic: true
  description: >-
    Optic nerve pallor and atrophy with visual impairment, reflecting loss of
    retinal ganglion cell axonal function in the optic nerve. In some patients
    optic atrophy and hearing loss precede any recognised acute episode and are
    the earliest detectable signs. Generated by the Persistent Multimodal
    Neurological Deficit node.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:25895915
    reference_title: "CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with permanent areflexia and optic nerve pallor"
    explanation: Documents permanent optic nerve pallor in a CAPOS family.
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mother had been previously diagnosed with sensorineural hearing loss and optic nerve atrophy."
    explanation: >-
      Shows optic atrophy as a recognised standing diagnosis in an affected
      parent, supporting it as a persistent trait feature.
- name: Sensorineural hearing impairment
  category: Otologic
  diagnostic: true
  description: >-
    Bilateral sensorineural hearing loss that is mechanistically an auditory
    neuropathy: outer hair cell function (otoacoustic emissions, cochlear
    microphonics) is preserved while auditory brainstem responses are grossly
    abnormal. Pure-tone thresholds may progress over long follow-up. Generated
    by the Auditory Neuropathy with Preserved Outer Hair Cell Function node.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN)."
    explanation: >-
      The largest genotype-confirmed CAPOS audiological series characterises the
      hearing impairment as auditory neuropathy.
  - reference: PMID:34692702
    reference_title: "Auditory Neuropathy as the Initial Phenotype for Patients With ATP1A3 c.2452 G > A: Genotype-Phenotype Study and CI Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the 15 years follow-up of patient 1, we observed delayed neurological events and progressive bilateral sensorineural hearing loss in pure tone threshold (pure tone audiometry, PTA)."
    explanation: >-
      Long-term follow-up documents progressive bilateral sensorineural hearing
      loss in a p.E818K carrier.
- name: Abnormal auditory evoked potentials
  category: Otologic
  description: >-
    Grossly abnormal auditory brainstem responses in the presence of preserved
    otoacoustic emissions and cochlear microphonic potentials - the objective
    electrophysiological signature that localises the CAPOS hearing lesion to
    the auditory nerve rather than the cochlear hair cells. Generated by the
    Auditory Neuropathy with Preserved Outer Hair Cell Function node.
  phenotype_term:
    preferred_term: Abnormal auditory evoked potentials
    term:
      id: HP:0006958
      label: Abnormal auditory evoked potentials
  evidence:
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony"
    explanation: >-
      Directly documents grossly abnormal auditory brainstem responses in CAPOS.
- name: Encephalopathy
  category: Neurologic
  description: >-
    Acute encephalopathy accompanies the febrile ataxia episode in most
    patients, ranging from lethargy to loss of consciousness and coma. Generated
    by the Acute Febrile Encephalopathy and Cerebellar Decompensation node.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
    temporality: ACUTE
  evidence:
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients typically present at an early age with an acute-onset fever-induced episode of ataxia frequently associated with encephalopathy and weakness."
    explanation: Supports acute encephalopathy as a typical accompaniment of the febrile episode.
- name: Hypotonia
  category: Neurologic
  description: >-
    Hypotonia and flaccidity are prominent during the acute febrile episode,
    generated by the Acute Febrile Encephalopathy and Cerebellar Decompensation
    node.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    temporality: ACUTE
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
    explanation: Lists hypotonia among the acute febrile encephalopathy features.
- name: Nystagmus
  category: Ophthalmologic
  description: >-
    Nystagmus is one of the abnormal eye movements seen in CAPOS, prominent
    acutely; generated by the Acute Febrile Encephalopathy and Cerebellar
    Decompensation node.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
    explanation: Lists nystagmus among the acute CAPOS features.
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Strabismus is among the abnormal eye movements described in CAPOS, generated
    by the Acute Febrile Encephalopathy and Cerebellar Decompensation node.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
    explanation: Lists strabismus among the acute CAPOS features.
- name: Ophthalmoparesis
  category: Ophthalmologic
  description: >-
    Impaired extraocular movement documented during the acute paroxysmal
    episodes, generated by the Acute Febrile Encephalopathy and Cerebellar
    Decompensation node.
  phenotype_term:
    preferred_term: Ophthalmoparesis
    term:
      id: HP:0000597
      label: Ophthalmoparesis
    temporality: ACUTE
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness"
    explanation: Documents ophthalmoparesis during the fever-associated episodes.
- name: Dysarthria
  category: Neurologic
  description: >-
    Dysarthria or, in severe episodes, anarthria, as part of the acute
    cerebellar/bulbar decompensation, often persisting to some degree. Generated
    by the Acute Febrile Encephalopathy and Cerebellar Decompensation node.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
    explanation: Lists dysarthria/anarthria among the acute CAPOS features.
- name: Lethargy
  category: Neurologic
  description: >-
    Reduced arousal during the acute episode, at the mild end of the
    encephalopathy spectrum that extends to coma. Generated by the Acute Febrile
    Encephalopathy and Cerebellar Decompensation node.
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
    temporality: ACUTE
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness"
    explanation: Documents lethargy as an acute febrile-episode feature.
- name: Dystonia
  category: Neurologic
  description: >-
    Dystonia is reported as a possible additional sequela in CAPOS, overlapping
    with the movement-disorder features of the allelic ATP1A3 phenotypes. It is
    not a cardinal CAPOS feature and its attribution is explicitly hedged in the
    source, so it is recorded with PARTIAL support and is not tied to a specific
    pathophysiology node.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Besides the persisting CAPOS features, other possibly related sequelae included dystonia, myoclonus, and emotional and behavioral changes."
    explanation: >-
      The source describes dystonia as a "possibly related" sequela rather than
      an established CAPOS feature, so support is recorded as PARTIAL.
- name: Myoclonus
  category: Neurologic
  description: >-
    Myoclonus is reported alongside dystonia as a possible additional sequela in
    CAPOS. Like dystonia it is not a cardinal feature, its attribution is
    explicitly hedged in the source, and it is therefore recorded with PARTIAL
    support and not tied to a specific pathophysiology node.
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Besides the persisting CAPOS features, other possibly related sequelae included dystonia, myoclonus, and emotional and behavioral changes."
    explanation: >-
      The source lists myoclonus as a "possibly related" sequela rather than an
      established CAPOS feature, so support is recorded as PARTIAL.
- name: Developmental regression
  category: Neurologic
  description: >-
    Loss of previously acquired developmental skills has been documented
    following the presenting ataxic episode in a genetically confirmed CAPOS
    patient. This is the clinical expression of the Incomplete Recovery and
    Stepwise Deficit Accrual node - the episode does not simply resolve, and in
    the more severely affected patients the residuum is a net loss of function
    rather than a static deficit. Support is PARTIAL because the observation
    comes from the single CAPOS patient in a mixed AHC/CAPOS/RECA cohort.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:36484864
    reference_title: "ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial symptom of the patient with CAPOS was ataxia followed by developmental regression, seizures, deafness, visual impairment, and dysarthria"
    explanation: >-
      The sentence describes the single CAPOS patient of this mixed
      AHC/CAPOS/RECA cohort, so the attribution is CAPOS-specific; support is
      PARTIAL because it is one patient.
- name: Seizure
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Seizures are an uncommon but reported accompaniment of the acute febrile
    decompensation rather than a persisting feature. In the Demos cohort the
    single affected patient had brief focal seizures arising during the first
    febrile ataxic episode. Generated by the Acute Febrile Encephalopathy and
    Cerebellar Decompensation node.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:36484864
    reference_title: "ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial symptom of the patient with CAPOS was ataxia followed by developmental regression, seizures, deafness, visual impairment, and dysarthria"
    explanation: >-
      Documents seizures in the single CAPOS patient of this mixed
      AHC/CAPOS/RECA cohort; support is PARTIAL because it is one patient.
  - reference: PMID:24468074
    reference_title: "A novel recurrent mutation in ATP1A3 causes CAPOS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Table 1 Clinical features of 10 patients from three families with CAPOS syndrome"
    explanation: >-
      Establishes the denominator (10 patients) used for the frequency band
      assigned from the Table 1 rows quoted on this and other phenotypes.
  - reference: PMID:24468074
    reference_title: "A novel recurrent mutation in ATP1A3 causes CAPOS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures - - - - + c -- - - -"
    explanation: >-
      Table 1 row: 1 of the 10 tabulated patients is marked present (+) for
      seizures. 1/10 = 10%, which falls in the OCCASIONAL band (5-29%). The
      denominator is read off the Table 1 title quoted above, not derived.
  - reference: PMID:24468074
    reference_title: "A novel recurrent mutation in ATP1A3 causes CAPOS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cBrief focal seizures (unilateral arm jerking) developed in association with first episode of fever and ataxic encephalopathy."
    explanation: >-
      Table 1 footnote characterising the seizures as brief and focal and
      time-locked to the first febrile ataxic episode.
- name: Visual impairment
  category: Ophthalmologic
  description: >-
    Reduced vision - progressing in some patients to legal blindness - is the
    functional consequence of the optic atrophy curated separately above, and is
    what patients and families actually report. Generated by the Persistent
    Multimodal Neurological Deficit node.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "by mixed combinations of areflexia, pes cavus, profound visual impairment, and/or sensorineural hearing loss"
    explanation: >-
      Lists profound visual impairment among the persisting CAPOS features that
      should prompt ATP1A3 testing.
  - reference: PMID:36484864
    reference_title: "ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial symptom of the patient with CAPOS was ataxia followed by developmental regression, seizures, deafness, visual impairment, and dysarthria"
    explanation: >-
      Independent documentation of visual impairment in the CAPOS patient of a
      mixed AHC/CAPOS/RECA cohort; PARTIAL because it is one patient.
- name: Cerebellar atrophy
  category: Neurologic
  description: >-
    Structural cerebellar atrophy is reported only inconsistently in CAPOS and,
    where present, is mild. Brain MRI is frequently unremarkable, which is why a
    normal scan does not argue against the diagnosis. Whether any fixed
    cerebellar neuronal loss occurs at all is the open question recorded in the
    capos_degeneration_vs_dysfunction knowledge gap, and is the reason this
    entry declines conformance to the cerebellar_purkinje_degeneration module.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    severity: MILD
  evidence:
  - reference: PMID:36484864
    reference_title: "ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the brain MRI indicated mild cerebellar atrophy"
    explanation: >-
      The clause describes the single CAPOS patient of this mixed
      AHC/CAPOS/RECA cohort. Support is PARTIAL because it is one case and MRI
      findings across reported CAPOS patients are inconsistent.
- name: Coma
  category: Neurologic
  description: >-
    At the severe end of the acute febrile decompensation, depressed
    consciousness may progress from lethargy through loss of consciousness to
    frank coma, which can be prolonged. Generated by the Acute Febrile
    Encephalopathy and Cerebellar Decompensation node.
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
    temporality: ACUTE
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma."
    explanation: >-
      GeneReviews places coma at the severe end of the CAPOS acute febrile
      encephalopathy spectrum.
  - reference: PMID:24468074
    reference_title: "A novel recurrent mutation in ATP1A3 causes CAPOS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most severe episode occurred at age 4.5 years, when he was comatose for a week."
    explanation: >-
      A genotyped CAPOS proband was comatose for a week during his most severe
      febrile episode, documenting that the coma can be prolonged.
- name: Muscle weakness
  category: Neurologic
  description: >-
    Generalised motor weakness, often with flaccidity, accompanies the acute
    febrile episodes and is one of the manifestations that makes the acute
    presentation resemble an encephalitis rather than an isolated ataxia.
    Generated by the Acute Febrile Encephalopathy and Cerebellar Decompensation
    node.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
    temporality: ACUTE
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness."
    explanation: >-
      Lists motor weakness among the manifestations of the paroxysmal
      fever-associated episodes in four genotyped CAPOS patients.
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients typically present at an early age with an acute-onset fever-induced episode of ataxia frequently associated with encephalopathy and weakness."
    explanation: >-
      A review of the published CAPOS literature reports weakness as a frequent
      accompaniment of the acute fever-induced episode.
- name: Abnormal EKG
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    ATP1A3-related disorders are cardiac as well as neurological diseases. The
    only systematic cardiac study of the spectrum found resting ECG
    abnormalities in two of the three CAPOS patients it enrolled, and estimated
    the risk of life-threatening rhythm disturbance across ATP1A3 syndromes as
    comparable to that in established cardiac channelopathies. The CAPOS
    denominator in that study is only three patients, so the band below should
    be read as the best available systematic estimate rather than a stable
    frequency. This is the phenotype behind the baseline-ECG surveillance
    recommendation curated under diagnosis.
  phenotype_term:
    preferred_term: resting ECG abnormality
    term:
      id: HP:0003115
      label: Abnormal EKG
  evidence:
  - reference: PMID:32913013
    reference_title: "Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP."
    explanation: >-
      Directly quantitative and CAPOS-specific: 2/3 = 67%, which falls in the
      FREQUENT band (30-79%). Both numerator and denominator are read off the
      sentence, not derived. The CAPOS arm of this multicentre cohort is only
      three patients, which is stated here rather than hidden behind the band.
  - reference: PMID:32913013
    reference_title: "Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies"
    explanation: >-
      Establishes the clinical significance of the ECG findings across the
      ATP1A3 spectrum, which is what makes cardiac surveillance actionable. The
      claim is spectrum-level rather than CAPOS-specific.
- name: Migraine
  category: Neurologic
  description: >-
    Hemiplegic migraine has been reported in a single c.2452G>A carrier in a
    three-generation CAPOS pedigree, and the reporting authors state that
    migraine had not previously been documented in ATP1A3 mutation carriers at
    all. Recorded with PARTIAL support and no frequency band: it is one patient
    in one pedigree. The HPO binding uses the general Migraine term rather than
    a with-aura subtype, because HPO has no hemiplegic-migraine class (searched
    2026-08-01: `t~hemiplegic migraine` returns nothing and `l^Migraine`
    returns only HP:0002076 Migraine, HP:0002077 Migraine with aura and
    HP:0002083 Migraine without aura) and assigning "with aura" would be an
    inference the source does not make.
  phenotype_term:
    preferred_term: hemiplegic migraine
    term:
      id: HP:0002076
      label: Migraine
  evidence:
  - reference: PMID:26453127
    reference_title: CAPOS syndrome and hemiplegic migraine in a novel pedigree with the specific ATP1A3 mutation.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The ATP1A3 c.2452G>A mutation was identified in the affected members of the family, while one of the mutation carriers exhibited both CAPOS and hemiplegic migraine."
    explanation: >-
      Anchors the migraine to a genotype-confirmed CAPOS carrier. Support is
      PARTIAL because it is a single patient and the same paper notes migraine
      had not previously been reported in ATP1A3 carriers.
- name: Wolff-Parkinson-White syndrome
  category: Cardiovascular
  description: >-
    One of the ten patients tabulated in the Demos cohort was treated for
    Wolff-Parkinson-White syndrome in adulthood, and the authors carried
    "cardiac arrhythmia" as a row in their clinical-features table. This is
    recorded with PARTIAL support and no frequency band: it is a single patient,
    the authors do not assert a CAPOS-cardiac mechanism, and WPW is not rare in
    the general population. The systematic cardiac signal for CAPOS is carried
    by the Abnormal EKG phenotype above rather than by this single case.
  phenotype_term:
    preferred_term: Wolff-Parkinson-White syndrome
    term:
      id: HP:0001716
      label: Wolff-Parkinson-White syndrome
  evidence:
  - reference: PMID:24468074
    reference_title: "A novel recurrent mutation in ATP1A3 causes CAPOS syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "He was treated for Wolff-Parkinson-White syndrome at age 24 years."
    explanation: >-
      Narrative report of WPW in one genotyped CAPOS patient; PARTIAL because a
      single case does not establish a disease association.
  - reference: PMID:24468074
    reference_title: "A novel recurrent mutation in ATP1A3 causes CAPOS syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac arrhythmia - - - + h -- - - - -"
    explanation: >-
      Table 1 row: the authors tabulated cardiac arrhythmia as a clinical
      feature and marked 1 of the 10 patients present. No frequency band is
      assigned from n=1 with no asserted mechanism.
diagnosis:
- name: ATP1A3 targeted sequencing after a fever-induced ataxia episode
  description: >-
    Because CAPOS is genetically homogeneous for c.2452G>A, targeted ATP1A3
    sequencing is a high-yield first-line molecular test in the right clinical
    context: a child with paroxysmal fever-induced ataxia, or an adult with a
    stationary or slowly progressive childhood-onset cerebellar syndrome
    combined with areflexia, pes cavus, visual impairment and/or sensorineural
    hearing loss.
  presence: >-
    Detection of a heterozygous ATP1A3 c.2452G>A (p.Glu818Lys) variant confirms
    the diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted sequencing of the ATP1A3 gene is recommended in children exhibiting paroxysmal, fever-induced ataxia and in adults with a more or less stationary or slowly progressive cerebellar syndrome since childhood accompanied by mixed combinations of areflexia, pes cavus, profound visual impairment, and/or sensorineural hearing loss."
    explanation: >-
      An explicit recommendation for targeted ATP1A3 sequencing in exactly the
      two clinical scenarios described by this diagnostic entry.
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of ATP1A3-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in ATP1A3 identified by molecular genetic testing."
    explanation: >-
      GeneReviews defines the clinical-plus-molecular diagnostic standard for
      the ATP1A3-related disorder spectrum, including CAPOS.
- name: Audiological testing for auditory neuropathy (OAE/CM with ABR)
  description: >-
    Otoacoustic emissions and cochlear microphonic testing paired with auditory
    brainstem response testing is the diagnostic manoeuvre that identifies the
    CAPOS hearing loss as an auditory neuropathy: preserved OAE/CM with grossly
    abnormal ABR. This is not just a phenotyping detail - it directs
    rehabilitation away from conventional hearing aids and is why speech
    perception must be assessed separately from the pure-tone audiogram.
  presence: >-
    Preserved otoacoustic emissions and cochlear microphonic potentials with
    grossly abnormal auditory brainstem responses.
  diagnosis_term:
    preferred_term: evoked response audiometry (OAE/CM plus ABR)
    term:
      id: NCIT:C85857
      label: Evoked Response Audiometry
  evidence:
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony."
    explanation: >-
      Defines the exact audiological test combination and result pattern that
      establishes auditory neuropathy in CAPOS.
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This has implications for diagnosis and patient management."
    explanation: >-
      The authors themselves frame the auditory neuropathy finding as
      diagnostically and managerially consequential.
- name: Brain MRI to assess cerebellar structure
  description: >-
    Brain MRI is used to exclude alternative causes of acute childhood ataxia
    (acute disseminated encephalomyelitis, posterior fossa tumour, stroke) and
    to document any cerebellar atrophy. MRI findings in CAPOS are variable and
    frequently unremarkable; mild cerebellar atrophy has been reported. A normal
    MRI does not argue against the diagnosis.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:36484864
    reference_title: "ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the brain MRI indicated mild cerebellar atrophy"
    explanation: >-
      A single CAPOS patient in a cohort study showed mild cerebellar atrophy;
      support is PARTIAL because this is one case and MRI findings across
      reported CAPOS patients are inconsistent.
- name: Baseline and periodic electrocardiography
  description: >-
    A resting 12-lead ECG at diagnosis, and on identification of an at-risk
    relative by cascade testing, is warranted because ATP1A3-related disorders
    carry cardiac conduction abnormalities alongside the neurological phenotype.
    GeneReviews explicitly frames clarification of the genetic status of at-risk
    relatives as the step that identifies who should be evaluated for cardiac
    conduction abnormalities, and the multicentre cardiac cohort found resting
    ECG abnormalities in two of its three CAPOS patients. This is an
    ATP1A3-spectrum recommendation: no CAPOS-specific surveillance interval has
    been published, so none is stated here.
  presence: >-
    Resting ECG abnormalities, including conduction delay, in a majority of the
    small published CAPOS cardiac series.
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:32913013
    reference_title: "Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP."
    explanation: >-
      Establishes that resting ECG is informative in CAPOS, in the only
      systematic cardiac study of the ATP1A3 spectrum.
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clarification of the genetic status of apparently asymptomatic older and younger at-risk relatives is appropriate to identify as early as possible those who should be evaluated for cardiac conduction abnormalities"
    explanation: >-
      GeneReviews ties cascade genetic testing to cardiac evaluation. The
      statement is made for ATP1A3-related disorder as a whole, of which CAPOS
      is one of the four named phenotypes, rather than for CAPOS specifically.
differential_diagnoses:
- name: Alternating hemiplegia of childhood
  disease_term:
    preferred_term: alternating hemiplegia of childhood
    term:
      id: MONDO:0016241
      label: alternating hemiplegia of childhood
  description: >-
    The best-known allelic ATP1A3 disorder and the most important entity to keep
    distinct from CAPOS. AHC is defined by recurrent paroxysmal hemiplegic
    episodes beginning before 18 months with remission during sleep, and it does
    not encompass the hearing or visual impairment that define CAPOS. AHC is
    also usually de novo and caused by a different, heterogeneous set of ATP1A3
    variants (D801N, E815K, G947R predominating), not by p.Glu818Lys. Note the
    E815K/E818K near-collision in residue numbering - a named-entity-confusion
    trap when reading the ATP1A3 literature.
  evidence:
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment."
    explanation: >-
      States the discriminating feature: the allelic disorders lack the hearing
      and visual impairment that define CAPOS.
- name: Rapid-onset dystonia-parkinsonism
  disease_term:
    preferred_term: rapid-onset dystonia-parkinsonism
    term:
      id: MONDO:0007496
      label: dystonia 12
  description: >-
    The third classical ATP1A3 phenotype (DYT12). Presents from 18 months to
    adulthood with abrupt-onset, usually stress-triggered, bulbar-predominant
    generalised dystonia and parkinsonism. Like AHC it lacks the CAPOS
    sensory-organ involvement, and the movement-disorder predominance is
    extrapyramidal rather than cerebellar.
  evidence:
  - reference: PMID:25895915
    reference_title: "CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement."
    explanation: >-
      Explicitly contrasts CAPOS with rapid-onset dystonia-parkinsonism and AHC
      on age of onset, course, cerebellar-versus-extrapyramidal predominance and
      peripheral involvement.
- name: Relapsing encephalopathy with cerebellar ataxia (RECA/FIPWE)
  description: >-
    The closest CAPOS mimic and the hardest differential, because RECA/FIPWE is
    also an ATP1A3 disorder defined by fever-induced episodes of ataxia and
    encephalopathy in early childhood. RECA is associated with variants at
    ATP1A3 residue Arg756, not Glu818, and lacks the fixed optic atrophy,
    auditory neuropathy, areflexia and pes cavus that make up the CAPOS
    residuum. Molecular testing, not the acute episode phenotype, separates them.
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RECA/FIPWE primarily presents with fever-induced episodes (infancy to age 5 years); however, first episodes can occur occasionally in young adults during illnesses such as mononucleosis."
    explanation: >-
      Establishes RECA/FIPWE as a separately named fever-induced ATP1A3
      phenotype overlapping the CAPOS acute presentation window.
- name: Acute post-infectious cerebellar ataxia
  disease_term:
    preferred_term: acute post-infectious cerebellar ataxia
    term:
      id: MONDO:0850107
      label: postinfectious cerebellitis
  description: >-
    The commonest cause of acute ataxia after a febrile illness in a young
    child, and the diagnosis CAPOS is most often mistaken for at first
    presentation. It is typically monophasic with full recovery and no
    accompanying optic atrophy, hearing loss, areflexia or pes cavus. The
    presence of any of the fixed CAPOS features, or a second episode, or an
    affected parent, should prompt ATP1A3 testing.
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted sequencing of the ATP1A3 gene is recommended in children exhibiting paroxysmal, fever-induced ataxia"
    explanation: >-
      Supports the recommendation to test ATP1A3 in the fever-induced childhood
      ataxia population, i.e. the population that otherwise receives an acute
      post-infectious cerebellar ataxia label. Support is PARTIAL because the
      source does not itself contrast the two entities.
treatments:
- name: Aggressive fever management and febrile-trigger avoidance
  description: >-
    Because febrile illness is the near-obligate trigger for the episodes that
    accrue permanent deficit, early and aggressive antipyresis during
    intercurrent illness, prompt treatment of infections, and general avoidance
    of the physical, environmental and metabolic stressors known to provoke
    ATP1A3-related episodes are treated as preventive rather than merely
    symptomatic measures. This is the one intervention that is directly
    mechanism-linked in CAPOS. Its efficacy in reducing episode frequency has
    not been formally trialled - the rationale is mechanistic plus the
    consistency of the fever association.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Febrile Illness Unmasking of Pump Reserve Failure
    treatment_effect: INHIBITS
    description: >-
      Antipyresis and trigger avoidance act on the febrile-unmasking node itself,
      upstream of the acute decompensation and therefore upstream of the
      irreversible stepwise deficit accrual.
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "individuals who are heterozygous for an ATP1A3 pathogenic variant should avoid the known triggers for manifestations and/or episodes"
    explanation: >-
      The GeneReviews Agents/Circumstances to Avoid recommendation, the
      authoritative source for trigger avoidance in ATP1A3-related disorder.
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The fact that both siblings were assessed before the first acute-onset episode contributes to the description of early symptoms and signs of the disease, which could aid early diagnosis and management before the onset of acute episodes."
    explanation: >-
      Supports the value of pre-episode identification so that trigger
      management can be instituted; PARTIAL because the source describes the
      opportunity rather than demonstrating benefit.
- name: Acetazolamide episode prophylaxis
  description: >-
    Acetazolamide, borrowed from the episodic ataxias, has been tried as
    prophylaxis against CAPOS episodes. The evidence is genuinely conflicting
    and should not be presented as established: two patients in one series had
    no further episodes after starting acetazolamide, while a separate cohort
    reported no fluctuation benefit in its CAPOS patient. The originating
    authors themselves say further study is required.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acetazolamide
      term:
        id: CHEBI:27690
        label: acetazolamide
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "After initiation of acetazolamide in two patients, no further episodes occurred."
    explanation: >-
      Uncontrolled observation in two patients; PARTIAL because episodes are
      naturally infrequent (one to three per lifetime) so absence of further
      episodes is weak evidence of benefit.
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "acetazolamide may be considered in patients with CAPOS syndrome to prevent or attenuate bouts of ataxia, but this requires further study."
    explanation: >-
      The authors explicitly flag the recommendation as tentative and requiring
      further study.
  - reference: PMID:36484864
    reference_title: "ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No fluctuation was noted after using Acetazolamide."
    explanation: >-
      A separate cohort's CAPOS patient showed no response to acetazolamide,
      directly counterbalancing the positive series and justifying the
      conflicting-evidence framing.
- name: Cochlear implantation for auditory neuropathy
  description: >-
    Conventional hearing aids perform poorly in CAPOS because the lesion is
    neural dyssynchrony rather than loss of cochlear amplification. A cochlear
    implant is the rehabilitative option, but outcomes reported to date are
    inconsistent: one series reported preliminary speech-perception improvement
    and another reported a poor result in an implanted p.E818K patient. Counsel
    accordingly rather than promising benefit. therapeutic_modality is DEVICE
    because the therapy is an implanted prosthesis; the treatment_term records
    the surgical action by which it is delivered, since NCIT's Cochlear Implant
    concept (NCIT:C157820) is a Medical Device and is therefore not reachable
    from the Clinical Intervention or Procedure root that treatment_term is
    bound to.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:29305691
    reference_title: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients."
    explanation: >-
      Supports the poor performance of conventional amplification and offers
      preliminary, explicitly hedged support for cochlear implantation.
  - reference: PMID:34692702
    reference_title: "Auditory Neuropathy as the Initial Phenotype for Patients With ATP1A3 c.2452 G > A: Genotype-Phenotype Study and CI Management."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 2 underwent CI on his left ear, and the result was poor."
    explanation: >-
      Documents a poor cochlear implantation outcome in a genotype-confirmed
      p.E818K patient, the counterweight to the optimistic report.
  - reference: PMID:34692702
    reference_title: "Auditory Neuropathy as the Initial Phenotype for Patients With ATP1A3 c.2452 G > A: Genotype-Phenotype Study and CI Management."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study further demonstrates the significance of genetic testing for this specific mutation for identifying the special subtype of AN with somewhat favorable CI outcome"
    explanation: >-
      The same study nonetheless concludes the genotype identifies an auditory
      neuropathy subtype with a somewhat favourable implantation outcome,
      capturing the genuine uncertainty in the field.
- name: Multidisciplinary supportive and rehabilitative care
  description: >-
    There is no disease-modifying therapy for CAPOS. Management is supportive
    and multidisciplinary: physical therapy and mobility support for ataxia and
    pes cavus, low-vision support for optic atrophy, speech and language
    therapy for dysarthria, and orthopaedic assessment of the foot deformity,
    coordinated across neurology, ophthalmology, audiology, rehabilitation and
    genetics.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is no cure for ATP1A3-related disorder. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended."
    explanation: >-
      GeneReviews establishes supportive care as the standard of management for
      ATP1A3-related disorder including CAPOS.
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This ideally involves multidisciplinary care by specialists in neurology, developmental pediatrics, orthopedics, physical medicine and rehabilitation, speech-language therapy, psychology, mental health, ophthalmology, social work, and medical genetics."
    explanation: >-
      Specifies the multidisciplinary composition of supportive care recommended
      by GeneReviews.
- name: Genetic counselling and predictive testing
  description: >-
    Autosomal dominant transmission with a 50% recurrence risk per child, and a
    roughly even split between inherited and de novo variants, make genetic
    counselling central. Parental testing is important because a mildly affected
    parent may be recognised only after the child is diagnosed - several
    published families were ascertained this way. Once the familial variant is
    known, predictive and prenatal/preimplantation testing are possible.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301294
    reference_title: "ATP1A3-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with ATP1A3-related disorder has a 50% chance of inheriting the pathogenic variant. Once the ATP1A3 pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
    explanation: >-
      Establishes the recurrence risk and the availability of predictive and
      prenatal testing that this counselling entry describes.
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe three new patients, a woman and her two sons diagnosed with CAPOS syndrome."
    explanation: >-
      Illustrates the multigenerational ascertainment pattern (affected mother
      plus two affected sons) that makes family-wide evaluation important.
definitions:
- name: Fever-associated acute ataxia case-finding query for undiagnosed CAPOS
  definition_type: PHENOTYPE_ALGORITHM
  derivation_basis: MECHANISTIC_HYPOTHESIS
  validation_status:
    status: PROPOSED
    rationale: >-
      No published computable phenotype exists for CAPOS and none has been
      evaluated against a genotyped gold standard. The query is proposed here on
      the basis of the fever-triggered pump-reserve-failure hypothesis: if fever
      is the mechanistically privileged trigger, then the EHR signature of an
      undiagnosed CAPOS carrier is an acute ataxia or acute encephalopathy
      encounter temporally locked to a documented febrile illness in a young
      child, with subsequent coded optic atrophy, sensorineural hearing loss or
      areflexia. Expected yield is very low in absolute terms given the disease's
      rarity, so validation would need a genotype-linked biobank of substantial
      size (All of Us, UK Biobank, eMERGE) and would most usefully be run as an
      ATP1A3-spectrum query rather than a CAPOS-specific one.
  attaches_to:
  - pathophysiology#Febrile Illness Unmasking of Pump Reserve Failure
  - pathophysiology#Incomplete Recovery and Stepwise Deficit Accrual
  description: >-
    EHR/OMOP case-finding query: identify children with an acute ataxia or acute
    encephalopathy encounter occurring during or immediately after a documented
    febrile illness, who subsequently acquire codes for optic atrophy,
    sensorineural hearing loss or areflexia, as candidates for undiagnosed
    ATP1A3 p.Glu818Lys CAPOS warranting targeted sequencing. The discriminating
    feature versus the far commoner acute post-infectious cerebellar ataxia is
    the later accrual of fixed sensory-organ deficits rather than full recovery.
    Directly analogous in structure to the Brugada_Syndrome fever-unmasking
    query, but with derivation_basis MECHANISTIC_HYPOTHESIS rather than
    ESTABLISHED_CRITERIA because the fever-to-decompensation mechanism in CAPOS
    is hypothesised (pump reserve failure) rather than demonstrated.
  scope: >-
    EHR/OMOP case-finding for undiagnosed CAPOS/ATP1A3-spectrum carriers;
    predicated on the unvalidated fever_triggered_pump_reserve_failure
    hypothesis.
  criteria_sets:
  - name: Fever-locked acute ataxia with later fixed sensory-organ deficit
    description: >-
      An acute ataxia or acute encephalopathy encounter in a child aged roughly
      6 months to 5 years, temporally coincident with a documented febrile
      illness, followed at any later time by a code for optic atrophy,
      sensorineural hearing loss or areflexia.
    inclusion_criteria:
    - preferred_term: Documented febrile illness
      description: Fever or febrile-illness diagnosis code serving as the index exposure.
    - preferred_term: Acute ataxia or acute encephalopathy encounter
      description: >-
        Acute-onset ataxia or encephalopathy coded during or within days of the
        febrile episode.
    - preferred_term: Later fixed sensory-organ or reflex deficit
      description: >-
        A subsequent code for optic atrophy, sensorineural hearing loss, or
        areflexia, marking incomplete recovery rather than the monophasic full
        recovery of post-infectious cerebellar ataxia.
    exclusion_criteria:
    - preferred_term: Established alternative cause of acute ataxia
      description: >-
        Posterior fossa tumour, stroke, acute disseminated encephalomyelitis,
        intoxication, or an already-established ATP1A3 or other genetic
        diagnosis.
  evidence:
  - reference: PMID:27091223
    reference_title: "The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted sequencing of the ATP1A3 gene is recommended in children exhibiting paroxysmal, fever-induced ataxia and in adults with a more or less stationary or slowly progressive cerebellar syndrome since childhood accompanied by mixed combinations of areflexia, pes cavus, profound visual impairment, and/or sensorineural hearing loss."
    explanation: >-
      Supplies the clinical logic the query operationalises: fever-induced
      ataxia plus fixed sensory-organ deficits should trigger ATP1A3 testing.
  - reference: PMID:28483396
    reference_title: Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia-Review of the Literature and a New Family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The acute symptoms improve within days, but most patients show slow progression afterward."
    explanation: >-
      Supports the discriminating element of the query - incomplete recovery
      with later accrual of deficit - versus monophasic post-infectious ataxia.
  notes: >-
    Counterpart to the Brugada_Syndrome fever-unmasking query
    (ESTABLISHED_CRITERIA) and the Timothy_Syndrome fever_exacerbated_cav1.2
    query (MECHANISTIC_HYPOTHESIS). CAPOS sits with Timothy: the fever
    association is clinically certain but the mechanism by which fever
    precipitates decompensation is hypothesised, and the computable phenotype
    itself is untested. See docs/hypothesis-based-phenotype-algorithms.md.
discussions:
- discussion_id: capos_degeneration_vs_dysfunction
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the persistent deficit in CAPOS reflect actual neuronal loss
    (degeneration) or persistent functional impairment of surviving neurons?
  attaches_to:
  - pathophysiology#Incomplete Recovery and Stepwise Deficit Accrual
  rationale: >-
    This is the central unresolved mechanistic question in CAPOS and it
    determines whether the disorder belongs with the neurodegenerations at all.
    The clinical picture - stepwise accrual of fixed deficit after discrete
    febrile events, with considerable interval recovery - is equally compatible
    with (a) each episode killing a tranche of vulnerable neurons, or (b) each
    episode leaving surviving neurons in a persistently deranged but living
    state. Neuroimaging does not settle it: MRI is frequently unremarkable and
    only mild cerebellar atrophy has been reported, in isolated cases. No
    neuropathological study of a CAPOS brain has been published, and no
    longitudinal quantitative imaging cohort exists. The answer has direct
    therapeutic consequences, because a functional lesion is in principle
    reversible while neuronal loss is not. This gap is also the reason CAPOS
    does not declare conformance to the cerebellar_purkinje_degeneration module.
  proposed_experiments:
  - experiment_id: capos_longitudinal_structural_imaging
    name: Longitudinal cerebellar volumetry and retinal OCT around febrile episodes
    description: >-
      Longitudinal volumetric MRI of the cerebellum and quantitative optical
      coherence tomography of the retinal nerve fibre layer in genotyped CAPOS
      patients, timed around febrile episodes, to test whether fixed structural
      loss accrues stepwise at each episode.
    would_support:
    - >-
      Stepwise loss of cerebellar volume and retinal nerve fibre layer thickness
      time-locked to episodes would support true neuronal loss.
    would_refute:
    - >-
      Stable structural measures despite accrued clinical deficit would support
      persistent functional impairment of surviving neurons.
  - experiment_id: capos_ipsc_febrile_challenge
    name: Patient-derived iPSC neuron febrile-temperature challenge
    description: >-
      Patient-derived iPSC neurons (cerebellar and sensory) carrying
      p.Glu818Lys, challenged at febrile temperature, assayed for both acute
      ion-gradient failure and subsequent cell death versus persistent
      functional derangement in survivors.
    would_support:
    - >-
      Measurable cell death after febrile-temperature challenge would support
      the degeneration model.
    would_refute:
    - >-
      Survival with persistent electrophysiological derangement and no excess
      death would support the functional-impairment model.
  evidence:
  - reference: PMID:36484864
    reference_title: "ATP1A3-related phenotypes in Chinese children: AHC, CAPOS, and RECA."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the brain MRI indicated mild cerebellar atrophy"
    explanation: >-
      The only structural evidence bearing on the question is a single case with
      mild cerebellar atrophy, which is insufficient to establish or exclude
      neurodegeneration.
- discussion_id: capos_allelic_lesion_selectivity
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does the single recurrent p.Glu818Lys allele produce the specific CAPOS
    lesion set (cerebellum, auditory nerve, optic nerve, dorsal root ganglion)
    while other ATP1A3 alleles in the same gene produce entirely different
    lesion sets?
  attaches_to:
  - pathophysiology#Impaired Neuronal Transmembrane Ion Gradient Restoration
  rationale: >-
    ATP1A3 is expressed broadly across neurons, yet allelic variants partition
    into strikingly discrete syndromes: p.Glu818Lys gives CAPOS with sensory
    organ and peripheral involvement, Arg756 variants give RECA, and a different
    heterogeneous set gives AHC or rapid-onset dystonia-parkinsonism. The
    biophysical characterisation of E818K explains that the pump fails, but not
    why the failure selects cerebellar, auditory, optic and dorsal root ganglion
    neurons specifically. Candidate explanations - regional differences in
    alpha-3 dependence, in firing rate and metabolic load, in compensating
    alpha-1 expression, or in the specific kinetic parameter each variant
    perturbs - have not been tested against each other. Resolving this would
    turn ATP1A3 genotype-phenotype correlation from empirical pattern-matching
    into prediction.
  proposed_experiments:
  - experiment_id: capos_celltype_pump_dependence
    name: Cell-type-resolved alpha-3 pump dependence profiling
    description: >-
      Cell-type-resolved measurement of alpha-3 versus alpha-1 pump dependence
      and firing-rate-dependent sodium load across cerebellar Purkinje, spiral
      ganglion, retinal ganglion and dorsal root ganglion neurons, correlated
      with each variant's specific kinetic defect.
    would_support:
    - >-
      A match between the CAPOS lesion set and the neurons with highest alpha-3
      dependence and lowest alpha-1 compensation would support a
      dependence-based selectivity model.
  - experiment_id: capos_comparative_variant_electrophysiology
    name: Head-to-head electrophysiology of E818K, R756H and AHC variants
    description: >-
      Comparative electrophysiological profiling of E818K, R756H and the common
      AHC variants in a single common expression system, testing whether the
      distinct clinical lesion sets track distinct kinetic signatures rather
      than overall pump activity.
    would_support:
    - >-
      Variant-specific kinetic signatures that predict the clinical lesion set
      would support parameter-specific rather than dose-dependent selectivity.
  evidence:
  - reference: PMID:36192182
    reference_title: The Phenotypic Continuum of ATP1A3-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study."
    explanation: >-
      Documents the variant-specific phenotype partitioning that this knowledge
      gap asks the mechanism for.
- discussion_id: capos_invitro_febrile_translational_validity
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Do heterologous-expression measurements of E818K pump kinetics, made at
    standard assay temperature in oocytes and cell lines, predict alpha-3 pump
    behaviour in human neurons at febrile temperature?
  attaches_to:
  - pathophysiology#Febrile Illness Unmasking of Pump Reserve Failure
  rationale: >-
    The entire mechanistic case for CAPOS rests on heterologous-expression
    electrophysiology and biochemistry: reduced sodium affinity, accelerated
    E1P-to-E2P transition, weakened voltage dependence, and failure of pump
    activation under "physiological conditions". But those conditions are the
    assay's physiological conditions, not a febrile human neuron's. The
    fever-trigger phenomenon - the single most characteristic clinical fact
    about CAPOS - has never been reproduced in any model system, and no study
    has measured mutant pump function across the normothermic-to-febrile
    temperature range. This is not an absence of evidence but a translational
    validity gap: strong in-vitro evidence exists, and its applicability to the
    defining in-vivo phenomenon is the open question.
  proposed_experiments:
  - experiment_id: capos_temperature_ramp_electrophysiology
    name: E818K pump characterisation across the febrile temperature range
    description: >-
      Repeat the E818K two-electrode voltage-clamp and biochemical
      characterisation across a 37 to 41 degrees Celsius range to test whether
      the mutant pump's deficit is disproportionately temperature-sensitive
      relative to wild type.
    would_support:
    - >-
      Disproportionate loss of mutant pump activity as temperature rises would
      support the fever-unmasking reserve-failure hypothesis.
    would_refute:
    - >-
      Parallel temperature responses in mutant and wild type would argue the
      fever trigger acts through some other route, such as systemic metabolic
      or inflammatory demand.
  - experiment_id: capos_knockin_fever_challenge
    name: E818K knock-in animal model fever challenge
    description: >-
      Establish a knock-in animal model carrying the orthologous E818K allele
      and test whether experimentally induced fever provokes an acute ataxic
      episode with incomplete recovery, which would be the first in-vivo
      recapitulation of the CAPOS trigger.
    would_support:
    - >-
      Fever-provoked ataxia with incomplete recovery in the knock-in would
      establish in-vivo validity of the mechanism.
    would_refute:
    - >-
      Absence of any fever-provoked phenotype despite the orthologous allele
      would indicate a human-specific determinant not captured by the model.
  evidence:
  - reference: PMID:30409907
    reference_title: "Functional consequences of the CAPOS mutation E818K of Na(+),K(+)-ATPase."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Here, using biochemical and electrophysiological approaches, we examined the functional characteristics of E818K, as well as of E818Q and E818A mutants."
    explanation: >-
      Confirms the mechanistic evidence base is biochemical and
      heterologous-expression electrophysiology, establishing the model system
      whose translational validity at febrile temperature is unresolved.
references:
- reference: PMID:20301294
  title: "ATP1A3-Related Disorder."
  tags:
  - GeneReviews
notes: >-
  LUMP-VS-SPLIT REASONING. CAPOS is curated as its own dismech entry rather than
  being folded into an ATP1A3-related disorder umbrella, and rather than being
  merged with the existing Alternating_Hemiplegia_of_Childhood entry, for three
  reasons. (1) Genotype: CAPOS is essentially monoallelic - every reported
  patient carries c.2452G>A p.Glu818Lys - whereas AHC and rapid-onset
  dystonia-parkinsonism arise from large heterogeneous variant sets. (2)
  Phenotype: the original CAOS report states that CAPOS "differs categorically"
  from the allelic disorders in age of onset, clinical course, cerebellar over
  extrapyramidal movement disorder predominance, and peripheral nervous system
  involvement; the sensory-organ involvement (optic atrophy, auditory
  neuropathy) is explicitly absent from AHC and RDP. (3) Mechanism: the
  fever-triggered, stepwise, incompletely-reversible decompensation pattern is
  the mechanistic signature modelled in the pathophysiology chain here and is
  not shared with AHC's sleep-remitting hemiplegic attacks. Counterweight, kept
  visible rather than suppressed: GeneReviews states these phenotypes "exist on
  a spectrum and should be regarded as classifications of convenience", and the
  phenotypic-continuum literature shows many ATP1A3 patients do not fit any
  named syndrome. The split is therefore a pragmatic curation decision at the
  level of a well-defined recurrent-allele syndrome, not a claim that the
  ATP1A3 phenotypes are biologically discontinuous. A future
  ATP1A3_Related_Disorders grouping in kb/groupings/ (grouping_basis
  SHARED_GENE_FAMILY plus SHARED_MECHANISM) would be the right structure to
  express both the split entries and their continuity; it is not created here.

  MODULE CONFORMANCE - deliberately declined for both candidate modules.
  (a) sensorineural_hair_cell_loss: NOT declared. That module's chain runs
  through "Hair Cell Mechanotransduction Failure and Death" as its central
  effector, with spiral ganglion degeneration as a downstream consequence of
  hair cell loss and lost endocochlear amplification. CAPOS inverts this: outer
  hair cell activity is demonstrably preserved (otoacoustic emissions and
  cochlear microphonic potentials intact) and the lesion is primary neural
  dyssynchrony in the auditory nerve. Declaring conformance would assert a
  mechanism the CAPOS evidence specifically excludes. The Auditory Neuropathy
  with Preserved Outer Hair Cell Function node captures the true mechanism
  instead. (b) cerebellar_purkinje_degeneration: NOT declared. That module's
  central effector is "Purkinje Neuron Degeneration" - apoptotic neuronal loss
  with cerebellar atrophy and gliosis - reached via calcium and proteostasis
  dysregulation. CAPOS has no published neuropathology, MRI is frequently
  unremarkable, and the only reported structural change is mild cerebellar
  atrophy in a single case; the ataxia is episodic and substantially reversible
  within each episode, which is not the module's degenerative phenotype. Whether
  CAPOS eventually qualifies is exactly the capos_degeneration_vs_dysfunction
  KNOWLEDGE_GAP discussion above; conformance should be revisited if neuronal
  loss is demonstrated.

  PATHOGRAPH SHAPE. The pathophysiology graph is a single connected component
  with no orphan nodes: pump dysfunction to impaired ion-gradient restoration to
  febrile unmasking to acute decompensation to incomplete recovery, which then
  branches to the persistent multimodal deficit and to the auditory neuropathy
  node. Every curated phenotype names the node that generates it in its
  description; the only phenotype not tied to a node is Dystonia, which the
  source itself reports only as a "possibly related" sequela and which is
  therefore recorded with PARTIAL support rather than wired into the graph.

  DEEP RESEARCH. The initial curation was built directly from primary
  literature identified via NCBI E-utilities PubMed search, with the
  GeneReviews ATP1A3-Related Disorder chapter (PMID:20301294) as the mandatory
  phenotype baseline, because `just research-disorder` exits non-zero when the
  target disorder file does not yet exist in kb/disorders/. That deviation has
  now been closed: `just research-disorder claude_code CAPOS_Syndrome` was
  re-run on 2026-08-01 once the file existed, completed successfully, and its
  artifact is committed as
  research/CAPOS_Syndrome-deep-research-claude_code.md plus its .citations.md
  sidecar. The chicken-and-egg failure is therefore a workflow-ordering bug in
  the recipe, not a provider failure.

  DEEP RESEARCH CROSS-CHECK - what was taken and what was refused. The report
  was treated as leads, not ground truth. Filled from it: Abnormal EKG
  (HP:0003115) with the CAPOS-specific 2/3 resting-ECG figure and the
  channelopathy-equivalent risk statement from the multicentre cardiac cohort
  PMID:32913013, plus a matching baseline-electrocardiography diagnosis entry;
  hemiplegic migraine (PMID:26453127); and confirmation of the frequency
  arithmetic independently derived here from the Demos Table 1 rows. Refused:
  (a) the report proposes HP:0031815 as "Auditory neuropathy" - HP:0031815 is
  actually *Abnormal oral physiology*, verified with OAK, and was discarded;
  (b) the report proposes HP:0002083 for migraine with aura - HP:0002083 is
  actually *Migraine without aura*; (c) quotations the report marked [P]
  (possibly paraphrased through a summarising fetch layer) were not used at
  all - every snippet in this entry is verbatim against a cached reference.

  AUDITORY NEUROPATHY HAS NO HPO TERM. Searched 2026-08-01 with OAK against
  sqlite:obo:hp: `t~auditory neuropathy`, `t~auditory synaptopathy`,
  `t~dyssynchrony`, `l^Auditory`, `l~cochlear nerve`, and `t~neuropathy`
  filtered for auditory/cochlear/acoustic/eighth. No class for auditory
  neuropathy or auditory neuropathy spectrum disorder exists. Candidates
  audited and rejected: HP:0011396 Abnormality of the cochlear nerve and
  HP:0034585 Cochlear nerve hypoplasia are both descendants of HP:0011391
  Abnormal inner ear nerve *morphology*, whereas the CAPOS lesion is functional
  dyssynchrony in a structurally normal nerve; HP:0025112 Auditory sensitivity
  and HP:5200410 Auditory agnosia are unrelated. HP:0006958 Abnormal auditory
  evoked potentials, already used here, remains the correct binding, and the
  mechanism itself is carried by the Auditory Neuropathy with Preserved Outer
  Hair Cell Function pathophysiology node. This is an HPO gap, not a curation
  gap.

  FREQUENCY BANDS - what was and was not assigned. Bands are assigned only
  where a denominator is quotable. Three come from Demos Table 1, whose title
  ("Clinical features of 10 patients from three families with CAPOS syndrome")
  is quoted as its own evidence item so the denominator is read off the paper
  rather than derived: pes cavus 3/10 = 30% (FREQUENT, at the band's lower
  boundary) and seizures 1/10 = 10% (OCCASIONAL). One comes from
  PMID:32913013, which states both numerator and denominator in the sentence
  quoted: resting ECG abnormality 2/3 = 67% (FREQUENT), with the three-patient
  CAPOS arm stated in the explanation. Deliberately NOT banded: cerebellar
  ataxia, areflexia, optic atrophy and sensorineural hearing loss are 10/10 in
  the same Demos table, but that cohort was ascertained on those very features,
  so 100% would report the case definition rather than a frequency; and
  Wolff-Parkinson-White is 1/10 with no asserted mechanism, which is too thin
  to band.

  REMAINING NARROWING, STATED EXPLICITLY. The following surfaced in the
  cross-check and were deliberately left out of this entry rather than curated
  thinly. (i) Blindness (HP:0000618, 2/10 in the HPO annotation set) is
  subsumed here by Visual impairment with a PROGRESSIVE clinical_course; the
  HPO annotation counts themselves were not used as evidence because they are
  a derived annotation product rather than a quotable primary source.
  (ii) Dysphagia and cognitive dysfunction are real Demos Table 1 rows but
  their +/- strings are broken across a page-extraction artifact in the cached
  full text, so no clean verbatim row can be quoted and no honest count can be
  made; the cognitive-dysfunction footnote in any case describes "low average
  to average IQ and reduced attention skills", which does not support an
  intellectual-disability term. (iii) Peripheral axonal neuropathy is in
  genuine tension with the original description's areflexia-without-neuropathy
  claim; that is a mechanistic question rather than a phenotype to add, and it
  belongs with the areflexia discussion. (iv) The cardiac work for the sibling
  Alternating_Hemiplegia_of_Childhood entry, and any surveillance-interval
  treatment entry, remain with issue #7648 - only the CAPOS-specific arm of
  PMID:32913013 is curated here.

  NEC PREFLIGHT. MONDO:0011038 was verified with OAK before curation:
  OMIM:601338, Orphanet:1171, is_a MONDO:0700002 ATP1A3-associated neurological
  disorder. The ATP1A3 spectrum is a high named-entity-confusion risk class -
  AHC, RDP/DYT12, CAPOS and RECA/FIPWE are allelic but distinct - and residue
  numbering is a specific trap, since the common AHC variant p.Glu815Lys (E815K)
  is three residues from the CAPOS p.Glu818Lys (E818K). Every genotype claim in
  this entry is anchored to the c.2452G>A nucleotide coordinate as well as the
  protein change.
📚

References & Deep Research

References

1
PMID:20301294
ATP1A3-Related Disorder.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-5[1m] 72 citations 2026-08-01T13:39:55.064830

1. Disease Information

Overview

CAPOS syndrome is a rare autosomal dominant neurological disorder whose acronym encodes its five cardinal features: Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss. Its defining natural-history signature is episodic: early-childhood onset of one to three acute, fever-triggered ataxic encephalopathy episodes, each followed by incomplete recovery leaving a stepwise-accumulating fixed deficit, with subsequently progressive optic atrophy and sensorineural hearing loss.

It is caused, in every genetically confirmed case reported to date, by a single recurrent heterozygous missense variant in ATP1A3: c.2452G>A, p.(Glu818Lys) — making CAPOS one of the most genetically homogeneous Mendelian disorders known.

The syndrome was delineated clinically in 1996 by Nicolaides, Appleton and Fryer (PMID:8733056) from a single three-generation family; the molecular cause remained unknown for 18 years until whole-exome sequencing in 2014 (PMID:24468074).

Original clinical delineation (PMID:8733056, J Med Genet 1996) [V]:

"We report three family members who presented with a relapsing, early onset cerebellar ataxia, associated with progressive optic atrophy and sensorineural deafness. All three patients have areflexia (in the absence of a peripheral neuropathy), a pes cavus deformity, and show varying degrees of severity. Extensive neurological investigations have been normal, and the aetiology and pathophysiology of this disorder remain unclear."

Prescient closing note from the same abstract [V]: "which is likely to either have an autosomal dominant or maternal mitochondrial pattern of inheritance" — the mitochondrial hypothesis was later excluded, but the phenotype's mitochondrial mimicry remains a recognized diagnostic pitfall (see §10).

Key Identifiers

Resource Identifier
MONDO MONDO:0011038 — "cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome" [OLS-verified]
OMIM (phenotype) 601338 — CEREBELLAR ATAXIA, AREFLEXIA, PES CAVUS, OPTIC ATROPHY, AND SENSORINEURAL HEARING LOSS; CAPOS
OMIM (gene) 182350 (ATP1A3)
Orphanet ORPHA:1171
MedGen CUI C1832466, UID 318633
MeSH (supplementary concept) C535351
UMLS C1832466
SNOMED CT 720634003
GARD 0001188
NANDO (Japan) 1200526
ICD-10 Not authoritatively confirmed in this pass; Orphanet maps most hereditary ataxia-plus syndromes to G11.8 ("Other hereditary ataxias"). Verify before curating.
ICD-11 Not confirmed. Verify.
HGNC (gene) HGNC:801 → dismech lowercase form hgnc:801
dbSNP rs587777771
ClinVar VCV 000156238

Synonyms and Alternative Names

  • CAPOS syndrome (exact synonym, MONDO)
  • CAOS syndrome — used when pes cavus is absent; pes cavus occurs in only ~30% of patients (PMID:25895915, PMID:29625811, PMID:31780320). Recommend curating "CAOS" as a related synonym and noting the acronym instability.
  • Cerebellar ataxia – areflexia – pes cavus – optic atrophy – sensorineural hearing loss (long form)
  • Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural deafness
  • Contextual umbrella term: ATP1A3-related disorder / ATP1A3 spectrum disorder — the currently preferred framing (see §2).

Information Provenance

Knowledge of CAPOS derives almost entirely from aggregated case-level literature (single families and small multi-family series), not from EHR/registry data. The largest CAPOS-specific series is 18 genetically confirmed patients from 11 families (PMID:29305691). GeneReviews (PMID:20301294, ATP1A3-Related Disorder) tabulates 53 individuals from 40 families reported to date [P]. There is no CAPOS-specific patient registry; affected individuals are captured within broader ATP1A3/AHC registries (e.g. the AHC Foundation, IAHCRC consortium). Consequently every frequency figure in this report is literature-ascertainment-biased toward severe/complete phenotypes.

2. Etiology

Disease Causal Factors

CAPOS is a pure monogenic channelopathy/pump-opathy with a single causal allele:

ATP1A3 NM_152296.5:c.2452G>A, p.(Glu818Lys) — heterozygous, autosomal dominant.

PMID:24468074 (Demos et al., Orphanet J Rare Dis 2014) established this [V]:

"We found an identical heterozygous missense mutation, c.2452G > A (p.(Glu818Lys)), in the Na⁺/K⁺ ATPase α₃(ATP1A3) gene in the proband and his affected sister and mother, but not in either unaffected maternal grandparent, in the first family. The same mutation was also identified in the proband and three other affected members of the second family and in all three affected members of the third family. This mutation was not found in more than 3600 chromosomes from unaffected individuals."

Genetic homogeneity was confirmed independently (PMID:27091223, Maas et al. 2016 — title: "The Genetic Homogeneity of CAPOS Syndrome") and re-affirmed in the 2021 animal-model review (PMID:34612482) [P]: "All of the reported cases of CAPOS, to date, are heterozygous for a single recurrent missense mutation, E818K."

Locus heterogeneity: none reported. No non-ATP1A3 cause and no second ATP1A3 allele has ever been shown to produce the full CAPOS phenotype. Other ATP1A3 variants produce different allelic disorders (see §4).

Risk Factors

Genetic risk factors - The only genetic risk factor is inheritance/de-novo occurrence of p.Glu818Lys. There are no known susceptibility loci or GWAS signals (CAPOS is far too rare for GWAS). - No modifier genes have been identified. However, the marked intrafamilial variability in severity within pedigrees carrying the identical allele (PMID:26453127, PMID:28483396, PMID:34655904) is strong indirect evidence that modifiers — genetic, epigenetic, or stochastic-developmental — exist. This is a genuine knowledge gap; curate as discussions: kind: KNOWLEDGE_GAP. - Parental age effects on the de novo rate have not been studied.

Environmental risk factors (episode triggers, not disease-causation factors)

The critical distinction for CAPOS: environment does not cause the disease, but it precipitates every acute decompensation. Documented triggers:

Trigger Evidence
Febrile illness (the dominant trigger) PMID:8733056, PMID:24468074, PMID:27091223 [V] — episodes "were consistently associated with febrile illness"; PMID:31410291 [V] — "three fever related episodes of acute neurological deterioration"
Pregnancy and the peripartum period PMID:29090527 [V] — "one of the affected individuals experienced markedly worsening features during her three pregnancies and in the immediate postpartum period, a potential element of the natural history of CAPOS previously unreported"
Physical/emotional/psychological stress; missed meals; sleep deprivation GeneReviews [P] (generic ATP1A3 guidance)
Environmental stress: bright/fluorescent light, heat/cold, excessive noise, crowds GeneReviews [P] (generic ATP1A3 guidance; strongest evidence in AHC)
Non-febrile infection (e.g. URTI) PMID:36484864 [V] — for AHC in the same cohort, "the most common trigger was an upper respiratory tract infection without fever"; extrapolation to CAPOS is uncertain
  • Age: onset window is narrow — usually 6 months to 5 years (GeneReviews [P]). The risk of a first episode falls sharply after early childhood, though adult-onset episodes occur (PMID:29625811 reports an episode at age 37).
  • Sex: no established sex bias for CAPOS; pregnancy is a female-specific additional trigger.
  • Family history: ~50% of cases are familial (see §9).

Protective Factors

  • Genetic protective factors: none known. No protective/modifier alleles reported.
  • Environmental protective factors: none proven. Plausible, biologically coherent, but unvalidated candidates:
  • Aggressive antipyresis and early treatment of febrile illness — PMID:35047275 [V]: "Aggressive management of febrile illness may be helpful in alleviating the symptoms." (This paper describes a residue-756 FIPWE patient, not CAPOS — apply with care.)
  • Prophylactic acetazolamide — PMID:27091223 [V]: "After initiation of acetazolamide in two patients, no further episodes occurred." (n=2, uncontrolled.)
  • Routine childhood immunization (indirect, by reducing febrile-illness burden) — plausible but entirely unstudied in CAPOS.

Gene–Environment Interaction

CAPOS is a textbook G×E disorder, and this is arguably its single most curation-worthy mechanistic feature. The mechanistic model:

A thermally/metabolically marginal Na⁺/K⁺-ATPase α3 pump (constitutive, genotype-determined) becomes functionally insufficient only when neuronal Na⁺ load and metabolic demand rise (fever-induced increases in metabolic rate, neuronal firing, and possibly temperature-dependent destabilization of the mutant pump), producing acute neuronal-excitability failure that manifests as an ataxic-encephalopathic episode.

The functional data supporting the "marginal pump" leg (PMID:30409907) show the mutant pump's deficits "precluded proper pump activation under physiological conditions" [V]. The fever leg is clinically overwhelming but mechanistically unproven at the molecular level — no study has shown temperature-dependent aggravation of E818K pump function in vitro.

Explicitly acknowledged as unknown (PMID:30862413, on the closely related RECA phenotype) [V]:

"The pathophysiology of the dysfunctions of the mutated ATPase pump, triggered by fever is unknown."

Curation recommendation: model this as a disease-level mechanistic_hypotheses entry with status: EMERGING, and attach a discussions entry of kind: KNOWLEDGE_GAP with proposed_experiments (temperature-dependent two-electrode voltage clamp of E818K-expressing oocytes; E818K knock-in mouse thermal challenge — see §15, no such mouse exists).

3. Phenotypes

3.1 HPO Annotations (from the official HPO annotation set for OMIM:601338)

These are the curated HPO annotations with their published n/N frequencies. These are directly usable as dismech phenotype_term bindings with frequency — but note the small denominators (n≤11) and severe ascertainment bias.

HP ID Label Frequency (n/N) dismech FrequencyEnum
HP:0000648 Optic atrophy 11/11 (100%) OBLIGATE / VERY_FREQUENT
HP:0001284 Areflexia 11/11 (100%) OBLIGATE / VERY_FREQUENT
HP:0002131 Episodic ataxia 10/10 (100%) VERY_FREQUENT
HP:0000407 Sensorineural hearing impairment 10/10 (100%) VERY_FREQUENT
HP:0001324 Muscle weakness 10/10 (100%) VERY_FREQUENT
HP:0000639 Nystagmus 7/10 (70%) FREQUENT
HP:0002066 Gait ataxia 6/11 (55%) FREQUENT
HP:0001260 Dysarthria 4/11 (36%) FREQUENT
HP:0001761 Pes cavus 3/10 (30%) FREQUENT / OCCASIONAL
HP:0002015 Dysphagia 3/11 (27%) FREQUENT / OCCASIONAL
HP:0006852 Episodic generalized hypotonia 3/10 (30%) FREQUENT / OCCASIONAL
HP:0000618 Blindness 2/10 (20%) OCCASIONAL
HP:0001310 Dysmetria 2/10 (20%) OCCASIONAL
HP:0002311 Incoordination 2/11 (18%) OCCASIONAL
HP:0000729 Autistic behavior 2/10 (20%) OCCASIONAL
HP:0001332 Dystonia 1/10 (10%) OCCASIONAL
HP:0001250 Seizure 1/10 (10%) OCCASIONAL
HP:0003477 Peripheral axonal neuropathy 1/10 (10%) OCCASIONAL
HP:0001716 Wolff-Parkinson-White syndrome 1/10 (10%) OCCASIONAL
HP:0000012 Urinary urgency 1/10 (10%) OCCASIONAL
HP:0007965 Undetectable visual evoked potentials 1/1 —
HP:0002067 Bradykinesia 1/1 —
HP:0002172 Postural instability 1/1 —
HP:0001269 Hemiparesis 1/1 —
HP:0031960 Arm dystonia 1/1 —
HP:0004372 Reduced consciousness 1/1 —
HP:0001252 Hypotonia 1/1 —
HP:0000505 Visual impairment 1/1 —
HP:0000365 Hearing impairment 1/1 —
HP:0000251 (see note) — — —
HP:0000529 Progressive visual loss no freq —
HP:0000572 Visual loss no freq —
HP:0000408 Progressive sensorineural hearing impairment no freq —
HP:0002078 Truncal ataxia no freq —
HP:0001251 Ataxia 1/1 —

Clinical course annotations: HP:0011463 Childhood onset (6/11), HP:0003593 Infantile onset (3/10), HP:0003621 Juvenile onset (2/10). Inheritance: HP:0000006 Autosomal dominant inheritance.

⚠️ Critical curation note on the acronym: Pes cavus (HP:0001761) is present in only 3/10 (30%) of annotated patients — the least frequent of the five acronym features. Meanwhile muscle weakness (HP:0001324) and episodic ataxia (HP:0002131) are at 100% but are not in the acronym. The name CAPOS is therefore a historically anchored misnomer regarding relative feature frequency, which is precisely why "CAOS" was proposed (PMID:25895915, PMID:29625811). Consider a notes field capturing this.

3.2 Phenotypes Organized by Type

A. Acute (episodic) manifestations — the fever-triggered decompensation

Per GeneReviews [P]: "CAPOS syndrome presents in infancy or childhood (usually ages 6 months to 5 years) with cerebellar ataxia during or after a fever." The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and coma.

Detailed acute phenomenology (PMID:27091223, Maas et al.) [V]:

"The individuals presented here experienced one to three paroxysmal, short-lasting episodes in childhood with cerebellar symptoms and signs, hypotonia, ophthalmoparesis, motor weakness, areflexia, and/or lethargy that were consistently associated with febrile illness."

Severe end of the acute spectrum (PMID:29625811, Hayashida et al.) [P]: "Acute manifestations encompassed unconsciousness, headache, abnormal ocular movements, flaccid paralysis with areflexia, ataxia, dysphagia, and movement disturbances."

Acute feature HPO suggestion Notes
Fever-triggered ataxic encephalopathy HP:0002131 Episodic ataxia + HP:0001298 Encephalopathy The signature event
Reduced consciousness / lethargy → coma HP:0004372 Reduced consciousness; HP:0001259 Coma
Acute flaccid weakness / hypotonia HP:0006852 Episodic generalized hypotonia; HP:0001324 Muscle weakness Can mimic Guillain-Barré / transverse myelitis
Ophthalmoparesis / abnormal eye movements HP:0000602 Ophthalmoplegia; HP:0000639 Nystagmus; HP:0000486 Strabismus
Anarthria/dysarthria; dysphagia HP:0001260 Dysarthria; HP:0002015 Dysphagia Brainstem/bulbar involvement
Areflexia (acute and persistent) HP:0001284 Areflexia
  • Onset: infantile to early childhood; 6 months – 5 years is the canonical window.
  • Severity: severe during episodes (can require ICU care and be mistaken for acute encephalitis/ADEM).
  • Progression: episodic/paroxysmal with incomplete inter-episode recovery — GeneReviews [P]: "Usually, considerable recovery occurs within days to weeks; however, persistence of some degree of ataxia and other manifestations is typical."
  • Number of episodes: typically 1–3 in childhood (PMID:27091223, PMID:28483396 [V] — "They usually present one to three episodes").
  • QoL: catastrophic acutely — loss of acquired motor milestones, temporary total dependence, ICU admission, parental distress; no formal QoL instrument has ever been applied.

B. Persistent / progressive neurological manifestations

GeneReviews enumerates the residual features [P]: hypotonia, flaccidity, hyporeflexia, areflexia, pes cavus, dystonia, choreiform movements, abnormal eye movements, progressive optic nerve atrophy with vision loss, progressive sensorineural hearing loss, brief generalized tonic-clonic seizures, dysarthria/anarthria, dysphagia, cognitive dysfunction, and neurobehavioral/psychiatric manifestations.

Feature HPO Onset Severity Course
Cerebellar/gait/truncal ataxia HP:0002066, HP:0002078, HP:0001251 Post-episode, childhood Mild→severe, variable Static-to-slowly-progressive; can improve (PMID:31410291)
Areflexia HP:0001284 Childhood, permanent — Static, non-progressive, present without demonstrable neuropathy
Pes cavus HP:0001761 Childhood Mild-moderate Slowly progressive skeletal deformity
Dystonia, chorea, myoclonus, tremor HP:0001332, HP:0002072, HP:0001336, HP:0001337 Variable, post-episode Variable Fluctuating (PMID:27091223, PMID:29625811)
Dysarthria HP:0001260 Childhood Mild-severe (to anarthria) Persistent

C. Sensory phenotypes — the discriminating features

Sensorineural hearing loss — specifically AUDITORY NEUROPATHY (auditory synaptopathy/neuropathy spectrum disorder, ANSD). This is the highest-value mechanistic phenotype in the entry.

PMID:29305691 (Tranebjærg et al., Hum Genet 2018) — the definitive audiological study, verbatim [V]:

"In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here."

and:

"In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons."

PMID:29184165 (Han et al., Sci Rep 2017) [V]:

"This ANSD phenotype was compatible with known expression of ATP1A3 mainly in the synapse between afferent nerve and inner hair cells." "Collectively, the de novo ATP1A3 variant can cause postlingual-onset auditory synaptopathy, making this gene a significant contributor to sporadic progressive ANSD and a biomarker ensuring favorable short-term CI outcomes."

Hearing loss may be the ONLY or FIRST manifestation. GeneReviews [P]: 14 individuals experienced hearing loss "as the first or only manifestation", and "Some individuals with the p.Glu818Lys pathogenic variant manifest only the auditory neuropathy phenotype of CAPOS syndrome." Confirmed independently in Chinese and Korean ANSD cohorts: PMID:34692702 [V] — "The other two patients (patient 3 and patient 4, who were 8 and 6 years old, respectively) denied any neurological symptoms."

Feature HPO Details
Sensorineural hearing impairment HP:0000407 10/10
Progressive SNHL HP:0000408 Progressive over years (PMID:34692702, 15-yr follow-up)
Auditory neuropathy HP:0031815 Auditory neuropathy (verify with OAK) Present OAEs/CM + absent-abnormal ABR
Abnormal ABR HP:0006958 Abnormal auditory evoked potentials
Speech-in-noise disproportion no clean HP term Speech perception worse than PTA predicts

Optic atrophy and visual loss.

Feature HPO Details
Optic atrophy HP:0000648 11/11 (100%) — the most consistent feature alongside areflexia
Progressive visual loss HP:0000529 Progressive after episodes
Blindness HP:0000618 2/10 (20%) — end-stage
Undetectable VEP HP:0007965 1/1
Nystagmus HP:0000639 7/10
Strabismus HP:0000486 Reported in acute and chronic phases

QoL impact of the dual sensory loss is the dominant lifelong burden: combined progressive deafblindness plus ataxia constitutes acquired deafblindness with motor disability — education, communication, employment, and independent mobility are all affected. No CAPOS-specific EQ-5D, SF-36, PROMIS, or disease-specific PRO data exist. This is a real gap.

D. Cognitive, behavioural and psychiatric

  • Cognitive dysfunction — HP:0001268 Mental deterioration / HP:0001249 Intellectual disability. PMID:29625811 reports "moderate intellectual disability" post-episodes [P].
  • Autistic behaviour — HP:0000729 (2/10). PMID:27276195 [V]: "Social behavioral deficits have been observed in patients diagnosed with alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism and CAPOS syndrome."
  • Emotional and behavioural changes — PMID:27091223 [V]: "other possibly related sequelae included dystonia, myoclonus, and emotional and behavioral changes."

E. Cardiac phenotype (under-recognized; safety-critical)

PMID:32913013 (Neurology 2020, 110-patient multicenter cohort) [V]:

"Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP." "We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases."

Also: incomplete right bundle branch block in a CAPOS patient (PMID:29625811) [P]; Wolff-Parkinson-White syndrome in the HPO annotation set (HP:0001716, 1/10).

⚠️ CAPOS-specific n = 3. Curate this as ATP1A3-spectrum-level evidence with explanation noting the tiny CAPOS denominator. Suggest HPO: HP:0001695 Cardiac arrest; HP:0011675 Arrhythmia; HP:0012722 Sudden cardiac death; HP:0011710 Bundle branch block; HP:0001716 Wolff-Parkinson-White syndrome.

F. Other reported associations (single reports — curate with frequency omitted)

  • Hemiplegic migraine — PMID:26453127 [V]: "This is also the first report showing the co-occurrence of hemiplegic migraine and CAPOS syndrome in a patient with ATP1A3 mutations. Migraine has not been previously documented in ATP1A3 mutation carriers." HP:0002083 Migraine / HP:0002076 Migraine with aura.
  • Peripheral axonal neuropathy — HP:0003477 (1/10). Note the tension with the original description's "areflexia (in the absence of a peripheral neuropathy)" (PMID:8733056). PMID:34655904 documented [V] "abnormal EMG showing low amplitude motor responses with acute denervation." The origin of areflexia — central vs. peripheral — is a genuine unresolved mechanistic question. Curate as KNOWLEDGE_GAP.
  • Urinary urgency — HP:0000012 (1/10).
  • Mild cerebellar atrophy on MRI — PMID:36484864 [V]: "the brain MRI indicated mild cerebellar atrophy." HP:0001272 Cerebellar atrophy. Note: MRI is normal in most CAPOS patients.

4. Genetic / Molecular Information

Causal Gene

Field Value
Gene symbol ATP1A3
Approved name ATPase Na+/K+ transporting subunit alpha 3
HGNC HGNC:801 → dismech CURIE hgnc:801
Cytogenetic location 19q13.2
NCBI Gene 478
Ensembl ENSG00000105409
UniProt P13637 (AT1A3_HUMAN)
OMIM (gene) 182350
MANE Select transcript NM_152296.5 (1,013 aa)

The Pathogenic Variant

Field Value
HGVS (coding) NM_152296.5:c.2452G>A
HGVS (protein) p.(Glu818Lys) / p.E818K
Genomic (GRCh38) chr19:41,970,275 G>A
Genomic (GRCh37/hg19) chr19:42,474,427 G>A
dbSNP rs587777771
ClinVar VCV000156238
ClinVar germline classification Pathogenic (last evaluated 2025-05-25)
ClinVar review status "criteria provided, multiple submitters, no conflicts" — 2★
Submissions 18 SCVs across 6 RCVs
Conditions in ClinVar ATP1A3-related disorder; Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome; Alternating hemiplegia of childhood 2; Dystonia 12; inborn genetic diseases
Variant type Missense (single-nucleotide substitution)
Origin Germline — either de novo or inherited. No somatic association.
Population frequency Absent from population controls. Demos 2014 [V]: "This mutation was not found in more than 3600 chromosomes from unaffected individuals." gnomAD could not be queried directly during this pass (JS-rendered); verify gnomAD v4 allele count before asserting a numeric AF. Expected: 0 or singleton, consistent with a highly penetrant de novo dominant allele.

⚠️ Transcript-Numbering Hazard

PMID:41235133 (Neurol Genet 2025, "Pathogenic Variants in ATP1A3: Why Is There So Much Confusion?") warns [P] that sequencing services use three different mRNA transcripts for variant numbering, causing misidentification, and recommends using only the MANE Select transcript (encoding 1,013 amino acids). Always curate CAPOS as NM_152296.5:c.2452G>A p.(Glu818Lys) and treat any alternate residue numbering in older reports with suspicion. This matters especially because the AHC variant p.Glu815Lys sits only 3 residues away.

Functional Consequence — Detailed Biophysics

The definitive functional characterization is PMID:30409907 (J Biol Chem 2019, "Functional consequences of the CAPOS mutation E818K of Na⁺,K⁺-ATPase"), verbatim [V]:

"We found that these amino acid substitutions reduce the apparent Na⁺ affinity at the cytoplasmic-facing sites of the pump protein and that this effect is more pronounced for the lysine and glutamine substitutions (3-4-fold) than for the alanine substitution. The electrophysiological measurements indicated a more conspicuous, ∼30-fold reduction of apparent Na⁺ affinity for the extracellular-facing sites in the CAPOS mutant, which was related to an accelerated transition between the phosphoenzyme intermediates E1P and E2P. The apparent affinity for K⁺ activation of the ATPase activity was unaffected by these substitutions, suggesting that primarily the Na⁺-specific site III is affected. Furthermore, the apparent affinities for ATP and vanadate were WT-like in E818K, indicating a normal E1-E2 equilibrium of the dephosphoenzyme. Proton-leak currents were not increased in E818K. However, the CAPOS mutation caused a weaker voltage dependence of the pumping rate and a stronger inhibition by cytoplasmic K⁺ than the WT enzyme, which together with the reduced Na⁺ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions. The functional deficiencies could be traced to the participation of Glu-818 in an intricate hydrogen-bonding/salt-bridge network, connecting it to key residues involved in Na⁺ interaction at site III."

Corroborating structural/electrophysiological data (PMID:29305691) [V]:

"Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected."

And structural destabilization prediction (PMID:25895915) [V]:

"Whole exome sequencing identified a deleterious heterozygous c.2452 G>A, p.(E818K) variant in the ATP1A3 gene and structural analysis predicted its protein-destabilizing effect."

Mechanistic classification. E818K is best described as a specific loss-of-function of Na⁺-site-III handling — a selective, partial, kinetic LoF, not a null and not a general leak. Two contrasts sharpen this:

  • Not a cation-leak mechanism. "Proton-leak currents were not increased in E818K" (PMID:30409907) [V]. Contrast p.Pro775Leu, which does leak — PMID:37043503 [V]: "Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell… Cation leak provides a molecular explanation for this genotype-phenotype correlation."
  • Not a simple haploinsufficiency. Whole-gene ATP1A3 deletion produces an AHC2-like phenotype, not CAPOS — PMID:34421501 [V]: "Our data suggest that the deletion of the ATP1A3 gene is a causative factor of the AHC2 phenotype in the patient." This is strong evidence that E818K is not merely LoF; the CAPOS-specific phenotype must arise from the particular kinetic signature (and/or dominant-negative interference within the α3 population).

Suggested dismech modifier values: DECREASED on Na⁺-affinity/pump-activity nodes; INCREASED on intracellular Na⁺ accumulation nodes.

Allelic Disorders — The ATP1A3 Spectrum

ATP1A3 variants produce a phenotypic continuum, not clean separate diseases. This is the single most important framing decision for the KB entry.

Phenotype Canonical variant(s) OMIM
CAPOS p.Glu818Lys (only) 601338
Alternating hemiplegia of childhood 2 (AHC2) p.Asp801Asn, p.Glu815Lys, p.Gly947Arg 614820
Rapid-onset dystonia-parkinsonism (RDP/DYT12) p.Thr613Met, others 128235
RECA / FIPWE (relapsing encephalopathy with cerebellar ataxia / fever-induced paroxysmal weakness and encephalopathy) residue 756: p.Arg756His, p.Arg756Cys, p.Arg756Leu —
Early-infantile epileptic encephalopathy various —
Polymicrogyria various de novo —
Complex spastic paraplegia / ID p.Pro775Leu —
Cone-rod dystrophy (adCORD) p.Asp591Val —

Key spectrum quotes: - PMID:33868146 [V]: "Because of this, ATP1A3-disorders are now beginning to be viewed as a phenotypic continuum representing discrete expressions along a broadly heterogeneous clinical spectrum." - PMID:26400718 [V]: "Rather than multiple overlapping syndromes, ATP1A3-related disorders might be seen as a phenotypic continuum." - PMID:41850905 (Mov Disord 2026, n=88) [P]: only 25% met criteria for a single canonical phenotype; 32% canonical-plus; 20% met criteria for multiple canonical phenotypes; 23% fit no canonical category. Chronic movement disorders in 75% (dystonia 53%); paroxysmal events in 88%. - PMID:33762331 [P]: de novo ATP1A3 variants cause "a severe form of polymicrogyria with epilepsy and developmental delay" — a "previously unidentified category."

However, GeneReviews maintains a genotype-specific exception for E818K [P]: "A unique correlation has been reported between the p.Glu818Lys pathogenic variant and its fever-induced ataxia phenotype" and "CAPOS syndrome has little clinical overlap with AHC" — despite p.Glu818Lys being only three residues from the AHC p.Glu815Lys.

Curation recommendation: create a dismech Grouping ATP1A3-Related_Disorders with grouping_basis: [SHARED_GENE_FAMILY, SHARED_MECHANISM] and a NECESSARY HAS_GENE criterion on hgnc:801, with CAPOS, AHC2, RDP, and RECA as members[] and per-member differentiating_mechanisms keyed to residue position and biophysical signature. This is a near-ideal grouping use case.

Blurred-boundary reports to cite in differentiating_mechanisms: CAPOS+hemiplegic migraine (PMID:26453127); CAPOS/AHC overlap (PMID:25056583, PMID:29625811); CAPOS+dystonia (PMID:32576493); E818K presenting as childhood rapid-onset ataxia without full CAPOS (PMID:29397530); E818K presenting as isolated auditory neuropathy (PMID:29184165, PMID:34692702).

Modifier Genes

None identified. See §2.

Epigenetics

No CAPOS-specific epigenetic data. No DNA-methylation episignature has been reported for ATP1A3 disorders (in contrast to many chromatinopathies). Not applicable / genuine gap.

Chromosomal Abnormalities

Not a mechanism in CAPOS. The one relevant ATP1A3 CNV report (PMID:34421501, 88.8 kb 19q13.2 deletion of RABAC1, ARHGEF1, ATP1A3) produced an AHC2-like, not CAPOS, phenotype — mechanistically informative (see above) but not a CAPOS cause. Chromosomal microarray has no diagnostic role in CAPOS.

5. Environmental Information

  • Environmental toxins / radiation / pollution / occupational exposure: No role. No toxicant is implicated in causation or triggering. Not applicable.
  • Lifestyle factors: No dietary, smoking, alcohol, or exercise association established. Missed meals and sleep deprivation are listed among general ATP1A3 stressors to avoid (GeneReviews [P]), but with no CAPOS-specific evidence.
  • Infectious agents: Infections are triggers, not causes. Any febrile illness — most commonly common childhood viral infections and URTIs — can precipitate an episode. No specific pathogen is implicated and no pathogen taxon should be curated as an etiologic agent. The relevant curation object is the fever/systemic-inflammatory state, not the organism.
  • Physiological states: Pregnancy and the peripartum period are a documented trigger (PMID:29090527) — clinically important, since it is modifiable through anticipatory obstetric planning.
  • Thermal: Fever is central. Whether the operative variable is temperature per se or the metabolic/inflammatory correlates of fever is unresolved. (In the Matoub/E815K AHC mouse, warm-water immersion induced hemiplegia — PMID:34612482 [P] — supporting a genuine thermal component in ATP1A3 biology generally.)

6. Mechanism / Pathophysiology

6.1 The Causal Chain (dismech pathograph skeleton)

[1] MOLECULAR — Heterozygous ATP1A3 c.2452G>A p.(Glu818Lys)
      ↓ (disrupts the H-bond/salt-bridge network anchoring Na+ site III)
[2] MOLECULAR — Impaired Na+ binding/release at Na+-specific site III of Na+/K+-ATPase α3
      • ~3-4x reduced apparent cytoplasmic Na+ affinity
      • ~30x reduced apparent extracellular Na+ affinity
      • accelerated E1P → E2P transition
      • weaker voltage dependence of pumping rate
      • stronger inhibition by cytoplasmic K+
      • K+ affinity, ATP affinity, E1-E2 equilibrium all normal; NO cation leak
      ↓
[3] MOLECULAR/CELLULAR — Failure of α3 pump activation under physiological conditions
      ↓
[4] CELLULAR — Impaired restoration of the transmembrane Na+/K+ gradient after
      high-frequency neuronal activity (α3 is the "rescue pump")
      ↓
[5] CELLULAR — Intracellular Na+ accumulation; depolarized/unstable resting potential;
      impaired repolarization; impaired Na+-gradient-dependent secondary transport
      (neurotransmitter reuptake, Na+/Ca2+ exchange → Ca2+ dysregulation)
      ↓
[6] CELLULAR — Neuronal excitability failure / conduction dyssynchrony, most severe
      in the highest-firing-rate, highest-Na+-load neurons
      ↓  ↘ (acute arm, gated by FEVER)              ↘ (chronic arm)
[7a] TISSUE/ORGANISM — ACUTE: fever raises metabolic and firing demand beyond the
      marginal pump's capacity → acute cerebellar/brainstem network failure
      → ataxic encephalopathy, flaccid weakness, ophthalmoparesis, coma
      → cortico-subcortical cerebral blood flow imbalance (PMID:30904181)
      ↓
[8a] Partial recovery over days-weeks with a RESIDUAL FIXED DEFICIT (stepwise accrual)

[7b] TISSUE — CHRONIC: sustained metabolic/ionic stress in long, high-firing,
      metabolically demanding projection neurons
      → spiral ganglion neuron / IHC-ribbon-synapse dysfunction → AUDITORY NEUROPATHY
      → retinal ganglion cell axon degeneration → OPTIC ATROPHY
      → cerebellar Purkinje/network dysfunction ± atrophy → PERSISTENT ATAXIA
      → reflex-arc failure → AREFLEXIA
      → chronic denervation of intrinsic foot muscles → PES CAVUS
      → cardiac conduction-system involvement → ECG abnormalities, arrhythmia risk

Upstream vs downstream. [1]–[3] are strictly upstream and genotype-determined. [4]–[6] are the shared cellular hub. [7a] is environmentally gated — this is the G×E node, and the correct attachment point for a mechanistic_hypotheses group. [7b] is the slow, cumulative, tissue-selective arm and explains why the sensory features progress even between episodes.

6.2 Molecular Pathways

  • Na⁺/K⁺-ATPase (P-type ATPase) ion-transport cycle (Post-Albers E1/E1P/E2P/E2 cycle). Not a KEGG/Reactome "signaling cascade" in the canonical sense — this is a primary active-transport pathway. Reactome: "Ion transport by P-type ATPases" (R-HSA-936837); KEGG: hsa04260/hsa04261 (cardiac muscle contraction / adrenergic signaling in cardiomyocytes) include ATP1A3.
  • Brain energy metabolism. The Na⁺/K⁺-ATPase is the largest single consumer of neuronal ATP; α3 dysfunction produces a functional energy-failure phenotype. PMID:26400718 [V]: "The phenotype of this patient, resembling mitochondrial oxidative phosphorylation defects, emphasizes the possible role of brain energy deficiency in patients with ATP1A3 mutations."
  • Glutamatergic signaling and the NKA-as-receptor role. PMID:27313535 [V]: "Data indicates that the central glutamatergic system is affected by mutations in the α2 isoform, however further investigations are required to establish a connection to mutations in the α3 isoform, especially given the diagnostic confusion and overlap with glutamate transporter disease." The NKA also acts as a signaling receptor interacting with NMDA receptors and via NOS/cGMP/PKG.
  • Calcium homeostasis (secondary). Reduced Na⁺ gradient impairs NCX-mediated Ca²⁺ extrusion. Demonstrated for another ATP1A3 variant, PMID:42116168 [P]: patient-derived neurons showed "significantly prolonged calcium transient decay times." Not yet shown for E818K — an explicit gap.
  • Neuronal autosis (autophagy-dependent cell death). PMID:38796484 [V]: "autosis is not dependent on the ubiquitous subunit ATP1a1 in neurons, as in dividing cell types, but on the neuronal specific ATP1a3 subunit." Speculative relevance to CAPOS neurodegeneration; curate as EMERGING at most.

GO biological process suggestions:

GO ID Label Status
GO:0005391 P-type sodium:potassium-exchanging transporter activity [OLS-verified] — molecular function
GO:0005890 sodium:potassium-exchanging ATPase complex [OLS-verified] — cellular component
GO:0035725 sodium ion transmembrane transport [OLS-verified]
GO:0006883 intracellular sodium ion homeostasis [OLS-verified]
GO:0042391 regulation of membrane potential [OLS-verified]
GO:0030007 intracellular potassium ion homeostasis verify
GO:0086009 membrane repolarization verify
GO:0007605 sensory perception of sound verify
GO:0007601 visual perception verify
GO:0006754 ATP biosynthetic process verify
GO:0006816 calcium ion transport verify
GO:0098662 inorganic cation transmembrane transport verify

Use modifier: DECREASED on GO:0005391 and GO:0035725; modifier: INCREASED on the intracellular-Na⁺ node.

6.3 Cellular Processes

The unifying cell-biological principle is α3 as the neuronal "rescue pump." PMID:27378932 [V]:

"The α3 isoform has approximately four-fold lower Na⁺ affinity compared to α1 and is specifically required for rapid restoration of large transient increases in [Na⁺]i. Conditions associated with α3 deficiency are therefore likely aggravated by suprathreshold neuronal activity. The α3 isoform been suggested to support re-uptake of neurotransmitters."

and:

"The α1 isoform is ubiquitously expressed in the adult central nervous system (CNS) whereas α2 primarily is expressed in astrocytes and α3 in neurons."

Corroborated by PMID:33868146 [V]: "The α3 isoform is required as a rescue pump, after repeated action potentials, with a distribution predominantly in neurons of the central nervous system."

The key insight for selectivity: because α3 already has ~4-fold lower Na⁺ affinity than α1 by design, an additional 3–4-fold reduction in cytoplasmic Na⁺ affinity is catastrophic specifically in cells that depend on rapid high-Na⁺-load clearance — i.e., high-firing-rate neurons under thermal/metabolic stress. This is the mechanistic explanation for both the fever-dependence and the tissue selectivity.

Cellular processes to curate: impaired membrane repolarization; impaired neurotransmitter reuptake; disrupted Na⁺-coupled secondary transport; Ca²⁺ dysregulation; energy-failure/metabolic stress; neural conduction dyssynchrony; axonal degeneration; possibly autosis.

6.4 Protein Dysfunction

  • Protein: UniProt P13637, Na⁺/K⁺-ATPase subunit α-3, 1,013 aa, 10-TM P-type ATPase; functions as a heteromeric α-β(-FXYD/γ) complex at the plasma membrane.
  • Residue Glu818: in transmembrane helix M6/M6-M7 region, part of a hydrogen-bonding/salt-bridge network coordinating the Na⁺-specific ion binding site III — the site that distinguishes the 3Na⁺-out/2K⁺-in stoichiometry.
  • Mechanism class: selective kinetic loss-of-function at Na⁺ site III, with predicted local structural destabilization of the C-terminal region (PMID:29305691, PMID:25895915). Not misfolding-with-aggregation; not cation leak; not null. Whether it exerts a dominant-negative effect on the α3 pool (as opposed to simple 50% functional dosage) is unresolved and is a stated gap — noting that whole-gene deletion gives AHC2 rather than CAPOS.
  • Expression level: studies on other AHC/RDP variants found no expression difference (PMID:27634470 [V]: "The expression of the mutant form (R756C) of ATP1A3 did not differ markedly from that of the wild-type and D801N proteins"); E818K-specific expression data were not located.
  • Structural resources: AlphaFold P13637; PDB structures of pig/shark Na⁺/K⁺-ATPase (e.g. 2ZXE, 3B8E) used as homology templates in the CAPOS modelling studies.

6.5 Metabolic Changes

No primary metabolic defect. The relevant abnormality is secondary neuronal energy insufficiency: the α3 pump's ATP demand cannot be met productively because pump activation itself is impaired. Clinically this produces a mitochondrial-disease mimic — PMID:26400718 [V] (see above) — and this mimicry is the single most common source of diagnostic delay. Lactate/pyruvate, CSF lactate, respiratory-chain enzymology and mtDNA analysis are characteristically normal or non-diagnostic in CAPOS. No metabolomic or lipidomic signature has been described.

6.6 Immune System Involvement

Not a primary immune disease. Two threads deserve curation as hypotheses, both explicitly framed as questions:

  1. Is fever's effect inflammatory rather than thermal? PMID:36339296 asks exactly this in its title: "ATP1A3-Related Relapsing Encephalopathy with Cerebellar Ataxia (RECA): A Genetic Disorder with an Inflammatory Basis?" (abstract not retrieved; fetch before citing).
  2. Autoantibody cross-reference. PMID:25809299 identified neuronal Na⁺/K⁺-ATPase (α3) as a paraneoplastic autoantibody target in a patient with colon adenocarcinoma and a cerebellar syndrome [P]. This is a phenocopy by a different route (autoimmune vs. genetic) hitting the same protein — an elegant convergent-mechanism data point, and a differential-diagnosis item for adult-onset cerebellar syndromes.

There is no evidence for autoimmunity, immunodeficiency, or chronic inflammation as a mechanism of CAPOS itself. Steroids/IVIG are frequently given empirically during acute episodes (mistaken for ADEM/encephalitis) with no demonstrated benefit.

6.7 Tissue Damage Mechanisms

  • Excitotoxicity / ionic-osmotic stress during acute decompensation (hypothesized).
  • Cerebral perfusion dysregulation — the best direct human in vivo mechanistic data in CAPOS. PMID:30904181 (serial SPECT in a CAPOS boy) [V]: "The serial CBF-SPECT findings using statistical methods showed progressive hyperperfusion in the frontal lobes, basal ganglia and thalamus, and hypoperfusion in the occipital and temporal lobes during the acute and subacute phases. Thereafter, the dynamic changes of CBF improved in the chronic but hypoperfusion in thalamus appeared to the chronic phase." and "The abnormal cortico-subcortical CBF may contribute to an acute encephalopathy-like condition in the acute stage of CAPOS syndrome."
  • Chronic axonal degeneration of long/high-demand projections — optic nerve (RGC axons) and spiral ganglion neurons.
  • Cerebellar atrophy in a minority (PMID:36484864).
  • Notably absent: fibrosis, necrosis, ischemia-as-primary, and inflammation. No neuropathological/autopsy study of a CAPOS patient has been published — a significant gap.

6.8 Biochemical Abnormalities

The core defect: deficient P-type sodium:potassium-exchanging transporter activity (GO:0005391) restricted to the α3 isoform, arising from impaired Na⁺ site-III occupancy. Quantitatively (PMID:30409907): ~3–4× reduced cytoplasmic apparent Na⁺ affinity; ~30× reduced extracellular apparent Na⁺ affinity; accelerated E1P→E2P; K⁺, ATP, vanadate affinities WT-like; no increased proton leak; weaker voltage dependence; enhanced cytoplasmic-K⁺ inhibition.

CHEBI entities for the pathograph: CHEBI:29101 sodium(1+); CHEBI:29103 potassium(1+); CHEBI:15422 ATP; CHEBI:29108 calcium(2+) (verify each with OAK).

6.9 Epigenetic Changes

None described. Not applicable.

6.10 Molecular Profiling

All four omics categories are essentially empty for CAPOS. Specifically:

  • Transcriptomics: no CAPOS patient-derived transcriptomic study. GTEx shows ATP1A3 is brain-enriched (highest in cerebellum, cortex, basal ganglia) — useful as background expression evidence but not disease-state data.
  • Proteomics: none. Human Protein Atlas confirms neuronal/brain-restricted ATP1A3 protein distribution.
  • Metabolomics / lipidomics: none.
  • Single-cell / spatial transcriptomics: none for CAPOS. Allen Brain Atlas and Human Cell Atlas data confirm ATP1A3 enrichment in neurons (vs. astrocytic ATP1A2) — the cell-type-selectivity evidence base.
  • Functional genomics (CRISPR/RNAi screens): no CAPOS-directed screen. DepMap is uninformative (neuronal, non-cancer gene).
  • Multi-omics integration: none.

This is the largest single evidence gap in the disease. Curate as discussions: kind: KNOWLEDGE_GAP with proposed_experiments including: patient-derived iPSC → cerebellar/retinal-ganglion/inner-ear-organoid differentiation with paired scRNA-seq and electrophysiology; isogenic E818K knock-in iPSC lines. (Note the MorPhiC framing in CLAUDE.md — ATP1A3 is not a listed MorPhiC anchor gene, so no MorPhiC-derived cellular phenotypes are available.)

7. Anatomical Structures Affected

Organ Level

Primary — nervous system (UBERON:0001016). CAPOS is a pure neurological disorder; no primary involvement of liver, kidney, lung, gut, or endocrine organs.

Structure UBERON Involvement
Cerebellum UBERON:0002037 Ataxia (episodic + persistent); mild atrophy in a minority
Optic nerve / cranial nerve II UBERON:0000941 [OLS-verified, label "cranial nerve II"] Progressive optic atrophy — 100%
Cochlea / spiral ganglion UBERON:0001844 cochlea [OLS-verified]; UBERON:0002227 spiral organ of cochlea [OLS-verified] Auditory neuropathy — 100%
Vestibulocochlear nerve UBERON:0001648 (verify) Cochlear-nerve conduction dyssynchrony
Brainstem UBERON:0002298 (verify) Acute brainstem dysfunction: ophthalmoparesis, dysphagia, altered consciousness (PMID:34464766)
Basal ganglia UBERON:0002420 (verify) Dystonia/chorea; SPECT hyperperfusion (PMID:30904181)
Thalamus UBERON:0001897 (verify) SPECT hyper- then hypo-perfusion (PMID:30904181)
Cerebral cortex (frontal, occipital, temporal) UBERON:0000956 (verify) Regional CBF imbalance; cognitive/behavioural sequelae
Retina UBERON:0000966 (verify) RGC/RNFL loss upstream of optic atrophy
Spinal cord / reflex arc UBERON:0002240 (verify) Areflexia
Peripheral nerve UBERON:0001021 (verify) Variable — axonal neuropathy in a minority (contested)

Secondary organ involvement: - Heart (UBERON:0000948) — cardiac conduction system; ECG abnormalities in 2/3 CAPOS patients studied; arrhythmia/SCD risk ≈3% across the ATP1A3 spectrum (PMID:32913013). Mechanism plausibly direct (α3 expression in cardiac conduction tissue) rather than truly "secondary." - Foot skeleton (UBERON:0002387) — pes cavus as a secondary neuro-orthopaedic deformity. - Musculoskeletal — secondary contractures, scoliosis from chronic ataxia/weakness.

Body systems: nervous (central, peripheral, autonomic), special sense organs (visual + auditory — the discriminating pair), cardiovascular (conduction), musculoskeletal (secondary).

Tissue and Cell Level

Tissue types: nervous tissue (neurons + their axons) predominantly; sensory neuroepithelium of the cochlea; retinal neural tissue. Muscle, connective tissue, and epithelium are not primarily affected.

Cell populations (Cell Ontology):

CL ID Label Role
CL:0000540 neuron The α3-expressing cell class — the fundamental unit of disease
CL:0011113 spiral ganglion neuron [OLS-verified] Primary site of auditory neuropathy — impaired impulse propagation (PMID:29305691)
CL:4023115 / CL:4023116 type 1 / type 2 spiral ganglion neuron [OLS-verified] Type 1 SGNs (95% of afferents, IHC-innervating) are the relevant subtype
CL:0000589 cochlear inner hair cell [OLS-verified] IHC–afferent ribbon synapse; PMID:29184165 [V]: "the synapse between afferent nerve and inner hair cells"
CL:0000601 cochlear outer hair cell [OLS-verified] SPARED — this is diagnostically decisive (preserved OAEs/CM). Curate with an explicit "spared" note.
CL:0000121 Purkinje cell [OLS-verified] Cerebellar output neuron; presumed but not histologically demonstrated in CAPOS
CL:0000740 retinal ganglion cell (verify) Optic atrophy substrate
CL:0000120 granule cell (verify) Cerebellar granule cells (high-firing, α3-rich)
CL:0000598 pyramidal neuron (verify) Cortical involvement
CL:0000127 astrocyte (verify) Express α2 (ATP1A2), not α3 — relevant as a contrast cell, not an affected one
CL:0000108 cholinergic neuron / motor neuron (verify) Reflex arc, weakness

Curation tip: the preserved OHC / affected SGN dissociation is the single most information-rich cell-level statement in the entry and directly supports the "post-synaptic / neural, not cochlear-sensory" mechanistic claim.

Subcellular Level

GO CC Label Relevance
GO:0005890 sodium:potassium-exchanging ATPase complex [OLS-verified] The dysfunctional machine
GO:0005886 plasma membrane (verify) Pump localization
GO:0043005 neuron projection (verify) Axonal/dendritic pump distribution
GO:0044304 main axon (verify) Nodal/internodal α3 for impulse propagation
GO:0045202 synapse (verify) Ribbon-synapse / afferent-terminal region
GO:0098793 presynapse (verify) IHC ribbon synapse
GO:0005739 mitochondrion (verify) ATP supply — secondary, not the primary compartment; important to state explicitly given the mitochondrial-mimic pitfall

Localization and Lateralization

  • Bilateral and largely symmetric for the chronic features: bilateral optic atrophy, bilateral SNHL, midline/appendicular cerebellar signs, symmetric areflexia, bilateral pes cavus.
  • Acute episodes may be asymmetric. PMID:34761051 [V] notes across the ATP1A3 spectrum: "Three common features were a sudden onset, asymmetrical neurological symptoms, as well as the presence of triggering factors." Hemiparesis (HP:0001269) is annotated in the CAPOS HPO set (1/1), and hemiplegic migraine has been reported (PMID:26453127).
  • Suggested descriptor: laterality: BILATERAL for chronic sensory/cerebellar features; note asymmetry as a possible acute feature.

8. Temporal Development

Onset

  • Typical age: 6 months to 5 years (GeneReviews [P]). HPO clinical-course annotations: childhood onset 6/11, infantile onset 3/10, juvenile onset 2/10.
  • Earliest reported: ~7 months (PMID:30904181 — episode at 7 months; PMID:29625811 — 7–8 months).
  • Onset pattern: ACUTE / paroxysmal. The disease announces itself as an abrupt neurological catastrophe during a febrile illness in a previously normal child, not as insidious developmental delay. This is the crucial diagnostic signature.
  • Important exception — pre-episode and non-episode presentations: PMID:28483396 documented a sibling who "developed generalized areflexia and mild instability without an acute episode" and a mother previously diagnosed only with SNHL and optic atrophy [V]; the paper is titled "Early Diagnosis of CAPOS Syndrome Before Acute-Onset Ataxia." And in ANSD cohorts, isolated hearing loss can be the sole and first presentation, sometimes with teenage onset (PMID:29184165, PMID:34692702).
  • Adult-onset first episodes occur but are rare (PMID:29625811 — an episode at 37 years, in a patient with prior childhood episodes; PMID:26400718 — the RECA patient presented at 34).

Suggested OnsetDescriptor: onset_category: INFANTILE_ONSET / CHILDHOOD_ONSET with a notes field on late/attenuated presentations. HPO onset terms: HP:0003593 Infantile onset, HP:0011463 Childhood onset, HP:0003621 Juvenile onset.

Progression

Stage model (proposed for curation as progression):

Stage Description
0. Pre-symptomatic carrier Genotype-positive, no/minimal signs. May show only areflexia or mild instability (PMID:28483396). Fully penetrant carriers may go undiagnosed for decades — PMID:34655904 [V]: "his symptomatic mother went undiagnosed for thirty years until his diagnosis."
1. Acute decompensation Fever-triggered ataxic encephalopathy ± flaccid weakness, ophthalmoparesis, reduced consciousness. Days.
2. Subacute recovery Considerable but incomplete recovery over days–weeks. PMID:28483396 [V]: "The acute symptoms improve within days, but most patients show slow progression afterward."
3. Residual/stepwise-accrual phase Fixed ataxia, areflexia; each subsequent episode (typically 1–3 total) adds deficit.
4. Chronic progressive sensory phase Optic atrophy and SNHL progress independently of episodes, over years-to-decades. Pes cavus develops.
5. Late/stable adult phase Variable. Many stabilize; some improve motorically.

Progression rate: slow. Course pattern: episodic-with-residuum, superimposed on a slowly progressive sensory neurodegeneration — a hybrid pattern that does not map cleanly onto a single enum value. Recommend RELAPSING or PROGRESSIVE at the disease level with per-phenotype clinical_course qualifiers: PROGRESSIVE on optic atrophy and SNHL; EPISODIC/RECURRENT on ataxic encephalopathy; STABLE on areflexia.

Duration: chronic, lifelong. Not self-limited.

Patterns

  • Remission: No true remission. Partial spontaneous recovery after each acute episode is the rule. A genuinely encouraging outlier — PMID:31410291 [V]: "Previous reports suggest a gradual progression of the disease after the initial episodes, while this patient showed a good outcome with improvement of motor skills from adolescence long after the last deterioration episode."
  • Treatment-induced episode suppression: anecdotally with acetazolamide — PMID:27091223 [V]: "After initiation of acetazolamide in two patients, no further episodes occurred." But contradicted in another cohort — PMID:36484864 [V]: "No fluctuation was noted after using Acetazolamide." (Note: that sentence is ambiguous in the original and should be read in full context before curation.)
  • Critical periods / windows of vulnerability:
  • Ages 6 mo – 5 yr — the window of maximal episode risk. Antipyretic vigilance matters most here.
  • Each febrile illness is a discrete vulnerability window throughout life.
  • Pregnancy and the peripartum period in affected women (PMID:29090527).
  • The pre-first-episode window is the key opportunity window: PMID:28483396's whole point is that identifying at-risk relatives before their first episode enables anticipatory management.
  • Post-diagnosis hearing/vision windows for cochlear implantation and low-vision/educational intervention.

9. Inheritance and Population

Epidemiology

  • Prevalence: not established. Orphanet does not publish a numeric prevalence class for ORPHA:1171 that could be retrieved in this pass. For dismech Prevalence, use:
  • measure_type: CASES_IN_LITERATURE
  • prevalence_class: ULTRA_RARE
  • rate_per_100000: omit (no defensible estimate)
  • notes: cumulative reported cases (see below)
  • Cumulative reported cases (the only real denominator): | Year | Count | Source | |---|---|---| | 1996 | 3 (1 family) | PMID:8733056 | | 2014 | ~10 (3 families) | PMID:24468074 | | 2016 | "seventh and eighth family identified worldwide" | PMID:27091223 [V] | | 2017 | 22 reported; 25 with the new Spanish family | PMID:28483396 [V]: "a rare disease that has been reported in 22 patients so far" … "Only 25 Individuals with CAPOS syndrome have been reported, including our family." | | 2018 | 18 genetically confirmed patients from 11 families in one series (10 previously unreported) | PMID:29305691 [V] | | current | 53 individuals from 40 families | GeneReviews (PMID:20301294) [P] |
  • Incidence: unknown. Cannot be estimated.
  • Under-ascertainment is near-certain and directional. Two independent reasons: (a) PMID:30904181 [V] — "CAPOS syndrome is not often reported, and is possibly an under-recognized syndrome in clinically mild cases"; (b) systematic discovery of E818K in sporadic progressive auditory neuropathy cohorts without neurological features (PMID:29184165 found 2/106 sporadic progressive hearing losses; PMID:34692702 found 4 AN patients with E818K, 2 with no neurological symptoms). CAPOS is very likely substantially more common than 53 cases, hidden inside the ANSD population.

Genetic Etiology Parameters

Parameter Value Evidence
Inheritance pattern Autosomal dominant (HP:0000006) PMID:24468074, PMID:25895915 [V]: "a unique inherited autosomal dominant neurologic syndrome"
De novo rate ~50% GeneReviews [P]: "About half of individuals reported to date with CAPOS syndrome (53 individuals from 40 families)…have an apparently de novo pathogenic variant"
Familial rate ~50%; >50% of case reports are multiplex families GeneReviews [P]: "more than half of CAPOS syndrome case reports include families with more than one affected member"
Penetrance Complete / no evidence of reduced penetrance GeneReviews [P]: "There is no evidence of reduced penetrance in the families/individuals reported to date." ⚠️ Caveat: penetrance for "some manifestation" is complete; penetrance for the full pentad is clearly incomplete, given isolated-ANSD carriers. Curate this distinction explicitly.
Expressivity Highly variable, including intrafamilial PMID:26453127 [V]: "The symptoms were triggered by fever and varied in severity in family members"; PMID:28483396 (three relatives, three different presentations)
Recurrence risk 50% per child of an affected parent GeneReviews [P]
Genetic anticipation None. Not a repeat-expansion disorder. Not applicable. —
Germline mosaicism Documented in ATP1A3 generally; not yet for E818K specifically PMID:27726050 [V]: "Both families displayed parental germline mosaicism… To our knowledge, mosaicism has not previously been reported in ATP1A3-related disorders. This report, therefore, provides evidence that germline mosaicism for ATP1A3 mutations is a likely explanation for familial recurrence and should be considered during recurrence risk counseling." ⚠️ Counselling-critical: the recurrence risk for apparently unaffected parents of a de novo case is low but NOT zero.
Founder effect None. Multi-ethnic, unrelated pedigrees worldwide — the recurrence reflects a mutational hotspot, not shared ancestry. PMID:26453127 [V]: "This study confirms that the specific c.2452G>A mutation in the ATP1A3 gene is associated with the CAPOS syndrome in pedigrees of different ethnic backgrounds." PMID:34692702 [V]: "Our study confirms that p.E818K in the ATP1A3 gene is a multiethnic cause of AN."
Consanguinity No role — dominant disorder. Not applicable.
Carrier frequency Not applicable (dominant, fully penetrant, essentially absent from controls). "Carriers" = affected individuals.

Population Demographics

  • Affected populations: no ethnic predilection. Reported in: UK (PMID:8733056), Canada (PMID:24468074), Israel (PMID:25895915), Serbia/SE Europe (PMID:26453127), Netherlands (PMID:27091223), Spain (PMID:28483396 — "the first time a Spanish family has been described" [V]), USA (PMID:29090527 — "the first ascertained in the United States" [V]), Korea (PMID:29184165 — "the first reported CAPOS allele in Koreans" [V]), Japan (PMID:29625811, PMID:30904181), Norway (PMID:31410291 — "the first Norwegian patient reported" [V]), China (PMID:32135597, PMID:34692702, PMID:36484864, PMID:38297853), Denmark, Sweden, Germany (PMID:29305691), Middle East / Turkey (PMID:41480049).
  • Geographic distribution: worldwide; the apparent European/East Asian concentration reflects genomic-medicine access, not biology.
  • Variant geography: the same single variant everywhere — genuinely notable, and consistent with a recurrent de novo hypermutable CpG-adjacent site rather than any founder haplotype. (A formal haplotype analysis across pedigrees appears never to have been published — a nice small gap.)
  • Sex ratio: no established bias; ~1:1 expected for an autosomal dominant. Females carry the additional pregnancy-related trigger. PMID:38243045 reported 14 F : 12 M across a mixed ATP1A3 cohort [V] and noted "higher females prevalence of atypical presentation" — ATP1A3-general, not CAPOS-specific, and likely ascertainment noise at that n.
  • Age distribution: bimodal in presentation — a large early-childhood peak (acute episodes) and a long tail of adults diagnosed retrospectively after a child's diagnosis (PMID:34655904, PMID:28483396) or via ANSD workup (PMID:29184165).

10. Diagnostics

Clinical Tests

Laboratory tests (all characteristically NORMAL — their normality is diagnostically informative): - Routine CSF (cell count, protein, glucose), serum/CSF lactate and pyruvate, plasma amino acids, urine organic acids, acylcarnitines, ammonia, CK, very-long-chain fatty acids, respiratory-chain enzymology, mtDNA. PMID:8733056 [V]: "Extensive neurological investigations have been normal." PMID:34464766 [V]: "These cases highlight ATP1A3-related disorders as a possible cause of acute brainstem dysfunction with normal ancillary testing." - PMID:30862413 [V]: "Severe recurrent neurological decompensation episodes triggered by fever, without any metabolic cause, should lead to the sequencing of ATP1A3."

Biomarkers: None. There is no biochemical, protein, or imaging biomarker for CAPOS. The genotype is the biomarker. (An interesting exception in framing: PMID:29184165 [V] calls the variant itself a biomarker — "a biomarker ensuring favorable short-term CI outcomes.")

Imaging: - Brain MRI: typically normal, both acutely and chronically (PMID:31410291, PMID:36484864 for other ATP1A3 phenotypes). Mild cerebellar atrophy in a minority (PMID:36484864). MRI's role is to exclude ADEM, encephalitis, stroke, and posterior-fossa lesions. - SPECT (research/selected): dynamic cortico-subcortical CBF imbalance (PMID:30904181) — the only imaging modality shown to be abnormal in the acute phase. - OCT (retinal nerve fibre layer): clinically indicated to quantify optic atrophy; specific CAPOS OCT/RNFL datasets were not retrieved in this pass.

Functional / electrophysiological tests — the diagnostic core:

Test Finding Evidence
Otoacoustic emissions (OAE) PRESENT / preserved PMID:29305691 [V]
Cochlear microphonic (CM) PRESENT / preserved PMID:29305691 [V]
Auditory brainstem response (ABR) Grossly abnormal or absent PMID:29305691 [V]: "the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony"
Pure-tone audiometry (PTA) Variable, progressive; underestimates functional disability PMID:29305691 [V]: speech perception "was beyond the hearing level obtained in the pure tone audiograms"
Speech audiometry, esp. in noise Disproportionately poor PMID:29305691 [V]
Visual evoked potentials (VEP) Abnormal to undetectable (HP:0007965) HPO annotation
EEG Non-specific; may show slowing PMID:38243045 [V]: "EEG and MRI were non-specific"
ECG (12-lead) ± Holter Abnormal in 2/3 CAPOS patients; dynamic changes PMID:32913013 [V]
Echocardiography Normal PMID:32913013 [V]: "Echocardiography was normal."
EMG / nerve conduction Usually normal; occasionally abnormal PMID:34655904 [V]: "abnormal EMG showing low amplitude motor responses with acute denervation"

The OAE-present / CM-present / ABR-absent triad is the pathognomonic non-genetic finding in CAPOS. It defines auditory neuropathy, immediately excludes cochlear (sensory) hearing loss, and is the single most actionable diagnostic clue in a child with fever-triggered ataxia plus deafness.

Biopsy / pathology: No role. Muscle and nerve biopsy are unrevealing and should be avoided; they are often performed during the mitochondrial-mimic workup. No autopsy neuropathology has been published — see §6.7.

Genetic Testing

Recommended approach (in order of yield-per-cost):

  1. Targeted single-variant / single-gene ATP1A3 sequencing — the highest-yield first-line test when the phenotype is recognized, because CAPOS is a single-variant disease. PMID:27091223 [V]: "Targeted sequencing of the ATP1A3 gene is recommended in children exhibiting paroxysmal, fever-induced ataxia and in adults with a more or less stationary or slowly progressive cerebellar syndrome since childhood accompanied by mixed combinations of areflexia, pes cavus, profound visual impairment, and/or sensorineural hearing loss." Also PMID:29090527 [V]: "Targeted sequencing of ATP1A3 should be considered in any patient presenting with cerebellar ataxia triggered by febrile illness, or pregnancy and delivery."
  2. Multigene panels — ATP1A3 is (or should be) on: hereditary ataxia panels, episodic ataxia panels, epileptic-encephalopathy panels, non-syndromic + syndromic hearing loss / auditory neuropathy panels, movement-disorder panels, optic-atrophy panels. Note the ANSD-panel route is how "isolated hearing loss" CAPOS is found.
  3. WES / WGS — how the disease was solved (PMID:24468074, PMID:25895915) and the appropriate route for unrecognized/atypical presentations. Trio WES is preferred to establish de-novo status. PMID:29396171 [V]: "The authors recommend extending ATP1A3 gene analysis to children exhibiting channelopathy-resembling episodes and those with early-onset, fever-associated encephalopathy." PMID:34761051 [V]: "the authors argue to perform exome sequencing in an early stage."
  4. Parental Sanger testing — mandatory for counselling (de novo vs. inherited; mosaicism).

Tests with NO role in CAPOS: chromosomal microarray (CMA), karyotype, FISH, mitochondrial DNA testing, repeat-expansion testing. Each is commonly ordered in the ataxia/mito-mimic workup and each is negative by design. (CMA has an incidental role only in the rare whole-gene-deletion AHC2 scenario — PMID:34421501.)

⚠️ Transcript caution: confirm the report uses MANE Select NM_152296.5 (PMID:41235133).

Omics-Based Diagnostics

  • RNA sequencing: no established role (missense variant, no splicing effect).
  • Proteomics / metabolomics / epigenomics (episignature) / liquid biopsy: no role; none validated.

Clinical Criteria

  • No formal consensus diagnostic criteria exist for CAPOS (unlike AHC, which has Aicardi criteria). Diagnosis = compatible phenotype + p.Glu818Lys.
  • GeneReviews [P]: "The combination of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss is unique to CAPOS syndrome." — but the same source cautions that individuals may present with only a subset or a single feature (especially hearing loss), causing diagnostic delay.
  • Proposed practical trigger for testing: acute fever-induced ataxic encephalopathy in a child aged 6 mo – 5 yr with normal ancillary testing, or unexplained progressive auditory neuropathy at any age, or a childhood-onset non-/slowly-progressive cerebellar syndrome with areflexia + optic atrophy + SNHL.

Differential diagnosis (with distinguishing features):

Differential How to distinguish
Mitochondrial disease (Leigh syndrome, MELAS, POLG, mtDNA disorders) The single most common misdiagnosis. Normal lactate, normal MRI (no Leigh lesions), normal respiratory chain; PMID:26400718 explicitly notes the resemblance [V]
Acute disseminated encephalomyelitis (ADEM) / acute encephalitis MRI normal; CSF bland; recurrent fever-triggered stereotyped episodes; family history
Miller Fisher syndrome / Guillain-Barré Areflexia + ataxia + ophthalmoparesis overlaps closely; anti-GQ1b negative, no CSF albuminocytological dissociation, recurrent + familial
Episodic ataxia types 1, 2, 5, 6 (KCNA1, CACNA1A, CACNB4, SLC1A3) EA episodes typically shorter, no encephalopathy, no optic atrophy/deafness; EA2 is also acetazolamide-responsive — response does not discriminate
Friedreich ataxia Ataxia + areflexia + pes cavus + optic atrophy + deafness overlaps substantially! Distinguish by: FXN GAA expansion, cardiomyopathy, diabetes, sensory neuropathy on NCS, no fever-triggered episodes
Charcot-Marie-Tooth / hereditary neuropathies Pes cavus + areflexia overlap; NCS clearly abnormal in CMT, normal/near-normal in CAPOS
Refsum disease, abetalipoproteinemia, AVED Treatable ataxia-plus-retinopathy mimics; phytanic acid, lipids, vitamin E
Other ATP1A3 phenotypes (AHC, RDP, RECA/FIPWE) RECA/FIPWE is the closest mimic — residue 756 variants, no optic atrophy/deafness (PMID:30862413, PMID:34342181)
Wolfram syndrome (WFS1) Optic atrophy + deafness; add diabetes mellitus/insipidus, no ataxic episodes
Autoimmune/paraneoplastic anti-Na⁺/K⁺-ATPase cerebellar syndrome Adult onset, tumour association, autoantibody positive (PMID:25809299)
Biotinidase deficiency / biotin-thiamine-responsive basal ganglia disease Treatable; ataxia + deafness + optic atrophy; enzyme/SLC19A3 testing

Screening

  • Newborn screening: Not included in any NBS panel. Not currently justifiable (no proven presymptomatic intervention) — though the existence of a possible prophylactic (acetazolamide) and a critical pre-first-episode window makes this a legitimate future question.
  • Newborn hearing screening: ⚠️ Important caveat — standard OAE-based newborn hearing screening will MISS CAPOS, because OAEs are preserved. Only ABR-based (AABR) screening detects auditory neuropathy. This is a concrete, actionable public-health point worth curating.
  • Carrier screening: not applicable (dominant).
  • Cascade testing: Strongly indicated. Targeted p.Glu818Lys testing of at-risk relatives is cheap, definitive, and clinically actionable — it identifies pre-episode children who need antipyretic vigilance and audiological/ophthalmological surveillance, and adults with unexplained deafness/ataxia. PMID:28483396 is the model case; PMID:34655904 [V] shows the cost of not doing it ("undiagnosed for thirty years").

11. Outcome / Prognosis

Survival and Mortality

  • No systematic survival data exist for CAPOS. No published mortality rate, 5-/10-year survival, or life-expectancy figure.
  • GeneReviews [P]: "Permanence of CAPOS symptoms, level of functioning, and life expectancy vary widely."
  • Most reported patients survive into adulthood, including into the fourth decade (PMID:29625811, age 38; PMID:26400718, age 34; PMID:29090527, three-generation pedigree with grandparental-generation carriers).
  • The one quantified mortality-relevant risk is cardiac. PMID:32913013 [V]: "a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%)" and "Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease." This is spectrum-wide; CAPOS n=3.
  • Acute episodes can involve coma and require intensive care; death during an acute episode has not, to my reading of this corpus, been reported in CAPOS — but the corpus is small and publication-biased toward survivors.

Curation guidance: record survival/mortality as UNKNOWN / not established, with the ≈3% ATP1A3-spectrum arrhythmia risk as the one quantified hazard, clearly scoped.

Morbidity and Function

The dominant burden is combined progressive sensory loss plus ataxia — i.e., a deafblind-plus-motor-disability phenotype accumulating from early childhood.

Disability domains: mobility (ataxia, weakness, pes cavus); vision (to blindness in 20%); hearing (to profound, with disproportionate speech-in-noise disability); communication (dysarthria/anarthria + deafness + visual loss compounding); swallowing (dysphagia, aspiration risk); cognition and behaviour; education and employment.

Quality of life: No CAPOS-specific QoL study has ever been performed. No EQ-5D, SF-36, PROMIS, PedsQL, or disease-specific instrument data. This is a stark, curable gap, and it is arguably the most patient-relevant one in the entire entry.

Disease Course and Complications

Complication Notes
Recurrent fever-triggered decompensations 1–3 typical; ICU-level care possible
Progressive blindness 20% reach HP:0000618
Progressive profound deafness Universal; auditory-neuropathy type
Aspiration pneumonia From dysphagia (HP:0002015, 3/11)
Seizures HP:0001250, 1/10; brief GTCS
Cardiac arrhythmia / SCD ≈3% spectrum-wide (PMID:32913013)
Orthopaedic sequelae Pes cavus, contractures, scoliosis
Psychiatric/behavioural Autistic features, emotional/behavioural change
Peripartum deterioration PMID:29090527

Recovery potential: partial and real. Recovery after each episode is "considerable" within days–weeks (GeneReviews [P]) but incomplete. Encouragingly, PMID:31410291 documented late motor improvement in adolescence long after the last episode [V], and PMID:29184165 documented remarkable benefit from cochlear implantation [V]. Vision and hearing loss, by contrast, are not recoverable — they progress.

Prognostic Factors

No validated prognostic model or biomarker exists. Candidate factors, all inferred from case series and unvalidated: - Number and severity of acute episodes (stepwise deficit accrual) - Age at first episode (earlier = presumed worse; unproven) - Degree of inter-episode recovery after the first episode - Presence of encephalopathy/coma vs. isolated ataxia during episodes - Successful trigger avoidance / antipyresis - Early cochlear implantation for auditory outcome - Presence of ECG abnormality for cardiac risk

Prognostic biomarkers: none. Not applicable.

12. Treatment

Bottom line: there is no disease-modifying therapy for CAPOS. All management is supportive, preventive, and rehabilitative. PMID:34655904 [V]: "Treatment remains mostly supportive." PMID:35047275 [V]: "The mainstay management for patients with ATP1A3 related diseases is symptomatic treatment as there is no specific proposed treatment."

Pharmacotherapy

Agent Rationale / Evidence Strength
Acetazolamide (carbonic anhydrase inhibitor; CHEBI:27690 [OLS-verified]) Episode prophylaxis, by analogy with episodic ataxia. PMID:27091223 [V]: "After initiation of acetazolamide in two patients, no further episodes occurred." Same paper's measured conclusion [V]: "Similar to some other types of episodic ataxia, acetazolamide may be considered in patients with CAPOS syndrome to prevent or attenuate bouts of ataxia, but this requires further study." Counter-evidence PMID:36484864 [V]: "No fluctuation was noted after using Acetazolamide." Very weak (n=2 uncontrolled, conflicting)
Flunarizine (calcium channel blocker; CHEBI:135652 [OLS-verified]) Standard AHC prophylaxis, extrapolated. PMID:29090527 [V]: "Prophylactic administration of acetazolamide or flunarizine may prevent acute episodes of ataxia or mitigate neurologic symptoms, although their efficacies have not been well studied." In AHC generally: PMID:32339621 [P] — symptom reduction in 83% of AHC cases. In the Matoub E815K mouse: shortened hemiplegia duration, no long-term benefit (PMID:34612482 [P]). Very weak for CAPOS
Antipyretics (paracetamol/acetaminophen, ibuprofen) Trigger mitigation — the most mechanistically coherent intervention. PMID:35047275 [V]: "Aggressive management of febrile illness may be helpful in alleviating the symptoms." Weak but universally recommended
Anti-seizure medications For the minority with seizures. Levetiracetam most used across ATP1A3 cohorts (PMID:38243045 [V]). Symptomatic
Topiramate AHC prophylaxis; PMID:32339621 [P] — 25% of AHC cases. Not CAPOS-specific. Very weak
Levodopa Effective for a specific ATP1A3 paroxysmal-oculogyria presentation (PMID:26417536). Not a CAPOS treatment. Not indicated
Benzodiazepines Acute abortive use during episodes (empirical practice) Anecdotal

Pharmacogenomics: No PharmGKB/CPIC guideline involves ATP1A3. No genotype-guided dosing. Not applicable.

⚠️ Anaesthesia caution (safety-relevant, weak evidence): the Atp1a3 D801Y mouse was "refractory to ketamine anesthesia" (PMID:39111836 [P]). Anaesthetic and perioperative planning should be cautious given the stress-trigger biology and cardiac conduction risk; there is no CAPOS-specific anaesthesia literature.

Advanced Therapeutics

None available for CAPOS. All are preclinical and developed against AHC alleles, not E818K.

  • Gene therapy (AAV): PMID:33577387 — AAV9-mediated gene therapy in the Mashlool (D801N) AHC mouse; PMID:34612482 [P] notes it "improved hemiplegic episodes and beam-walking performance."
  • Gene editing / prime editing — the most exciting recent development. PMID:40695277 (Cell, 2025): [P] "AAV9-mediated in vivo PE corrected Atp1a3 D801N and E815K mutations with up to 48% DNA correction" and treatment "restored ATPase activity; ameliorated paroxysmal spells, motor defects, and cognition deficits; and dramatically extended" lifespan. Note: E815K, three residues from E818K — the platform is directly transferable in principle, but E818K has not been targeted.
  • Antisense oligonucleotides: PMID:41048925 [P] highlights "emerging therapeutic strategies, including gene therapy, antisense oligonucleotides, and small-molecule interventions." No specific ASO program for E818K. (Note: an allele-selective ASO knockdown strategy is mechanistically awkward here since E818K is not a clean gain-of-function; a splice/steric approach has no obvious target. Curate as speculative.)
  • Cell therapy, immunotherapy, targeted small molecules: none.

Surgical and Interventional

Intervention Detail
Cochlear implantation (CI) — the highest-value intervention in CAPOS PMID:29305691 [V]: "Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients." PMID:29184165 [V]: "cochlear implantation (CI) was performed in the first proband, leading to remarkable benefits." Mixed results also reported — PMID:34692702 [V]: "Patient 2 underwent CI on his left ear, and the result was poor." Systematic review of post-synaptic auditory neuropathies incl. CAPOS, PMID:33136025 [P]: "Overall trend was towards good post-CI outcomes with 22 of the total 25 patients displaying modest to significant benefit." CI is the right default; counsel about variability.
Orthopaedic surgery for pes cavus/contractures Standard neuro-orthopaedic indications
Strabismus surgery As indicated
Pacemaker / ICD PMID:32913013 [V]: "We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator."
Gastrostomy For severe dysphagia/aspiration

Conventional hearing aids are explicitly of limited benefit in auditory neuropathy (PMID:29305691 [V]) — an important negative recommendation. FM/remote-microphone systems help with the speech-in-noise problem.

Supportive and Rehabilitative

  • Aggressive fever management and early treatment of infection; a written sick-day / emergency plan for families.
  • Physical therapy (ataxia, gait, balance, strength), occupational therapy, speech and language therapy (dysarthria + deafness), swallowing therapy.
  • Deafblind-specific services: tactile communication, orientation and mobility training, assistive technology, educational support.
  • Low-vision rehabilitation; audiological rehabilitation.
  • Nutrition and aspiration-risk management.
  • Psychological/psychiatric support; family and genetic counselling.

Experimental Treatments / Clinical Trials

No CAPOS-specific interventional clinical trial was identified in this pass. No NCT identifier could be attributed to CAPOS. Relevant activity is in the AHC/ATP1A3 space (natural-history registries; preclinical gene-therapy programs). Recommend a targeted ClinicalTrials.gov query for "ATP1A3" before curating a clinical_trials block, and populate only with verified NCT IDs.

Treatment Outcomes

  • Response rates: unquantified for every intervention except CI (see above).
  • Adverse events: acetazolamide — paraesthesia, anorexia, metabolic acidosis, nephrolithiasis, growth effects in children; flunarizine — sedation, weight gain, depression, extrapyramidal effects; CI — surgical risks, device failure, variable benefit.

Treatment Strategy

No published treatment algorithm or guideline exists for CAPOS. A defensible pragmatic pathway synthesized from the corpus:

  1. Confirm genotype (ATP1A3 p.Glu818Lys) → stop the mitochondrial/metabolic workup.
  2. Baseline multidisciplinary assessment (GeneReviews [P]): ophthalmology (acuity, optic atrophy, refraction, strabismus); audiology with ABR + OAE (not PTA alone); neurology + imaging; cardiology with ECG and echocardiogram; developmental/cognitive assessment in children.
  3. Trigger management plan: antipyretic protocol, illness action plan, avoidance of physical/emotional/environmental stressors, peripartum planning in women.
  4. Consider prophylaxis (acetazolamide ± flunarizine) after explicit shared decision-making about the weak evidence base.
  5. Sensory habilitation: early CI evaluation for auditory neuropathy; low-vision services; deafblind educational planning.
  6. Rehabilitation: PT/OT/SLT.
  7. Surveillance (GeneReviews [P]): at least once or twice yearly, focused on progression of hearing and vision.
  8. Genetic counselling + cascade testing of at-risk relatives.
  9. Personalized medicine: genotype-guided only in the trivial sense that the genotype is the diagnosis. No genotype-stratified therapy exists.

Suggested NCIT Treatment Annotations

Treatment treatment_term therapeutic_agent therapeutic_modality
Acetazolamide prophylaxis NCIT:C15986 Pharmacotherapy CHEBI:27690 acetazolamide [OLS-verified] SMALL_MOLECULE
Flunarizine prophylaxis NCIT:C15986 Pharmacotherapy CHEBI:135652 flunarizine [OLS-verified] SMALL_MOLECULE
Antipyretic therapy NCIT:C15986 Pharmacotherapy CHEBI:46195 paracetamol (verify) SMALL_MOLECULE
Anti-seizure medication NCIT:C15986 Pharmacotherapy CHEBI:6437 levetiracetam (verify) SMALL_MOLECULE
Cochlear implantation NCIT:C15329 Surgical Procedure (no NCIT clinical-action term for "cochlear implantation" was found under NCIT:C25218; NCIT:C157820 "Cochlear Implant" is a DEVICE term and likely fails the TreatmentTerm dynamic enum — verify with just validate-terms) — DEVICE
Physical therapy NCIT:C15302 Physical Therapy — BEHAVIORAL
Occupational therapy NCIT:C121351 Occupational Therapy (verify) — BEHAVIORAL
Speech therapy NCIT:C159273 Speech Therapy (verify) — BEHAVIORAL
Low-vision / deafblind rehabilitation NCIT:C15315 Rehabilitation — BEHAVIORAL
Supportive care NCIT:C15747 Supportive Care — OTHER
Genetic counseling NCIT:C15240 Genetic Counseling — BEHAVIORAL
Pacemaker / ICD insertion NCIT:C15329 Surgical Procedure — DEVICE
Orthopaedic surgery (pes cavus) NCIT:C16186 Orthopedic Surgical Procedure — SURGERY

13. Prevention

Primary Prevention (preventing the disease)

Not possible. CAPOS is caused by a germline de novo or inherited dominant variant. There is no modifiable exposure that prevents its occurrence.

The only meaningful primary prevention is reproductive: preventing transmission from an affected parent (see Genetic Screening below).

Secondary Prevention (early detection and pre-emptive management)

This is where the real opportunity lies, and it is well-supported:

  • Cascade genetic testing of first-degree relatives of an index case. PMID:28483396 is the model — identifying children before their first acute episode "could aid early diagnosis and management before the onset of acute episodes" [V].
  • ABR-inclusive hearing screening. Because CAPOS causes auditory neuropathy, OAE-only newborn screening misses it. Where a family is known to segregate p.Glu818Lys, AABR screening plus serial ABR should be specified.
  • Early consideration of ATP1A3 testing in sporadic progressive auditory neuropathy — the highest-yield diagnostic-discovery route (PMID:29184165: 2/106; PMID:34692702: 4 patients).
  • Baseline and serial ophthalmological and audiological surveillance in known carriers.
  • Baseline ECG in all ATP1A3 patients (PMID:32913013).

Tertiary Prevention (preventing complications in affected individuals)

  • Trigger avoidance and aggressive antipyresis — the central tertiary-prevention measure (§2, §12).
  • Peripartum planning in affected women (PMID:29090527).
  • Prophylactic acetazolamide/flunarizine — offered, with honest uncertainty.
  • Cardiac surveillance with ECG ± Holter; pacemaker/ICD in selected high-risk patients (PMID:32913013).
  • Aspiration prevention (swallow assessment, diet modification).
  • Sensory habilitation (CI, low-vision services) to prevent secondary developmental, communicative, and educational deficits.
  • Falls/injury prevention given ataxia + visual loss.

Immunization

No vaccine prevents CAPOS. However, routine childhood immunization is a rational, low-cost tertiary-prevention measure because it reduces the burden of febrile illness — the dominant episode trigger. Notably, influenza and COVID-19 vaccination should be encouraged for the same reason.

⚠️ A real and under-discussed tension: vaccination itself commonly causes fever, and post-vaccination fever could plausibly trigger an episode. I found no published CAPOS case of a vaccine-triggered episode and no guidance on this. Pragmatic practice would be to vaccinate with prophylactic antipyretic cover. Flag this explicitly as a knowledge gap with clinical consequence.

Screening and Early Detection

  • Population newborn screening: not currently indicated (no proven presymptomatic intervention meeting Wilson-Jungner criteria). Revisit if acetazolamide prophylaxis or gene therapy is validated.
  • Genetic screening / reproductive options for an affected parent (50% transmission risk):
  • Prenatal diagnosis — CVS or amniocentesis with targeted p.Glu818Lys testing.
  • Preimplantation genetic testing for monogenic disease (PGT-M) — technically straightforward for a known single-nucleotide variant.
  • Donor gametes; adoption.
  • ⚠️ Counselling caveat: because expressivity is highly variable within families (from isolated hearing loss to severe encephalopathic disease), genotype does not predict severity. This must be central to any prenatal counselling conversation.
  • ⚠️ For parents of an apparently de novo case: recurrence risk is low but not zero because of documented germline mosaicism in ATP1A3 (PMID:27726050). Offer prenatal testing.
  • Risk stratification: the only stratifier is genotype. No polygenic or clinical risk score exists.

Behavioural Interventions

Illness-action planning; fever vigilance; sleep hygiene and meal regularity (per general ATP1A3 guidance); avoidance of extreme heat/cold, excessive noise, and crowds; stress management; injury-prevention adaptations.

Counselling

Genetic counselling is a core, non-optional component. Content should cover: autosomal dominant inheritance and 50% recurrence risk; ~50% de novo rate; complete penetrance for some manifestation but highly variable expressivity; germline-mosaicism caveat; reproductive options (PGT-M, prenatal diagnosis); cascade testing of relatives; the fact that a positive genotype in a currently asymptomatic relative predicts risk, not severity — GeneReviews [P]: "individuals and family members with the p.Glu818Lys pathogenic variant should be considered at risk of disease progression and development of other features."

Public Health and Environmental Interventions

Largely not applicable. The two systemic levers with real reach: 1. Include ATP1A3 on all clinical hearing-loss/auditory-neuropathy gene panels — the single highest-yield systems-level change for CAPOS ascertainment. 2. Promote ABR-based (not OAE-only) newborn hearing screening, which would surface auditory neuropathy generally, CAPOS included.

Prophylaxis

Covered above: acetazolamide/flunarizine (unproven), antipyretics (rational), immunization (rational, with the caveat noted).

14. Other Species / Natural Disease

  • Taxonomy: CAPOS is a human-only disease entity. NCBITaxon:9606 (Homo sapiens). No naturally occurring CAPOS-equivalent disease has been described in any other species.
  • Breed (VBO): Not applicable. No breed-associated ATP1A3 disorder is recorded.
  • Orthologous genes: | Species | Gene | NCBI Gene ID | Notes | |---|---|---|---| | Homo sapiens | ATP1A3 | 478 | Glu818 in TM6 region | | Mus musculus | Atp1a3 | 232975 | High conservation; basis of all mouse models | | Rattus norvegicus | Atp1a3 | 24213 | | | Danio rerio | atp1a3a, atp1a3b | (verify) | Duplicated paralogs | | Drosophila melanogaster | ATPα | (verify) | Single α gene | | C. elegans | eat-6 | (verify) | Single α gene | (Verify all non-human Gene IDs against NCBI Gene before curating.) Glu818 lies in a highly conserved region of the P-type ATPase; the corresponding Drosophila and C. elegans models used equivalent residues at other positions (PMID:34612482 [P]: CJ10 G744S "equivalent to G755 variants in humans"; DTS2 D981N "equivalent to D992 region in humans"), demonstrating that residue-mapping across these orthologs is routine.
  • Natural disease in other species: None reported. A targeted OMIA (Online Mendelian Inheritance in Animals) search for a spontaneous ATP1A3 disorder was not performed in this pass; recommend an OMIA check before asserting absence definitively, but the literature corpus contains no such report.
  • Veterinary relevance: none currently.
  • Comparative pathology: Not available for CAPOS specifically. Across ATP1A3 models generally, comparative work shows that the pattern of neurological dysfunction differs substantially between mouse and human even for identical residues — see §15 limitations.
  • Evolutionary conservation of mechanism: The Na⁺/K⁺-ATPase is deeply conserved across Metazoa; the α-isoform diversification (α1 ubiquitous, α2 glial, α3 neuronal) is a vertebrate innovation. Invertebrate models have a single α gene, which is a fundamental limitation: they cannot model isoform-specific pathology. PMID:34612482 [P] flags this: Drosophila models have "ubiquitous expression; not neurone-specific."
  • Transmission / zoonotic potential: Not applicable. CAPOS is genetic and non-transmissible.

15. Model Organisms

🔴 Headline Finding: No CAPOS Model Exists

There is no animal or organoid model carrying the CAPOS E818K variant. This was explicitly documented in the 2021 comprehensive review (PMID:34612482) and my search of the 2022–2026 Atp1a3 animal-model literature (19 papers) found no E818K model has been generated since. Every published Atp1a3 mouse targets a different allele: D801N, D801Y, E815K, I810N, D591V, or hypomorphic/null alleles.

This is the single largest translational gap for CAPOS, and it is particularly consequential because: - The fever-trigger mechanism cannot be tested without a thermally challengeable in vivo model. - The auditory-neuropathy and optic-atrophy phenotypes — the two features that define CAPOS against AHC/RDP — have never been modelled. - Gene-editing therapy has now been demonstrated for the neighbouring E815K allele in mice (PMID:40695277), so the platform exists; only the CAPOS-specific model and target validation are missing.

Curate this as a discussions entry with kind: HUMAN_MODEL_MISMATCH — the situation is not merely "evidence absent" but "all available model evidence comes from mechanistically distinct alleles whose fidelity to CAPOS biology is unestablished."

Available ATP1A3 Models (all non-CAPOS alleles)

Source: PMID:34612482 (Dis Model Mech 2021) [P] unless otherwise noted.

Mouse (Mus musculus, NCBITaxon:10090)

Model Allele Phenotype recapitulation Limitations
Myshkin I810N (ENU) "spontaneous and vestibular stress-induced seizures, medial temporal sclerosis, sleep abnormalities, and a variety of motor, cognitive, social and other behavioural deficits"; models AHC; hypofrontality. Social deficits in nest building, pup retrieval, three-chamber test (PMID:27276195). Cognitive deficits (PMID:27549929). Homozygous neonatal lethal. AHC, not CAPOS.
Mashlool / Mashl D801N Transient hemiplegia/hemiparesis in ~40%; age-dependent worsening; core AHC features. AAV9 gene therapy improved hemiplegic episodes and beam-walking (PMID:33577387). Used for the cardiac-death study in PMID:32913013 [V]: "resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death." Homozygous lethal at birth.
Matoub E815K Most severe AHC phenotype; fever/heat-induced hemiplegia after warm-water exposure — the only model with a demonstrated thermal trigger, and therefore the closest available proxy for CAPOS fever biology. Flunarizine shortened hemiplegia duration, no long-term benefit. ~33% mortality during seizures; none survive beyond 9 months. E815K, not E818K.
Atp1a3 D801Y D801Y Cold-induced dystonia (not heat-induced); seizure susceptibility; learning impairment. Hyperactivity, diminished posture, motor deficits, "refractory to ketamine anesthesia" (PMID:39111836 [P]). Temperature trigger direction is opposite to human RDP/CAPOS. Neither this nor tm1Ling shows fixed dystonia or human-type seizures.
Atp1a3^tm1Ling/+ Hypomorph Increased locomotor activity; spatial memory deficits; sex-dependent stress-induced motor deficits (females only); ethanol-induced hyperkinesia (PMID:39111836). Not a null; models no specific human variant.
Atp1a3^tm2Kwk Near-null Altered inhibitory neurotransmission; reduced social behaviour; decreased ascorbic acid. Mildest phenotype; no stress-induced seizures.
ROSA26-ATP1A3 D591V D591V transgene Models autosomal-dominant cone-rod dystrophy; retinal dysfunction by 12 months. The only retinal ATP1A3 model — of tangential interest for CAPOS optic atrophy, but adCORD is a photoreceptor disease and CAPOS optic atrophy is an RGC/axonal disease. Endogenous Atp1a3 intact; milder than human.
D801N & E815K comparative study Both PMID:40381892 [P]: "differential impact" of the two variants on paroxysmal episodes, motor function, and neuroinflammation. Important precedent that residue-adjacent alleles produce genuinely distinct biology. AHC alleles only.

Zebrafish (Danio rerio, NCBITaxon:7955)

  • atp1a3a / atp1a3b morpholino knockdown — hydrocephalus; delayed motor responses to tactile stimulation. Limitation: hydrocephalus is not a human ATP1A3 phenotype, so the model's construct validity is doubtful.
  • A813V zebrafish (PMID:42116168 [P]) — displayed "neuronal hyperexcitability before neurodegeneration"; a newer, more phenotypically relevant zebrafish approach.

Drosophila (Drosophila melanogaster, NCBITaxon:7227)

  • CJ10 (ATPα G744S) — age-dependent mechanical-stress-induced paralysis; heat-induced reversible paralysis (relevant to fever-trigger biology!); age-dependent neurodegeneration with vacuolar/spongiform pathology.
  • DTS2 (ATPα D981N) — age-dependent loss of locomotor activity; mechanical-stress-induced paralysis at 28 °C; heat-induced paralysis at 37–38 °C.
  • Limitation for both: ubiquitous rather than neurone-specific expression; single α isoform.

C. elegans (NCBITaxon:6239)

  • eat-6 G304S (modelling human ARA-related G316S) — viable homozygotes (hypomorphic); progressive bradykinesia of pharyngeal pumping by day 8; aldicarb hypersensitivity.
  • Limitation: minimal behavioural repertoire; great evolutionary distance; single α gene.

Cellular / in vitro systems (the actual workhorses for CAPOS)

  • Xenopus oocyte and mammalian cell heterologous expression — the only systems in which E818K itself has been characterized. Used in PMID:30409907 (biochemistry + electrophysiology) and PMID:29305691 (heterologous expression + molecular dynamics). These, plus molecular-dynamics simulation, constitute the entire experimental evidence base for CAPOS pathophysiology.
  • Pump-survival assays (ouabain-resistance rescue) — PMID:32653672 [P]: across 12 RDP/AHC variants, "All studied mutations led to functional impairment of the pump, as reflected by lower survival rate and reduced pump current", but "No difference in the extent of impairment, nor in the expression level, was found between the two phenotypes" — a key cautionary result: pump-function magnitude does not predict phenotype.
  • iPSC-derived neurons: demonstrated for A813V (PMID:42116168) but not for E818K.
  • Organoids: none.

Induced (non-genetic) Models

Ouabain infusion (pharmacological Na⁺/K⁺-ATPase inhibition) has been used historically to model dystonia; not CAPOS-specific.

Research Applications and Gaps

What existing models CAN support: general α3 pump biology; Na⁺ homeostasis and excitability; stress/thermal triggering (Matoub, Drosophila CJ10/DTS2); cardiac conduction and seizure-related death (Mashlool); gene-therapy and prime-editing platform development (Mashlool, Matoub).

What NO model can currently support: CAPOS auditory neuropathy; CAPOS optic atrophy; the specific fever→ataxic-encephalopathy sequence with incomplete recovery; E818K-specific target validation for gene editing; preclinical testing of acetazolamide/flunarizine in a CAPOS-relevant genetic background.

Priority proposed experiments (for proposed_experiments in the KNOWLEDGE_GAP/HUMAN_MODEL_MISMATCH entries): 1. Generate an Atp1a3^E818K/+ knock-in mouse; phenotype with ABR/OAE/DPOAE, OCT/RGC counts, rotarod/beam-walk, and a controlled thermal (fever-mimic) challenge. 2. Temperature-dependent electrophysiology of E818K in oocytes/HEK cells across 33–41 °C to test the thermal-lability hypothesis directly. 3. Patient-derived and isogenic iPSC → cerebellar, retinal-ganglion, and inner-ear/otic organoids with paired scRNA-seq and electrophysiology. 4. Prime-editing correction of E818K in patient iPSC-neurons, leveraging the PMID:40695277 platform. 5. Neuropathological study of a CAPOS brain, cochlea, and optic nerve (post-mortem tissue donation program).

Model Databases

MGI (mouse; Atp1a3 MGI:88107 — verify), IMPC, IMSR, MMRRC, ZFIN, FlyBase, WormBase, Alliance of Genome Resources, RGD, Cellosaurus, ATCC.

Appendix A — Consolidated Suggested Ontology Bindings

Disease: MONDO:0011038 — cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome [OLS-verified]

Gene: hgnc:801 — ATP1A3 (lowercase prefix per dismech convention) [HGNC-verified]

Inheritance: HP:0000006 — Autosomal dominant inheritance

Top phenotypes (all with published frequencies — see §3.1): HP:0000648 optic atrophy (11/11), HP:0001284 areflexia (11/11), HP:0002131 episodic ataxia (10/10), HP:0000407 sensorineural hearing impairment (10/10), HP:0001324 muscle weakness (10/10), HP:0000639 nystagmus (7/10), HP:0002066 gait ataxia (6/11), HP:0001761 pes cavus (3/10)

Molecular function / cellular component: GO:0005391 P-type sodium:potassium-exchanging transporter activity (modifier: DECREASED) [OLS-verified]; GO:0005890 sodium:potassium-exchanging ATPase complex [OLS-verified]

Biological processes: GO:0035725 sodium ion transmembrane transport (DECREASED) [OLS-verified]; GO:0006883 intracellular sodium ion homeostasis (DISRUPTED/INCREASED intracellular Na⁺) [OLS-verified]; GO:0042391 regulation of membrane potential (DECREASED) [OLS-verified]

Cell types: CL:0011113 spiral ganglion neuron [OLS-verified]; CL:0000589 cochlear inner hair cell [OLS-verified]; CL:0000601 cochlear outer hair cell (spared) [OLS-verified]; CL:0000121 Purkinje cell [OLS-verified]; CL:0000540 neuron; CL:0000740 retinal ganglion cell (verify)

Anatomy: UBERON:0000941 cranial nerve II [OLS-verified]; UBERON:0001844 cochlea [OLS-verified]; UBERON:0002227 spiral organ of cochlea [OLS-verified]; UBERON:0002037 cerebellum (verify)

Chemicals: CHEBI:27690 acetazolamide [OLS-verified]; CHEBI:135652 flunarizine [OLS-verified]; CHEBI:29101 sodium(1+) (verify); CHEBI:29103 potassium(1+) (verify); CHEBI:15422 ATP (verify)

Appendix B — Candidate Mechanism-Module Relationships

For dismech conforms_to consideration:

  • peripheral_axonal_degeneration — partial fit for the areflexia/pes cavus arm, but the corpus is genuinely conflicted on whether CAPOS areflexia is peripheral at all (PMID:8733056 says "in the absence of a peripheral neuropathy"; PMID:34655904 documents abnormal EMG). Recommend NOT declaring conformance until the central-vs-peripheral question is resolved; instead curate the conflict as a KNOWLEDGE_GAP.
  • cerebellar_purkinje_degeneration — plausible for the persistent-ataxia arm, but there is no histological evidence of Purkinje loss in CAPOS and MRI is usually normal. Conformance would be aspirational. Consider declaring at the "loss of cerebellar cortical output" node only, with an explicit note.
  • photoreceptor_degeneration — poor fit. CAPOS optic atrophy is an RGC/axonal disease, not a photoreceptor disease. Do not declare conformance. (Note the contrast with ATP1A3 p.D591V adCORD, which IS a photoreceptor disease — a nice illustration of allele-specific tissue targeting.)
  • sensorineural_hair_cell_loss — explicitly wrong for CAPOS and worth saying so. That module's chain runs through "Hair Cell Mechanotransduction Failure and Death"; CAPOS hair cells are preserved (OAEs and CM present). CAPOS is post-synaptic/neural. This is a good candidate for a new module — e.g. auditory_neuropathy_synaptopathy (afferent synapse/spiral-ganglion-neuron conduction failure with preserved OHC function), which would also serve OTOF, OPA1, DIAPH3, and AIFM1 disorders. Strong recommendation.
  • cardiac_ion_channel_repolarization — partial fit for the ATP1A3-spectrum arrhythmia risk, but the mechanism is pump-mediated conduction delay rather than channel repolarization. Weak; curate the cardiac risk as a phenotype with evidence rather than as module conformance.
  • epilepsy_excitation_inhibition_imbalance — applicable only to the 1/10 with seizures; weak.

Appendix C — Priority Knowledge Gaps (for discussions)

Gap Kind Attaches to
Mechanism by which fever triggers decompensation is unknown (explicitly stated, PMID:30862413) KNOWLEDGE_GAP acute-decompensation node
No E818K animal model exists; all in vivo evidence comes from mechanistically distinct alleles HUMAN_MODEL_MISMATCH whole pathograph
Is CAPOS areflexia central or peripheral? Original report vs. PMID:34655904 EMG KNOWLEDGE_GAP areflexia node
Why does E818K produce sensory (auditory/optic) disease when the adjacent E815K produces AHC? KNOWLEDGE_GAP genotype→phenotype edge
Is E818K dominant-negative or simple partial LoF? (whole-gene deletion → AHC2, not CAPOS) KNOWLEDGE_GAP molecular node
Modifier genes explaining intrafamilial severity variation KNOWLEDGE_GAP disease level
No omics data of any kind (transcriptomic, proteomic, metabolomic, single-cell) KNOWLEDGE_GAP disease level
No neuropathology/autopsy study published KNOWLEDGE_GAP tissue-damage nodes
No QoL/PRO data; no natural-history registry KNOWLEDGE_GAP disease level
Acetazolamide efficacy unproven and contradicted (PMID:27091223 vs PMID:36484864) KNOWLEDGE_GAP treatment
Vaccination-associated fever as a potential trigger — unstudied, clinically consequential KNOWLEDGE_GAP trigger node
True prevalence unknown; likely substantially underestimated within the ANSD population KNOWLEDGE_GAP prevalence

Sources

Primary literature (PubMed): PMID:8733056 · PMID:24468074 · PMID:25056583 · PMID:25447930 · PMID:25809299 · PMID:25895915 · PMID:26400718 · PMID:26417536 · PMID:26453127 · PMID:27091223 · PMID:27276195 · PMID:27313535 · PMID:27378932 · PMID:27549929 · PMID:27634470 · PMID:27726050 · PMID:28483396 · PMID:29090527 · PMID:29184165 · PMID:29287866 · PMID:29291920 · PMID:29305691 · PMID:29396171 · PMID:29397530 · PMID:29625811 · PMID:30409907 · PMID:30554714 · PMID:30862413 · PMID:30904181 · PMID:31410291 · PMID:32339621 · PMID:32653672 · PMID:32913013 · PMID:33136025 · PMID:33577387 · PMID:33762331 · PMID:33868146 · PMID:34342181 · PMID:34421501 · PMID:34464766 · PMID:34612482 · PMID:34655904 · PMID:34692702 · PMID:34761051 · PMID:35047275 · PMID:36339296 · PMID:36484864 · PMID:37043503 · PMID:38243045 · PMID:38297853 · PMID:38796484 · PMID:38821025 · PMID:39111836 · PMID:39533828 · PMID:40381892 · PMID:40695277 · PMID:41048925 · PMID:41235133 · PMID:41480049 · PMID:41850905 · PMID:42116168 · PMID:42151635

Databases and reference resources: GeneReviews — ATP1A3-Related Disorder (PMID:20301294) · OMIM #601338 · Orphanet ORPHA:1171 · MedGen C1832466 · ClinVar VCV000156238 · MONDO:0011038 via EBI OLS · Human Phenotype Ontology annotations for OMIM:601338 · HGNC:801 · Europe PMC · NCBI E-utilities

Handoff Notes for the Curator

  1. Run the reference-fetch loop first. Every PMID cited here needs just fetch-reference PMID:XXXX; every snippet needs just validate-references. Quotes marked [P] are the highest-risk — assume they need replacement with a verified exact quote or removal.
  2. Verify all non-[OLS-verified] ontology IDs with just validate-terms. The NCIT cochlear-implantation term in particular is likely to fail the TreatmentTerm dynamic-enum reachability check from NCIT:C25218.
  3. The NEC preflight passed — but note that a naive PubMed query on "CAPOS" returns five unrelated entities. Any future automated literature sweep for this disease must anchor on ATP1A3 or the full expanded acronym, never on the bare string.
  4. Consider proposing a new auditory_neuropathy_synaptopathy module (Appendix B) — CAPOS would be its flagship conformer, and it would immediately serve OTOF, OPA1, AIFM1, and DIAPH3 disorders. The existing sensorineural_hair_cell_loss module is mechanistically wrong for this class.
  5. Consider a ATP1A3-Related_Disorders Grouping (§4) with CAPOS, AHC2, RDP, and RECA as members and residue-position-keyed differentiating_mechanisms.
  6. Do not overstate prevalence. Use measure_type: CASES_IN_LITERATURE and prevalence_class: ULTRA_RARE; omit rate_per_100000.
  7. The pes cavus / acronym mismatch (30% frequency for the "P" in CAPOS) is worth a notes field — it is a recurring source of missed diagnoses.