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Classifications

Harrison's Chapter

Channelopathy

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Definitions

1

Bruno diagnostic criteria for idiopathic paroxysmal kinesigenic dyskinesia

The consensus clinical criteria for idiopathic PKD, derived from review of 121 affected individuals: an identified kinesigenic trigger (sudden movements); short attack duration, under one minute; no loss of consciousness and no pain during attacks; responsiveness to antiepileptic drugs; exclusion of other organic disease, with a normal neurological examination; and age at onset between 1 and 20 years where there is no family history (applied less stringently in familial cases).

DIAGNOSTIC_CRITERIA Clinical recognition of idiopathic PKD; the criteria were designed to homogenise cohorts for gene discovery and remain the reference case definition.

Inclusion criteria

Identified kinesigenic trigger (sudden voluntary movement)
Attack duration under one minute
Preserved consciousness and absence of pain during attacks
Responsiveness to antiepileptic drugs
Age at onset between 1 and 20 years when there is no family history

Exclusion criteria

Other organic disease accounting for the attacks

Show evidence (2 references)

PMID:15623687 SUPPORT Human Clinical

"The authors propose the following diagnostic criteria for idiopathic PKD based on this phenotype: identified trigger for the attacks (sudden movements), short duration of attacks (<1 minute), lack of loss of consciousness or pain during attacks, antiepileptic drug responsiveness, exclusion of..."

Verbatim statement of the criteria set curated here.

PMID:15623687 PARTIAL Human Clinical

"A clear kinesigenic trigger was not elicited in all cases, antiepileptic response was not universal, and some infants had attacks while asleep."

Records the authors' own caveats limiting the sensitivity of the criteria.

Notes: The authors themselves note that these criteria are not universally satisfied: a clear kinesigenic trigger was not elicited in every case, antiepileptic response was not universal, and some infants had attacks during sleep. A separate infantile-onset group with different characteristics was identified.

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Inheritance

1

Autosomal dominant with incomplete, phenotype-dependent penetrance HP:0000006

The primary paroxysmal dyskinesias are predominantly autosomal dominant (PRRT2, TMEM151A, PNKD, SLC2A1, KCNMA1, ADCY5). Reported penetrance depends critically on which phenotype is counted: for PRRT2 it is about 61% when only PKD is scored but nearly complete when infantile convulsions are also counted. Expressivity is highly variable within a single kindred — the same PRRT2 allele may produce isolated infantile seizures, isolated kinesigenic dyskinesia, both sequentially (ICCA), hemiplegic migraine, episodic ataxia, or nothing at all. Autosomal recessive and de novo mechanisms occur, particularly for SLC2A1 (frequently de novo), biallelic PRRT2, and the metabolic PED mimics.

Autosomal dominant inheritance Penetrance: INCOMPLETE Penetrance %: 61 Expressivity: VARIABLE

Show evidence (1 reference)

PMID:22875091 SUPPORT Human Clinical

"The estimated penetrance of PRRT2 mutations was 61%, if only the PKD phenotype was considered; however, if infantile convulsions were also taken into account, the penetrance was nearly complete."

Direct source for the penetrance figure and for the observation that it is phenotype-definition dependent.

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Subtypes

6

Paroxysmal kinesigenic dyskinesia (PRRT2, TMEM151A) MONDO:0044202

PRRT2 hgnc:30500 TMEM151A hgnc:28497

The commonest paroxysmal dyskinesia. Attacks of dystonia and/or choreoathetosis are triggered by sudden voluntary movement (rising from a chair, starting to walk, startle), typically last under one minute, and may occur many times a day, often preceded by a sensory aura in the affected limb. Onset is in childhood or early adolescence with a 2-4:1 male excess, and attacks usually decline in the third decade. Most cases carry heterozygous loss-of-function PRRT2 variants (recurrent c.649dupC); TMEM151A is a second locus in PRRT2-negative cases. Low-dose carbamazepine or oxcarbazepine is dramatically effective.

Show evidence (1 reference)

PMID:38091244 SUPPORT Other

"Paroxysmal kinesigenic dyskinesia (PKD), the most common type of paroxysmal movement disorder, is characterized by sudden and brief attacks of choreoathetosis or dystonia triggered by sudden voluntary movements. PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene."

Defines the PKD subtype by its kinesigenic trigger and brief attack duration and names PRRT2 and TMEM151A as the two causative loci.

Paroxysmal non-kinesigenic dyskinesia (PNKD/MR-1) MONDO:0700088

PNKD hgnc:9153

Attacks of dystonia and choreoathetosis that arise spontaneously at rest or are precipitated by alcohol, coffee or tea, emotional stress, excitement and fatigue, but never by sudden movement. Attacks are much longer than in PKD (typically tens of minutes to hours) and correspondingly less frequent, sometimes only a few per year. Classic autosomal dominant PNKD is caused by the recurrent N-terminal p.Ala7Val and p.Ala9Val variants in PNKD (myofibrillogenesis regulator 1, MR-1). Pharmacological response is unreliable, so trigger avoidance is the mainstay.

Show evidence (1 reference)

PMID:15496428 SUPPORT Human Clinical

"Paroxysmal non-kinesigenic dyskinesia (PNKD) is characterized by spontaneous hyperkinetic attacks that are precipitated by alcohol, coffee, stress and fatigue."

Establishes the defining non-kinesigenic trigger profile that separates PNKD from PKD.

Paroxysmal exercise-induced dyskinesia (SLC2A1/GLUT1 deficiency) MONDO:0012805

SLC2A1 hgnc:11005

Attacks of leg-predominant dystonia and choreoathetosis provoked by prolonged exertion (and sometimes by fasting), relieved by rest or carbohydrate. The critical genotype is heterozygous SLC2A1 loss of function causing GLUT1 deficiency, which frequently co-segregates with generalised epilepsy. This is the treatable cause of paroxysmal dyskinesia: the ketogenic diet supplies ketone bodies that bypass the defective blood-brain-barrier glucose transporter. The biochemical clue is hypoglycorrhachia with a reduced CSF:blood glucose ratio in a normoglycaemic patient. The broader SLC2A1 phenotype is curated in GLUT1_Deficiency_Syndrome; only the paroxysmal-dyskinesia presentation is modelled here.

Show evidence (2 references)

PMID:18577546 SUPPORT Human Clinical

"In conclusion, co-occurring PED and epilepsy can be due to autosomal dominant heterozygous SLC2A1 mutations, expanding the phenotypic spectrum associated with GLUT1 deficiency and providing a potential new treatment option for this clinical syndrome."

Establishes SLC2A1/GLUT1 deficiency as the molecular cause of the PED subtype and flags its treatability.

PMID:20301603 SUPPORT Human Clinical

"When first diagnosed in later childhood to adulthood (occasionally in a parent following the diagnosis of an affected child), the predominant clinical findings of Glut1DS are usually complex paroxysmal movement disorders, spasticity, ataxia, dystonia, speech difficulty, and intellectual disability."

GeneReviews confirms that later-presenting GLUT1 deficiency is dominated by paroxysmal movement disorder, which is the presentation modelled in this entry.

Generalized epilepsy with paroxysmal dyskinesia (KCNMA1, PNKD3) MONDO:0012276

KCNMA1 hgnc:6284

Autosomal dominant co-occurrence of paroxysmal dyskinesia and generalised (usually absence) epilepsy in the same individual or family, caused by gain-of-function variants in KCNMA1 encoding the BK calcium-activated potassium channel alpha subunit (p.Asp434Gly is the index allele). This subtype makes the movement-disorder and epilepsy continuum explicit at the level of a single channel.

Show evidence (2 references)

PMID:35286197 SUPPORT Model Organism

"We characterized a mouse model carrying a gain-of-function BK channelopathy D434G from a large family of patients with absence epilepsy and paroxysmal dyskinesia."

Anchors the KCNMA1 D434G gain-of-function allele to the combined absence-epilepsy plus paroxysmal-dyskinesia human phenotype. Model-organism evidence; the human evidence for the same subtype is the item below.

PMID:15937479 SUPPORT Human Clinical

"Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the alpha subunit of the BK channel causes this syndrome."

Human genetic evidence establishing the PNKD3 syndrome and its KCNMA1 cause, independent of the mouse model.

ADCY5-related dyskinesia with orofacial involvement MONDO:0800028

ADCY5 hgnc:236

Childhood- or adolescent-onset mixed hyperkinetic disorder caused by gain-of-function ADCY5 variants, with paroxysmal choreiform, dystonic and myoclonic movements of the limbs, neck and face, characteristic perioral and periorbital involvement, nocturnal exacerbation, and frequent axial hypotonia. ADCY5 is the clearest single-gene demonstration that the trigger-based classification does not map one-to-one onto genotype: attacks may be kinesigenic, exercise-induced, non-kinesigenic or nocturnal in the same gene.

Show evidence (1 reference)

PMID:26537056 SUPPORT Human Clinical

"ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements."

Defines the ADCY5 subtype as a childhood-onset hyperkinetic disorder distinct from the trigger-defined classic subtypes.

Infantile convulsions and choreoathetosis (PRRT2 pleiotropy) MONDO:0011178

PRRT2 hgnc:30500

The bridging phenotype of the PRRT2 spectrum: benign familial infantile seizures in the first year of life followed, years later in the same individual or kindred, by kinesigenic dyskinesia. ICCA is the clearest demonstration that PRRT2 haploinsufficiency produces an age-dependent shift in paroxysmal phenotype rather than two separate diseases.

Show evidence (1 reference)

PMID:22875091 SUPPORT Human Clinical

"PRRT2 mutations are the major cause of PKD or ICCA, but they do not seem to be involved in the etiology of febrile convulsions and migraine."

Establishes ICCA as a PRRT2-determined entity within the same allelic series as isolated PKD.

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Mechanistic Hypotheses

1

Cerebellar rather than basal-ganglia origin of the PKD attack

cerebellar_origin_of_pkd EMERGING PKD

Evidence balance 1 support

The traditional assumption that paroxysmal dyskinesia is a basal-ganglia disorder is under revision for PKD specifically. Work in PRRT2-deficient models points to the cerebellum as the pivotal generator, with dyskinetic episodes tightly coupled to spreading depolarization in cerebellar cortex, while the contribution of cortex, thalamus and striatum is comparatively unresolved. The competing and complementary view remains that the basal-ganglia-thalamo-cortical loop generates the motor output. This matters practically because it predicts different neuromodulation targets.

Pathograph links

Presynaptic Release Failure and Neuronal Hyperexcitability -> Cerebellar Spreading Depolarization and Circuit Instability DIRECT

Cerebellar Spreading Depolarization and Circuit Instability -> Trigger-Dependent Breach of the Motor Network Attack Threshold DIRECT

Show evidence (1 reference)

PMID:38091244 SUPPORT Other

"Whereas, in PKD, other than the cerebellum, the role of the cerebrum including the cortex and thalamus needs to be further investigated."

States both the cerebellar-primacy position and the explicit acknowledgement that the cerebral contribution is unresolved.

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Discussions and Knowledge Gaps

4

Is paroxysmal hypnogenic dyskinesia (PHD) a genuine fourth subtype of paroxysmal dyskinesia, or is it entirely subsumed by sleep-related hypermotor epilepsy?

CONTROVERSY OPEN phd_nosology

Attached to

pathophysiology#Trigger-Dependent Breach of the Motor Network Attack Threshold

The dominant position, formalised by the 2016 consensus that renamed nocturnal frontal lobe epilepsy as sleep-related hypermotor epilepsy, is that sleep-related dyskinetic attacks are epileptic seizures with hypermotor semiology. This entry follows that position and does not curate PHD as a mechanistically distinct dyskinesia. However, a 2016 screening study of 11 PHD patients found PRRT2 variants in 2 patients with typical (short-attack) PHD and no variants in any of the epilepsy genes screened, and its authors concluded the opposite — that PHD is a subtype of paroxysmal dyskinesia rather than NFLE. The honest reading is that the PHD label historically pooled two populations: a majority with genetic focal epilepsy and a minority with short-attack PRRT2-related dyskinesia occurring in sleep. Video-EEG is the discriminator, and the label itself should be retired in favour of the specific diagnosis.

Proposed experiments

Prospective video-EEG plus broad panel sequencing in sleep-related paroxysmal motor attacks

phd_video_eeg_genotype_cohort

Recruit an unselected cohort of patients with sleep-related paroxysmal motor attacks, obtain video-EEG on all, and sequence PRRT2, TMEM151A, CHRNA4, CHRNB2, CHRNA2, KCNT1 and DEPDC5. Report the proportion with an ictal epileptiform correlate, stratified by genotype and by attack duration.

Decision criterion

If PRRT2-positive sleep-related cases consistently lack an ictal epileptiform correlate, a residual non-epileptic PHD population is supported; if they show one, PHD is fully subsumed by SHE.

Treatment-response and semiology profiling of PRRT2-positive sleep-related attacks

phd_prrt2_treatment_profile

Determine whether PRRT2-positive sleep-related cases show the carbamazepine-responsive, aura-preceded, short-attack profile of waking PKD or the clustered hypermotor profile of SHE.

Show evidence (2 references)

PMID:27123484 SUPPORT Human Clinical

"The present study identified PRRT2 mutations in PHD, extending the phenotypic spectrum of PRRT2 and supporting the classification of PHD as a subtype of paroxysmal dyskinesia but not NFLE."

The minority position, with direct genetic evidence, that must be represented rather than suppressed.

PMID:27164717 REFUTE Human Clinical

"It was recommended that the name be changed to sleep-related hypermotor epilepsy (SHE), reflecting evidence that the attacks are associated with sleep rather than time of day, the seizures may arise from extrafrontal sites, and the motor aspects of the seizures are characteristic."

The consensus position that sleep-related hypermotor attacks are epileptic; recorded as REFUTE with respect to the proposition that PHD is a distinct dyskinesia.

Does the striatal indirect-pathway (iMSN) hypoactivity that causes dyskinetic attacks in PNKD mice actually occur in human PNKD?

HUMAN MODEL MISMATCH OPEN pnkd_imsn_human_translation

Attached to

pathophysiology#Striatal Indirect-Pathway Medium Spiny Neuron Hypoactivity

The iMSN mechanism is unusually strong causal evidence — optically identified single-unit recordings during spontaneous attacks, chemogenetic sufficiency, and an identified endocannabinoid synaptic substrate — but all of it is mouse. It also runs against the classical model in which dyskinesia arises from direct-pathway hyperactivity, so it is not simply a confirmation of expectation. There is no human biomarker, imaging correlate or post-mortem finding that indexes iMSN firing in PNKD patients, and no human tissue or iPSC-derived striatal system has tested it. Until that gap is closed the node should be read as a well-supported model-organism mechanism whose translational validity is untested, not as established human pathophysiology.

Proposed experiments

Endocannabinoid-system pharmacology in human PNKD

pnkd_cb1_pharmacology_trial

Test whether CB1-directed pharmacology modifies attack frequency in patients with genetically confirmed PNKD, as the mouse endocannabinoid mechanism predicts.

Decision criterion

A reduction in attack frequency with CB1 antagonism would be the first human evidence that the mouse endocannabinoid-iMSN mechanism operates in patients.

Patient-derived iPSC striatal system carrying PNKD p.Ala7Val or p.Ala9Val

pnkd_ipsc_striatal_model

Build iPSC-derived striatal organoid or corticostriatal co-culture systems from PNKD patients and assay endocannabinoid-dependent suppression of glutamatergic input onto D2 or indirect-pathway neurons.

Attack-locked functional imaging in PNKD patients

pnkd_attack_locked_imaging

Use task-based or attack-locked functional imaging in PNKD patients to seek an indirect-pathway signature during provoked attacks.

Show evidence (1 reference)

PMID:35165171 SUPPORT Model Organism

"These data show that striatal iMSN dysfunction contributes to the etiology of dyskinesia in PNKD, and suggest that indirect pathway hypoactivity may be a key mechanism for the generation of involuntary movements in other disorders."

The mouse claim whose human validity is the open question. The authors themselves frame the generalisation as a suggestion.

How far can the trigger-based classification (PKD, PNKD, PED) still be trusted as a guide to genotype and therefore to treatment?

OPEN QUESTION OPEN trigger_genotype_mapping_breakdown

Attached to

pathophysiology#Trigger-Dependent Breach of the Motor Network Attack Threshold

The trigger-to-gene-to-treatment mapping is the practical value of this entry, and it is under strain. SLC2A1 variants have been found in patients phenotyped as PKD and as PNKD, not only PED; PRRT2 variants appear in hemiplegic migraine and episodic ataxia; ADCY5 alone can produce kinesigenic, exertional, non-kinesigenic and nocturnal attacks. Whether the correct response is to keep trigger-based syndromes as a first-pass heuristic that gates a broad panel, or to move to genotype-first testing in all cases, is unresolved and has direct cost-effectiveness consequences.

Show evidence (2 references)

PMID:26598494 SUPPORT Human Clinical

"SLC2A1 mutations were associated with variable phenotypes including paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, episodic ataxia and myotonia"

Direct demonstration that one gene crosses all three trigger-defined syndromes, undermining a strict one-syndrome-one-gene mapping.

PMID:30242089 SUPPORT Human Clinical

"Classically, PxD have been categorised according to their triggers and duration of the attacks, but increasing evidence suggests that there is a certain degree of clinical and genetic overlap and challenges the concept that one phenotype is attributable to one single aetiology."

States the challenge to trigger-based nosology explicitly.

What is the actual magnitude of diagnostic delay in paroxysmal dyskinesia, and how much of it is attributable to misdiagnosis as epilepsy, tics, or a functional disorder?

KNOWLEDGE GAP OPEN diagnostic_delay

Attached to

pathophysiology#Trigger-Dependent Breach of the Motor Network Attack Threshold

Diagnostic delay in this group is repeatedly described qualitatively — PKD is often misdiagnosed clinically as epilepsy, individual patients carry Tourette or functional labels for years, and GLUT1 deficiency may be missed entirely despite being diet-responsive — but no cohort study quantifies the interval from first attack to correct diagnosis, its distribution across PKD, PNKD and PED, or the proportion of that interval attributable to each incorrect label. The gap matters because the delay is the principal preventable harm in an otherwise treatable and non-progressive group of disorders, and because a quantified delay is what would justify including paroxysmal dyskinesia in movement-disorder and epilepsy diagnostic pathways.

Proposed experiments

Multi-centre retrospective diagnostic-delay cohort

pxd_diagnostic_delay_cohort

Measure time from first attack to molecular or clinical diagnosis, stratified by subtype and by whether the patient first presented to epilepsy, movement-disorder, paediatric or psychiatric services, and record every incorrect label applied in the interval.

Outcome consequences of delayed ketogenic therapy in GLUT1-related PED

glut1_delayed_keto_outcome

Quantify the subset of GLUT1-related PED in which ketogenic therapy was started more than five years after symptom onset, and test whether delay correlates with residual cognitive or motor outcome.

Show evidence (1 reference)

PMID:22101681 SUPPORT Human Clinical

"Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal movement disorder and is often misdiagnosed clinically as epilepsy."

Establishes that misdiagnosis is common, which is precisely the qualitative statement that has never been quantified.

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Pathophysiology

12

PRRT2 and TMEM151A Loss of Function

Heterozygous truncating variants in PRRT2 (the recurrent c.649dupC frameshift accounts for the majority of carriers) yield no stable protein, producing a haploinsufficient state at the presynaptic terminal. TMEM151A truncating and missense variants behave similarly, with patient transcript evidence supporting loss of function; TMEM151A accounts for a share of PRRT2-negative PKD. This is the molecular initiating lesion of the kinesigenic subtype.

PRRT2 hgnc:30500 TMEM151A hgnc:28497

brain UBERON:0000955

Downstream

Presynaptic Release Failure and Neuronal Hyperexcitability

Age-Dependent PRRT2 Phenotype Shift from Infantile Seizures to Kinesigenic Dyskinesia

Show evidence (3 references)

PMID:22101681 SUPPORT Human Clinical

"Using whole-exome sequencing followed by Sanger sequencing, we identified three truncating mutations within PRRT2 (NM_145239.2) in eight Han Chinese families with histories of paroxysmal kinesigenic dyskinesia"

Original identification of truncating PRRT2 variants co-segregating with PKD.

PMID:26598493 SUPPORT Human Clinical

"The vast majority of mutations lead to a truncated protein or no protein at all and thus to a haploinsufficient state."

Establishes haploinsufficiency, rather than a dominant-negative or gain-of-function effect, as the operative molecular mechanism.

PMID:38091244 SUPPORT Other

"PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene."

Supports treating PRRT2 and TMEM151A as the two loss-of-function loci of the same kinesigenic mechanism node.

Presynaptic Release Failure and Neuronal Hyperexcitability

PRRT2 is enriched at presynaptic terminals, where it interacts with the SNARE proteins SNAP-25 and syntaxin-1A, with synaptotagmin 1/2 calcium sensors, and with Nav1.2/Nav1.6 sodium channels and the Na+/K+ ATPase. Loss of PRRT2 desynchronises calcium-triggered vesicle fusion (reduced release probability and calcium sensitivity, increased asynchronous release, more docked vesicles at rest) while simultaneously increasing sodium-current density and lowering the action-potential threshold. PKD is therefore simultaneously a synaptopathy and a channelopathy: the lesion does not produce continuous dysfunction but a network that is stable at baseline and unstable when abruptly perturbed.

Cerebellar rather than basal-ganglia origin of the PKD attack

neuron CL:0000540

chemical synaptic transmission GO:0007268 ⚠ ABNORMAL calcium-ion regulated exocytosis GO:0017156 ↓ DECREASED regulation of membrane potential GO:0042391 ⚠ ABNORMAL sodium ion transport GO:0006814 ↑ INCREASED

Downstream

Cerebellar Spreading Depolarization and Circuit Instability

Trigger-Dependent Breach of the Motor Network Attack Threshold

Migraine

Show evidence (2 references)

PMID:27052163 SUPPORT In Vitro

"PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca(2+) sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and..."

Directly demonstrates the presynaptic release defect and the SNARE/synaptotagmin interaction that make PKD a synaptopathy.

PMID:38091244 SUPPORT Other

"Based on abnormal ion channels and disturbed synaptic transmission in the absence of PRRT2, PKD may be channelopathy or synaptopathy, or both."

Supports the dual channelopathy/synaptopathy framing of this node and justifies its conformance to the epilepsy excitation-inhibition module's ion-channel-and-synaptic dysfunction trigger.

Cerebellar Spreading Depolarization and Circuit Instability

In PRRT2-deficient models the cerebellum, rather than the basal ganglia, emerges as the pivotal generator: granule-cell to Purkinje-cell circuits are hyperexcitable and dyskinetic episodes are tightly coupled to episodes of spreading depolarization in cerebellar cortex, which transiently disrupts cerebellar output to the deep nuclei and thalamus. The role of cortex and thalamus in PKD remains less well defined.

Cerebellar rather than basal-ganglia origin of the PKD attack

cerebellar granule cell CL:0001031 Purkinje cell CL:0000121

action potential GO:0001508 ⚠ ABNORMAL

cerebellum UBERON:0002037

Downstream

Trigger-Dependent Breach of the Motor Network Attack Threshold

Show evidence (1 reference)

PMID:38091244 SUPPORT Other

"In addition, the cerebellum is regarded as the key pathogenic area. Spreading depolarization in the cerebellum is tightly associated with dyskinetic episodes."

Identifies cerebellar spreading depolarization as the proximate circuit event linking the PRRT2 synaptic/channel lesion to a discrete attack.

PNKD (MR-1) Dysfunction and Impaired Methylglyoxal Detoxification

The recurrent p.Ala7Val and p.Ala9Val variants alter the N-terminal alpha helix of the brain-specific long isoform of PNKD (myofibrillogenesis regulator 1, MR-1), which is membrane-localised and homologous to hydroxyacylglutathione hydrolase. The homologous enzyme detoxifies methylglyoxal, a reactive dicarbonyl present in coffee and alcoholic drinks and generated as a by-product of oxidative stress — which supplies a direct chemical rationale for why exactly those exposures, plus stress and fatigue, precipitate PNKD attacks. Note this remains an inference from sequence homology plus trigger pharmacology; direct enzymatic proof in human neurons is not established.

PNKD hgnc:9153

methylglyoxal catabolic process GO:0051596 ↓ DECREASED

Downstream

Striatal Indirect-Pathway Medium Spiny Neuron Hypoactivity

Show evidence (3 references)

PMID:15496428 SUPPORT Human Clinical

"We report mutations in the myofibrillogenesis regulator 1 (MR-1) gene causing PNKD in 50 individuals from eight families."

Human genetic evidence establishing MR-1 as the PNKD locus.

PMID:15496428 PARTIAL Computational

"Bioinformatic analysis reveals that the MR-1 gene is homologous to the hydroxyacylglutathione hydrolase (HAGH) gene. HAGH functions in a pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic beverages and produced as a by-product of oxidative stress. Our results suggest a..."

The methylglyoxal-detoxification mechanism rests on sequence homology plus trigger pharmacology, not on a measured enzymatic assay. Recorded as COMPUTATIONAL and PARTIAL because the authors themselves frame it as a suggested mechanism.

PMID:15262732 SUPPORT Human Clinical

"These mutations were absent in control subjects and caused substitutions of valine for alanine at amino acid positions 7 and 9. The substitutions disturb interspecies conserved residues and are predicted to alter the MR-1 gene's amino-terminal alpha helix."

Independent identification of the same recurrent N-terminal MR-1 substitutions in PNKD kindreds.

Striatal Indirect-Pathway Medium Spiny Neuron Hypoactivity

In PNKD transgenic mice, caffeine and alcohol provoke dyskinetic attacks that coincide with a loss of firing in optically identified indirect-pathway striatal medium spiny neurons (iMSNs). Chemogenetic silencing of iMSNs is sufficient to trigger attacks, and the firing loss is attributable to aberrant endocannabinoid-mediated suppression of glutamatergic input. This inverts the classical dyskinesia model (direct-pathway hyperactivity) and places the causal lesion in indirect-pathway hypoactivity. The evidence is mouse-only; no human biomarker corresponds to it (see the discussions block).

indirect pathway medium spiny neuron CL:4023029

action potential GO:0001508 ↓ DECREASED chemical synaptic transmission GO:0007268 ↓ DECREASED

striatum UBERON:0002435

Downstream

Trigger-Dependent Breach of the Motor Network Attack Threshold

Show evidence (2 references)

PMID:35165171 SUPPORT Model Organism

"Using optically identified striatal single-unit recordings in freely moving PNKD mice, we found a loss of iMSN firing during dyskinesia bouts. Further, chemogenetic inhibition of iMSNs triggered dyskinetic episodes in PNKD mice."

Provides cell-type-resolved causal evidence that indirect-pathway hypoactivity generates the PNKD attack.

PMID:35165171 SUPPORT Model Organism

"Finally, we found that these decreases in iMSN firing are likely because of aberrant endocannabinoid-mediated suppression of glutamatergic inputs."

Identifies the endocannabinoid-dependent synaptic mechanism upstream of the iMSN firing loss.

GLUT1 Haploinsufficiency and Reduced Blood-Brain-Barrier Glucose Transport

Heterozygous SLC2A1 missense, frameshift, splice and deletion variants reduce the glucose-transport capacity of GLUT1 at the brain microvascular endothelium, the obligatory route by which glucose — the brain's principal fuel — crosses the blood-brain barrier. Reduced uptake by mutant transporters is directly demonstrable in Xenopus oocytes, and the resulting transport failure is visible clinically as hypoglycorrhachia with a low CSF:blood glucose ratio in a normoglycaemic patient.

brain microvascular endothelial cell CL:2000044

SLC2A1 hgnc:11005

D-glucose transmembrane transport GO:1904659 ↓ DECREASED transport across blood-brain barrier GO:0150104 ↓ DECREASED

D-glucose transmembrane transporter activity GO:0055056 ↓ DECREASED

Downstream

Exertion- and Fasting-Unmasked Corticostriatal Energy Failure

Hypoglycorrhachia

Show evidence (2 references)

PMID:18577546 SUPPORT Human Clinical

"A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients"

The biochemical signature of reduced blood-brain-barrier glucose transport measured directly in patients with PED.

PMID:18577546 SUPPORT In Vitro

"a reduced glucose uptake by mutated transporters compared with the wild-type as determined in Xenopus oocytes confirmed a pathogenic role of these mutations"

Heterologous-expression assay demonstrating that the patient variants directly reduce transporter function. Split from the patient CSF finding so each evidence item carries a single evidence_source.

Exertion- and Fasting-Unmasked Corticostriatal Energy Failure

A partially reduced glucose-transport reserve is sufficient at rest but becomes limiting when cerebral demand rises with sustained exertion or when substrate supply falls with fasting. Functional imaging in SLC2A1-related PED implicates altered glucose metabolism specifically in the corticostriate pathways (and in frontal cortex for the accompanying seizures), giving an energetic rather than a channel-based explanation for why the trigger is prolonged exercise and why rest or carbohydrate terminates the attack. This is the node the ketogenic diet targets, by supplying ketone bodies as a GLUT1-independent fuel.

striatum UBERON:0002435 cerebral cortex UBERON:0000956

Downstream

Trigger-Dependent Breach of the Motor Network Attack Threshold

Gait Disturbance During Attacks

Seizures

Show evidence (1 reference)

PMID:18577546 SUPPORT Human Clinical

"Functional imaging studies implicated alterations in glucose metabolism in the corticostriate pathways in the pathophysiology of PED and in the frontal lobe cortex in the pathophysiology of epileptic seizures."

Localises the metabolic failure to the corticostriatal circuit for the movement phenotype and to frontal cortex for the epilepsy phenotype.

KCNMA1 BK-Channel Gain of Function

Gain-of-function variants in KCNMA1 (p.Asp434Gly, p.Asn999Ser) increase calcium-activated BK potassium current, accelerating action-potential repolarisation and thereby permitting faster repetitive firing. In the D434G knock-in mouse this produces hyperexcitability of cortical pyramidal neurons and cerebellar Purkinje cells, and the animals recapitulate the human combination of absence epilepsy with dyskinesia; BK blockade with paxilline reverses both. Variant direction of effect, not merely the gene name, determines the mechanism: in heterologous cells p.Asn999Ser and p.Asp434Gly are gain-of-function while p.His444Gln is loss-of-function.

Purkinje cell CL:0000121

KCNMA1 hgnc:6284

calcium-activated potassium channel activity GO:0015269 ↑ INCREASED

Downstream

Trigger-Dependent Breach of the Motor Network Attack Threshold

Absence Seizures

Show evidence (4 references)

PMID:35286197 SUPPORT Model Organism

"The cortical pyramidal neurons and cerebellar Purkinje cells from the BK-D434G mice show hyperexcitability, which likely contributes to the pathogenesis of absence seizures and paroxysmal dyskinesia."

Establishes BK gain of function as a hyperexcitability mechanism producing both the dyskinesia and the absence epilepsy of PNKD3.

PMID:35286197 SUPPORT Model Organism

"Pharmacological inhibition of BK channels suppresses neuronal hyperactivity and mitigates absence seizure and the locomotor defects."

Pharmacological reversal by a BK blocker supports the gain-of-function direction of effect as causal rather than incidental. The blocker used, paxilline, is a research tool and not a human therapy.

PMID:35819138 SUPPORT In Vitro

"In heterologous cells, BKN999S and BKD434G channels displayed gain-of-function (GOF) properties, whereas BKH444Q channels showed loss-of-function (LOF) properties."

Source for the p.Asn999Ser gain-of-function allele and for the statement that loss-of-function KCNMA1 alleles (p.His444Gln) behave differently in the same assay.

+ 1 more reference

ADCY5 Striatal cAMP Signalling Gain of Function

Gain-of-function variants in ADCY5, the adenylate cyclase isoform enriched in striatal medium spiny neurons, raise cAMP production downstream of dopamine and adenosine receptors and produce a mixed hyperkinetic disorder — dystonia, chorea and myoclonus with characteristic facial/perioral involvement — that fluctuates and worsens paroxysmally, notably at night. Recurrent variants at residues 418 and 726 dominate, and somatic mosaicism attenuates severity. Because ADCY5 attacks may be kinesigenic, exercise-induced, non-kinesigenic or nocturnal within one gene, ADCY5 is the clearest single-gene demonstration that trigger-based classification does not map one-to-one onto genotype.

medium spiny neuron CL:1001474

ADCY5 hgnc:236

cAMP biosynthetic process GO:0006171 ↑ INCREASED

adenylate cyclase activity GO:0004016 ↑ INCREASED

striatum UBERON:0002435

Downstream

Trigger-Dependent Breach of the Motor Network Attack Threshold

Orofacial Dyskinesia

Show evidence (2 references)

PMID:26537056 SUPPORT Human Clinical

"These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background."

Documents the mixed hyperkinetic phenomenology with facial involvement and episodic exacerbation that distinguishes ADCY5-related dyskinesia.

PMID:26537056 SUPPORT Human Clinical

"Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia."

Anchors the characteristic nocturnal exacerbation and perioral/facial dyskinesia to the recurrent ADCY5 residue-418 alleles.

Secondary and Acquired Causes of Paroxysmal Dyskinesia

Paroxysmal dyskinesia is not always genetic. Acquired causes act by imposing a focal or diffuse insult on the same motor circuits: demyelinating lesions in multiple sclerosis (classically producing paroxysmal tonic spasms that are the acquired mimic of PKD, likewise carbamazepine-responsive), hypoparathyroidism and other metabolic derangements (often with basal-ganglia calcification), perinatal hypoxic-ischaemic injury, transient cerebral ischaemia, stroke, trauma, encephalitis and autoimmune disease, structural basal-ganglia lesions, and drugs or toxins. Adult onset, inconsistent triggers, evolving phenomenology, or any abnormality on interictal examination should prompt a search for a secondary cause.

brain UBERON:0000955

Downstream

Trigger-Dependent Breach of the Motor Network Attack Threshold

Show evidence (2 references)

PMID:32443735 SUPPORT Human Clinical

"From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known."

Establishes that acquired aetiologies are a recognised and distinct arm of the paroxysmal movement disorder group.

PMID:10323309 SUPPORT Human Clinical

"Tonic spasms in multiple sclerosis and Sandiffers syndrome producing intermittent torticollis in infants and children are other paroxysmal movement disorders."

Names multiple sclerosis paroxysmal tonic spasms as an acquired paroxysmal movement disorder within the same clinical group.

Trigger-Dependent Breach of the Motor Network Attack Threshold

The convergence node of the entry. Whatever the upstream lesion — presynaptic release failure, striatal indirect-pathway hypoactivity, corticostriatal energy failure, BK or cAMP dysregulation, or an acquired structural insult — the result is the same: a basal-ganglia-thalamo-cortical and cerebello-thalamic motor network that behaves normally at baseline but has a reduced margin before a discrete, self-limited episode of aberrant motor output. The trigger (sudden movement, stimulant, stress, exertion, sleep state) supplies the perturbation that breaches the margin. This trigger-threshold architecture is what explains the two defining features of the group: attacks are stereotyped and provoked, and the examination between them is normal.

regulation of membrane potential GO:0042391 ⚠ ABNORMAL

striatum UBERON:0002435 cerebellum UBERON:0002037 cerebral cortex UBERON:0000956

Downstream

Paroxysmal Dyskinetic Attacks

Paroxysmal Dystonia

Paroxysmal Choreoathetosis

Hemiballismus During Attacks

Sensory Aura Preceding Attacks

Show evidence (1 reference)

PMID:30242089 SUPPORT Human Clinical

"Classically, PxD have been categorised according to their triggers and duration of the attacks, but increasing evidence suggests that there is a certain degree of clinical and genetic overlap and challenges the concept that one phenotype is attributable to one single aetiology."

Supports modelling the attack as a shared trigger-dependent convergence point that several distinct genotypes reach, rather than as a phenotype uniquely determined by one gene.

Age-Dependent PRRT2 Phenotype Shift from Infantile Seizures to Kinesigenic Dyskinesia

The single most instructive feature of PRRT2 biology: one haploinsufficient allele produces benign familial infantile epilepsy in the first year of life, kinesigenic dyskinesia from later childhood, or both sequentially in the same person (the ICCA syndrome), with hemiplegic migraine and episodic ataxia at the phenotypic margins. Across 1444 published carriers, benign familial infantile epilepsy (41.7%), PKD (38.7%) and ICCA (14.3%) account for almost the entire spectrum. Penetrance depends on which phenotype is counted: about 61% for PKD alone, but nearly complete once infantile convulsions are included. Curatorially this means seizures and dyskinesia must be modelled as age-dependent expressions of one lesion, not as comorbidity.

PRRT2 hgnc:30500

Downstream

Benign Infantile Seizures

Show evidence (2 references)

PMID:26598493 SUPPORT Human Clinical

"Benign familial infantile epilepsy (41.7%; n = 602), paroxysmal kinesigenic dyskinesia (38.7%; n = 560) and infantile convulsions and choreoathetosis (14.3%; n = 206) constitute the vast majority of PRRT2-associated diseases"

Quantifies the pleiotropy across a 1444-patient review, showing epilepsy and dyskinesia as roughly co-equal expressions of the same gene.

PMID:22875091 SUPPORT Human Clinical

"The estimated penetrance of PRRT2 mutations was 61%, if only the PKD phenotype was considered; however, if infantile convulsions were also taken into account, the penetrance was nearly complete."

Shows that the apparent incomplete penetrance of PKD is largely an artefact of ignoring the infantile-seizure expression of the same allele.

⬡

Pathograph

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

●

Phenotypes

11

Nervous System 6

Sensory Aura Preceding Attacks VERY_FREQUENT Paresthesia HP:0003401

Temporal: TRANSIENT

Show evidence (2 references)

PMID:29276650 SUPPORT Human Clinical

"Aura-like symptoms (paresthesias and stiffness in the affected limb) before the attacks, as described in this case, are very common."

Establishes premonitory paraesthesia in the affected limb as a feature of PKD attacks. The band VERY_FREQUENT maps the source's qualitative term "very common" per the literature-term-to-enum mapping in docs/frequency-evidence-guidelines.md.

PMID:20301400 SUPPORT Human Clinical

"may be accompanied by a preceding aura"

GeneReviews confirms a preceding aura in the non-kinesigenic subtype too, though without a frequency qualifier.

Benign Infantile Seizures OBLIGATE Seizure HP:0001250

Onset: INFANTILE

The band is OBLIGATE, not a partial frequency, because this phenotype is scoped to the ICCA subtype (subtype: ICCA), in which infantile seizures are definitionally required: MONDO:0011178 defines infantile convulsions and choreoathetosis as "a neurological condition characterized by the occurrence of seizures during the first year of life ... and choreoathetotic dyskinetic attacks during childhood or adolescence". Across unselected PRRT2 carriers, by contrast, infantile seizures are present in roughly 56% (BFIE 41.7% plus ICCA 14.3% of 1444 published carriers, PMID:26598493), which is the figure that would apply at gene rather than subtype level.

Show evidence (1 reference)

PMID:22875091 SUPPORT Human Clinical

"To describe the phenotypes and penetrance of paroxysmal kinesigenic dyskinesia (PKD), a movement disorder characterized by attacks of involuntary movements occurring after sudden movements, infantile convulsion and choreoathetosis (ICCA) syndrome, and benign familial infantile convulsions..."

Places benign infantile convulsions inside the PRRT2 phenotype set that includes PKD.

Seizures Seizure HP:0001250

No FrequencyEnum band is asserted. The source cohort was ascertained as PED co-occurring with epilepsy, so the apparent frequency is 100% by construction and cannot be read as the seizure frequency among unselected SLC2A1-related PED.

Show evidence (1 reference)

PMID:18577546 SUPPORT Human Clinical

"PED was characterized by choreoathetosis, dystonia or both, affecting mainly the legs. Predominant epileptic seizure types were primary generalized."

Documents co-occurring primary generalised epilepsy in the SLC2A1-related PED kindreds.

Absence Seizures Generalized non-motor (absence) seizure HP:0002121

Show evidence (2 references)

PMID:35286197 SUPPORT Model Organism

"We characterized a mouse model carrying a gain-of-function BK channelopathy D434G from a large family of patients with absence epilepsy and paroxysmal dyskinesia."

Links absence epilepsy to the KCNMA1 D434G family from which the model derives. Model-organism evidence; the human evidence is the item below. No frequency band is asserted because the sources describe single kindreds.

PMID:15937479 SUPPORT Human Clinical

"Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22"

Human evidence that generalised epilepsy co-occurs with paroxysmal dyskinesia in the KCNMA1 syndrome.

Gait Disturbance During Attacks Gait disturbance HP:0001288

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:27351150 SUPPORT Human Clinical

"At age 16 years, she again began to have paroxysmal gait disturbances lasting from a few minutes to several hours. The episodes occurred several times in a month. They were triggered by prolonged exercise or fasting, and could be relieved by carbohydrate intake or rest."

Illustrates the exercise/fasting-triggered gait disturbance and its relief by carbohydrate, the clinical signature of the GLUT1 energy-supply mechanism. This is a single case report, so no frequency band is asserted.

Migraine Migraine HP:0002076

Show evidence (1 reference)

PMID:26598494 PARTIAL Human Clinical

"The phenotypes associated with PRRT2 mutations included a high frequency of migraine and hemiplegic migraine."

Supports the association at cohort level. Marked PARTIAL because PMID:22875091 reports that PRRT2 mutations did not cosegregate with migraine in their families; no frequency band is asserted for that reason.

Other 5

Paroxysmal Dyskinetic Attacks OBLIGATE Paroxysmal dyskinesia HP:0007166

Temporal: RECURRENT

Show evidence (1 reference)

PMID:30242089 SUPPORT Human Clinical

"Paroxysmal dyskinesias (PxD) refer to a rare group of clinically and genetically heterogeneous disorders presenting with recurrent attacks of abnormal movements, typically dystonia, chorea or a combination thereof, without loss of consciousness."

Directly states the obligate, defining phenotype including preservation of consciousness.

Paroxysmal Dystonia Paroxysmal dystonia HP:0002268

Temporal: RECURRENT

No FrequencyEnum band is asserted. Dystonia is one of two alternating core attack phenomenologies rather than a separately enumerable feature, and no cited source reports a band-mappable proportion across the umbrella group.

Show evidence (2 references)

PMID:10323309 SUPPORT Human Clinical

"Paroxysmal exercise induced dystonia (PED) is a rare disorder manifesting as episodes of dystonia mostly affecting the feet induced by continuous exercise like walking or running."

Documents episodic dystonia as the attack phenomenology, and its leg/foot predominance in the exercise-induced subtype.

PMID:20301400 SUPPORT Human Clinical

"Attacks involve dystonic posturing with choreic and ballistic movements, may be accompanied by a preceding aura, occur while the individual is awake, and are not associated with seizures."

GeneReviews confirms dystonic posturing as the core attack phenomenology in the non-kinesigenic subtype as well.

Paroxysmal Choreoathetosis Paroxysmal choreoathetosis HP:0007098

Temporal: RECURRENT

No FrequencyEnum band is asserted: the cited sources state that attacks comprise choreoathetosis OR dystonia without giving a band-mappable proportion.

Show evidence (1 reference)

PMID:38091244 SUPPORT Other

"Paroxysmal kinesigenic dyskinesia (PKD), the most common type of paroxysmal movement disorder, is characterized by sudden and brief attacks of choreoathetosis or dystonia triggered by sudden voluntary movements."

Names choreoathetosis alongside dystonia as the core attack phenomenology of the commonest subtype.

Hemiballismus During Attacks Hemiballismus HP:0100248

Temporal: TRANSIENT

No FrequencyEnum band is asserted: the sources state that ballism "can occur" and that attacks "involve dystonic posturing with choreic and ballistic movements", neither of which maps to a frequency band.

Show evidence (2 references)

PMID:29276650 SUPPORT Human Clinical

"Other hyperkinesias that can occur in PKD patients include chorea and/or ballism."

Documents ballism as part of the attack repertoire in PKD.

PMID:20301400 SUPPORT Human Clinical

"Attacks involve dystonic posturing with choreic and ballistic movements"

GeneReviews confirms ballistic movements as part of the attack repertoire in PNKD.

Orofacial Dyskinesia Orofacial dyskinesia HP:0002310

No FrequencyEnum band is asserted: the source says facial involvement occurs "often" within ADCY5-related dyskinesia specifically, and no cited source quantifies the ADCY5 share of the umbrella group, so neither a subtype-level nor an umbrella-level band can be justified.

Show evidence (1 reference)

PMID:26537056 SUPPORT Human Clinical

"These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement."

Documents facial involvement as a recurrent feature of ADCY5-related dyskinesia.

🧬

Genetic Associations

6

PRRT2

Gene: PRRT2 hgnc:30500 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant

Show evidence (1 reference)

PMID:22744660 SUPPORT Human Clinical

"Mutations introducing premature termination codons were identified in 22 of 34 patients including 13 of 14 families and 9 of 20 patients with sporadic cases."

Quantifies PRRT2 as the major cause of PKD in an independent European cohort, with the familial/sporadic split.

TMEM151A

Gene: TMEM151A hgnc:28497 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant

Show evidence (1 reference)

PMID:38091244 SUPPORT Other

"PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene."

Review naming TMEM151A alongside PRRT2 as the two described causative genes for PKD.

PNKD

Gene: PNKD hgnc:9153 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant

Show evidence (1 reference)

PMID:15496428 SUPPORT Human Clinical

"We report mutations in the myofibrillogenesis regulator 1 (MR-1) gene causing PNKD in 50 individuals from eight families."

Original gene identification across eight PNKD kindreds.

SLC2A1

Gene: SLC2A1 hgnc:11005 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant

Show evidence (1 reference)

PMID:18577546 SUPPORT Human Clinical

"Based on a whole genome linkage analysis we screened SLC2A1, encoding the glucose transporter of the blood-brain-barrier, GLUT1 and identified heterozygous missense and frameshift mutations segregating in this and three other nuclear families with a similar phenotype."

Establishes SLC2A1 as the PED locus with segregating heterozygous variants in four families.

KCNMA1

Gene: KCNMA1 hgnc:6284 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant

Show evidence (3 references)

PMID:35286197 SUPPORT Model Organism

"A growing number of gain-of-function (GOF) BK channelopathies have been identified in patients with epilepsy and movement disorders."

Establishes gain-of-function KCNMA1/BK channelopathy as a recognised cause of combined epilepsy and movement disorder in patients.

PMID:15937479 SUPPORT Human Clinical

"Here we report a genetic locus associated with a human syndrome of coexistent generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a mutation of the alpha subunit of the BK channel causes this syndrome."

Original human gene identification for the combined generalised-epilepsy plus paroxysmal-dyskinesia syndrome.

PMID:35819138 SUPPORT Human Clinical

"Recently, genetic screening identified heterozygous KCNMA1 variants in a subset of patients with debilitating paroxysmal non-kinesigenic dyskinesia, presenting with or without epilepsy (PNKD3)."

Confirms in patients that heterozygous KCNMA1 variants cause PNKD3 with or without epilepsy. Source also for the differing direction of effect between alleles.

ADCY5

Gene: ADCY5 hgnc:236 relationship_type: CAUSATIVE variant_origin: GERMLINE_AND_SOMATIC

Autosomal dominant

Show evidence (1 reference)

PMID:26537056 SUPPORT Human Clinical

"Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis."

Documents the recurrent residues and the role of mosaicism in ADCY5-related dyskinesia.

💊

Medical Actions

6

Low-Dose Carbamazepine

Action: Pharmacotherapy NCIT:C15986

Agent: carbamazepine CHEBI:3387

First-line and often dramatically effective treatment for PKD, frequently at doses well below those used for epilepsy. Response is so characteristic that antiepileptic drug responsiveness is one of the formal PKD diagnostic criteria, and a PRRT2 mutation predicts near-complete abolition of attacks. Monitor for rash, hyponatraemia, sedation, hepatic and haematological toxicity and drug interactions; HLA-B*15:02 screening is indicated in at-risk ancestries because carbamazepine can precipitate Stevens-Johnson syndrome and toxic epidermal necrolysis.

Mechanism Target:

INHIBITS Presynaptic Release Failure and Neuronal Hyperexcitability — Use-dependent sodium-channel blockade counteracts the lowered action-potential threshold and increased sodium-current density produced by PRRT2 loss, restoring the margin between baseline and attack.

Target Phenotypes: Paroxysmal dyskinesia HP:0007166

Show evidence (3 references)

PMID:24661410 SUPPORT Human Clinical

"Interestingly, the presence of PRRT2 mutations also predicted a good response to carbamazepine therapy, especially at low dose."

Establishes both the efficacy and the low-dose requirement, and links response to PRRT2 genotype.

PMID:24661410 SUPPORT Human Clinical

"the follow-up study revealed that p.R217Pfs 8-positive patients showed dramatic improvement with complete abolition of dyskinetic episodes with carbamazepine treatment, while only 7 of the 18 patients without PRRT2 mutations showed a response to the antiepileptic drug."

Quantifies the genotype-stratified response: complete abolition in PRRT2 carriers versus 7 of 18 in non-carriers.

PMID:10323309 SUPPORT Human Clinical

"Antiepileptic drugs particularly carbamazepine are very helpful in a large proportion of cases."

Independent confirmation of carbamazepine efficacy in PKD across a review of the clinical literature.

Oxcarbazepine

Action: Pharmacotherapy NCIT:C15986

Agent: oxcarbazepine CHEBI:7824

Structural analogue of carbamazepine used as an equally effective alternative in PKD, particularly where carbamazepine is not tolerated. It has been used successfully after carbamazepine-induced Stevens-Johnson syndrome, although cross-reactivity is possible and reintroduction requires caution.

Mechanism Target:

INHIBITS Presynaptic Release Failure and Neuronal Hyperexcitability — Sodium-channel blockade, as for carbamazepine.

Show evidence (1 reference)

PMID:40943684 SUPPORT Human Clinical

"Antiseizure drugs-particularly sodium channel blockers such as carbamazepine and oxcarbazepine-were the most frequently reported treatment, with complete efficacy documented in 59.7% of the studies describing their use."

Systematic review evidence that sodium-channel blockers including oxcarbazepine are the mainstay and frequently produce complete efficacy.

Ketogenic Diet

Action: Ketogenic Diet NCIT:C173168

Disease-directed therapy for SLC2A1/GLUT1-related PED, and the reason GLUT1 deficiency must not be missed. Ketone bodies enter the brain via monocarboxylate transporters, bypassing the defective GLUT1 route entirely and restoring cerebral fuel supply, so the diet treats the mechanism rather than the symptom. Modified Atkins and other ketogenic formulations are used where the classic diet is not tolerated; management requires a specialist ketogenic team.

Mechanism Target:

INHIBITS Exertion- and Fasting-Unmasked Corticostriatal Energy Failure — Supplies ketone bodies as a GLUT1-independent cerebral fuel, replenishing the energy reserve that exertion and fasting deplete.

Target Phenotypes: Paroxysmal dyskinesia HP:0007166

Show evidence (4 references)

PMID:18577546 SUPPORT Human Clinical

"Three patients were successfully treated with a ketogenic diet."

Direct clinical evidence of ketogenic-diet response in genetically confirmed SLC2A1-related PED.

PMID:27351150 PARTIAL Human Clinical

"Proper identification of the paroxysmal events and early diagnosis is important since the disease is potentially treatable."

Supports the clinical imperative of early recognition because the GLUT1 form is treatable. Marked PARTIAL because this source does not itself mention the ketogenic diet; it establishes treatability, not the specific therapy.

PMID:20301603 SUPPORT Human Clinical

"Targeted therapy: Age-specific KDTs primarily provide a supplemental fuel, namely, ketone bodies, for brain energy metabolism."

GeneReviews states the targeted mechanism of ketogenic dietary therapy curated in this treatment node.

+ 1 more reference

Trigger Avoidance and Lifestyle Modification

Action: Lifestyle Therapy NCIT:C15900

The mainstay in PNKD, where drug response is unreliable: systematic avoidance of coffee, tea, alcohol, sleep deprivation and, so far as possible, emotional stress. In PED, pacing of exertion and avoidance of fasting reduce attack burden alongside the ketogenic diet. Structured counselling about identified personal triggers, together with fall precautions and school or workplace accommodation, addresses much of the disability even when no drug is effective.

Show evidence (2 references)

PMID:15496428 PARTIAL Human Clinical

"Paroxysmal non-kinesigenic dyskinesia (PNKD) is characterized by spontaneous hyperkinetic attacks that are precipitated by alcohol, coffee, stress and fatigue."

Identifies the modifiable precipitants that trigger avoidance targets. Marked PARTIAL because this establishes the triggers rather than trialling the avoidance strategy.

PMID:20301400 SUPPORT Human Clinical

"Treatment of manifestations: Avoid triggers (e.g., caffeine, alcohol, excitement, stress, fatigue). Response to pharmacologic treatment is poor; clonazepam or diazepam can be effective in some individuals."

GeneReviews management recommendation stating both that trigger avoidance is the first-line intervention and that pharmacological response in PNKD is poor, which is the entry's rationale for making avoidance the mainstay of this subtype.

Genetic Counselling and Cascade Testing

Action: Genetic Counseling NCIT:C15240

Molecular diagnosis changes management (sodium-channel blocker for PRRT2/TMEM151A, ketogenic diet for SLC2A1) and changes counselling. Because penetrance is incomplete and phenotype-dependent, an unaffected carrier does not refute pathogenicity, and families must be counselled that the same allele may present as infantile seizures in one member and kinesigenic dyskinesia in another. Cascade testing is appropriate once a familial variant is identified.

Show evidence (2 references)

PMID:22875091 SUPPORT Human Clinical

"The identification of PRRT2 as a major gene for the PKD-ICCA-BFIC spectrum allows better disease classification, molecular confirmation of the clinical diagnosis, and genetic testing and counseling."

States the counselling and diagnostic-confirmation value of molecular diagnosis in this spectrum.

PMID:20301400 SUPPORT Human Clinical

"Offspring of an affected individual have a 50% chance of inheriting the PNKD pathogenic variant. Once the PNKD pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews genetic-counselling content: the autosomal dominant 50% transmission risk and the reproductive options that cascade testing enables.

Deep Brain Stimulation

Action: Deep Brain Stimulation NCIT:C21024

Reserved for severe, medication-refractory hyperkinetic disease, principally in the pleiotropic genotypes (ADCY5, GNAO1) rather than in classic PKD, PNKD or PED. Globus pallidus internus is the usual target. Evidence is limited to case reports and small series, so this is recorded as a practice-level option rather than an established standard.

Show evidence (1 reference)

PMID:26537056 PARTIAL Human Clinical

"In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea."

Documents the severe refractory ADCY5 phenotype in which deep brain stimulation is considered. Marked PARTIAL: this supports the clinical context, not efficacy.

🌍

Environmental Factors

3

Sudden Voluntary Movement or Startle

The defining precipitant of PKD: rising from a chair, initiating gait, being startled or making any abrupt voluntary movement provokes an attack within seconds. The trigger is so specific that its presence is one of the formal diagnostic criteria.

Show evidence (1 reference)

PMID:15623687 SUPPORT Human Clinical

"The authors propose the following diagnostic criteria for idiopathic PKD based on this phenotype: identified trigger for the attacks (sudden movements), short duration of attacks (<1 minute), lack of loss of consciousness or pain during attacks, antiepileptic drug responsiveness, exclusion of..."

Formalises the kinesigenic trigger as a diagnostic criterion for PKD.

Caffeine and Alcohol

Coffee, tea and alcohol are the reproducible precipitants of PNKD attacks and are also the exposures whose shared chemistry (methylglyoxal content) motivated the stress-response-pathway hypothesis of MR-1 function. Avoiding them is the principal intervention in PNKD.

Show evidence (1 reference)

PMID:15496428 SUPPORT Human Clinical

"HAGH functions in a pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic beverages and produced as a by-product of oxidative stress. Our results suggest a mechanism whereby alcohol, coffee and stress may act as precipitants of attacks in PNKD."

Documents caffeine and alcohol as precipitants and supplies the chemical rationale linking them to the causal gene.

Prolonged Exertion and Fasting

Sustained exercise and, less commonly, fasting precipitate PED attacks by pushing cerebral glucose demand beyond the reduced GLUT1 transport reserve. Rest and carbohydrate intake terminate attacks, which is itself a useful diagnostic manoeuvre.

Show evidence (1 reference)

PMID:27351150 SUPPORT Human Clinical

"They were triggered by prolonged exercise or fasting, and could be relieved by carbohydrate intake or rest."

Documents exertion and fasting as the triggers and carbohydrate/rest as the relief, consistent with the energy-supply mechanism.

🔬

Biochemical Markers

1

Hypoglycorrhachia (PRESENT)

Show evidence (2 references)

PMID:18577546 SUPPORT Human Clinical

"A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients and a reduced glucose uptake by mutated transporters compared with the wild-type as determined in Xenopus oocytes confirmed a pathogenic role of these mutations."

Provides the quantitative CSF:blood glucose ratio in a genetically confirmed PED cohort together with the normal reference threshold.

PMID:27351150 SUPPORT Human Clinical

"The cerebrospinal fluid to blood glucose ratio, obtained after 10 hours of fasting, was slightly decreased (0.54, Normal>0.59)."

Shows that the ratio may be only marginally reduced in mild GLUT1 phenotypes, which is why a borderline value must not be used to exclude the diagnosis.

🔀

Differential Diagnoses

7

Conditions with similar clinical presentations that must be differentiated from Paroxysmal Dyskinesia:

Focal epilepsy, including sleep-related hypermotor epilepsy Not Yet Curated MONDO:0100631

Overlapping Features The single most important and most frequent misdiagnosis in both directions. PKD is often misdiagnosed clinically as epilepsy, while most historically diagnosed paroxysmal hypnogenic dyskinesia is in fact sleep-related hypermotor epilepsy (SHE), formerly nocturnal frontal lobe epilepsy. Curated as an entry-level differential precisely because the boundary defines the scope of this entry.

Distinguishing Features

Paroxysmal dyskinesia: consciousness is fully preserved with no postictal confusion
Paroxysmal dyskinesia: stereotyped external trigger (sudden movement, caffeine, exertion) with normal ictal and interictal EEG
Paroxysmal dyskinesia: dystonic or choreic semiology rather than tonic-hypermotor
SHE: attacks arise out of sleep in clusters, are hypermotor or asymmetric-tonic, may show ictal fear or vocalisation, and may secondarily generalise
SHE: video-EEG documentation is the definitive discriminator
Caveat: some short-attack hypnogenic cases do carry PRRT2 variants, so the boundary is probabilistic

Show evidence (2 references)

PMID:22101681 SUPPORT Human Clinical

"Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal movement disorder and is often misdiagnosed clinically as epilepsy."

Documents epilepsy as the commonest misdiagnosis of PKD.

PMID:27164717 SUPPORT Human Clinical

"Diagnostic criteria were developed with 3 levels of certainty: witnessed (possible) SHE, video-documented (clinical) SHE, and video-EEG-documented (confirmed) SHE."

Provides the graded video-EEG-anchored criteria that separate SHE from a nocturnal dyskinesia.

Episodic ataxia type 1 Not Yet Curated MONDO:0008047

Overlapping Features KCNA1 (Kv1.1) channelopathy producing brief attacks that, like PKD, are triggered by startle or sudden movement and last seconds to minutes; both are treated with antiepileptic drugs. Curated in dismech as Episodic_Ataxia.

Distinguishing Features

EA1 attacks are cerebellar (ataxia, dysarthria, tremor) rather than dyskinetic
Interictal examination in EA1 is NOT normal: continuous myokymia (fine muscle rippling, often periorbital or in the hands) is present between attacks
KCNA1 variants have been reported occasionally in PKD cohorts, so genetic overlap exists

Show evidence (1 reference)

PMID:26598494 SUPPORT Human Clinical

"We analysed all three genes (the whole coding regions of SLC2A1 and PRRT2 and exons one and two of PNKD) in a series of 145 families with paroxysmal dyskinesias as well as in a series of 53 patients with familial episodic ataxia and hemiplegic migraine"

Shows that episodic ataxia is routinely screened alongside paroxysmal dyskinesia because the two groups are clinically and genetically adjacent.

Episodic ataxia type 2 Not Yet Curated MONDO:0007163

Overlapping Features CACNA1A (Cav2.1) channelopathy with attacks of ataxia and vertigo triggered by stress or exertion — the same trigger profile as PNKD and PED respectively.

Distinguishing Features

EA2 attacks last hours and are cerebellar rather than hyperkinetic
Interictal nystagmus is usually present in EA2
EA2 attacks respond to acetazolamide rather than to carbamazepine or the ketogenic diet
Progressive interictal cerebellar signs develop in many EA2 patients, which does not occur in primary paroxysmal dyskinesia

Show evidence (1 reference)

PMID:32443735 SUPPORT Human Clinical

"Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs)."

States the phenomenological criterion (hyperkinetic versus cerebellar) that separates the two groups.

Functional (psychogenic) movement disorder Not Yet Curated MONDO:0002104

Overlapping Features Historically the default label for paroxysmal dyskinesia, and still a frequent misdiagnosis, because attacks are unwitnessed, bizarre-looking, emotionally precipitated, and accompanied by entirely normal examination and investigations. Getting this wrong denies patients a treatment that often abolishes the disorder outright.

Distinguishing Features

Favours paroxysmal dyskinesia: a highly consistent and specific trigger and a stereotyped sensory aura in the limb about to be involved
Favours paroxysmal dyskinesia: stereotyped short attack duration, positive family history, and dramatic response to low-dose carbamazepine
Favours a functional disorder: variable and distractible phenomenology, entrainment, incongruent triggers, and absence of a consistent aura
Trap: normal EEG and MRI do NOT favour a functional diagnosis, since they are also normal in primary paroxysmal dyskinesia

Show evidence (1 reference)

PMID:29276650 SUPPORT Human Clinical

"The patient's presentation was previously misinterpreted as Tourette's syndrome despite the absence of vocal tics."

A worked example of the diagnostic-delay problem: a PKD patient carried an incorrect hyperkinetic-disorder label for years before the correct diagnosis and an effective treatment.

Primary (non-paroxysmal) dystonia Not Yet Curated MONDO:0003441

Overlapping Features Isolated genetic and idiopathic dystonias (including dopa-responsive dystonia and myoclonus-dystonia, both curated in dismech) share the dystonic phenomenology but not the episodic architecture.

Distinguishing Features

Primary dystonia is continuous or task-specific and persists between episodes, whereas paroxysmal dyskinesia has a completely normal interictal examination
Dopa-responsive dystonia shows marked diurnal fluctuation that can be mistaken for paroxysmality, but responds to levodopa
Dopa-responsive dystonia worsens through the day rather than being movement-triggered, and does not remit completely between episodes

Show evidence (1 reference)

PMID:30242089 SUPPORT Human Clinical

"Here we review the increasing spectrum of genetic conditions, as well as of other non-genetic disorders, that might present with PxD, provide criteria for case definition and propose a diagnostic workup to reach a definitive diagnosis, on which treatment is heavily dependent."

Supports the need for explicit case definition to separate paroxysmal from continuous movement disorders, and the treatment consequences of getting it right.

Hypoparathyroidism with basal ganglia calcification Not Yet Curated MONDO:0001220

Overlapping Features A classic secondary cause: hypocalcaemia with basal-ganglia calcification can produce paroxysmal kinesigenic or exertion-induced dyskinesia that is phenotypically indistinguishable from the primary forms and remits on correction of calcium.

Distinguishing Features

Later or adult onset with absent family history
Associated tetany, paraesthesia, cataract or seizures
Low serum calcium with raised phosphate, and bilateral basal-ganglia calcification on CT
Treatment is calcium and vitamin D replacement rather than a sodium-channel blocker, so serum calcium should be checked in any atypical case

Show evidence (1 reference)

PMID:32443735 PARTIAL Human Clinical

"From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known."

Supports the existence of acquired and metabolic causes requiring exclusion. Marked PARTIAL because this citation establishes the category rather than the specific hypoparathyroidism association.

Multiple sclerosis with paroxysmal tonic spasms MONDO:0005301

Overlapping Features Demyelinating lesions, characteristically in the posterior limb of the internal capsule or brainstem, produce brief stereotyped painful tonic spasms often triggered by movement — the closest acquired mimic of PKD, and likewise carbamazepine-responsive.

Distinguishing Features

Attacks are typically painful, and pain is an exclusion criterion for idiopathic PKD
Onset is in adulthood with no family history
Other neurological signs or a prior demyelinating episode are usually present
MRI shows demyelinating lesions rather than being normal

Show evidence (1 reference)

PMID:10323309 SUPPORT Human Clinical

"Tonic spasms in multiple sclerosis and Sandiffers syndrome producing intermittent torticollis in infants and children are other paroxysmal movement disorders."

Places multiple sclerosis tonic spasms within the paroxysmal movement disorder differential.

🔬

Clinical Trials

2

NCT04023656 UNKNOWN

Korean prospective observational registry following adults with paroxysmal kinesigenic choreoathetosis to establish long-term prognosis (remission, degree of improvement, worsening, and medication requirement). Relevant because the natural history of PKD into adulthood — the reported decline in attack frequency in the third decade — rests almost entirely on retrospective series.

Target Phenotypes: Paroxysmal dyskinesia HP:0007166

Show evidence (1 reference)

clinicaltrials:NCT04023656 SUPPORT Human Clinical

"The aim of this study is to assess the prognosis of paroxysmal kinesigenic choreoathetosis (PKC) in Korean."

Confirms the registry's prognostic objective in PKD.

NCT06701851 RECRUITING

French mechanistic imaging study (ancillary to AMEDYST) using real-time functional imaging in PRRT2 patients who can voluntarily provoke and control their attacks, to test the striatum-cerebellum reciprocal-influence model of the attack. Directly interrogates the cerebellar-origin hypothesis recorded in this entry's mechanistic_hypotheses block. It is mechanistic, not therapeutic.

Target Phenotypes: Paroxysmal dyskinesia HP:0007166

Show evidence (1 reference)

clinicaltrials:NCT06701851 SUPPORT Human Clinical

"the pathological role of the reciprocal influence between the striatum and the cerebellum in paroxysmal dyskinesia episodes"

States the striatum-cerebellum question that this trial is designed to resolve, which is the open question recorded in mechanistic_hypotheses.

{ }

Source YAML

click to show

name: Paroxysmal Dyskinesia
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
description: >-
  Paroxysmal dyskinesias (PxD) are a clinically and genetically heterogeneous group of
  episodic movement disorders defined by recurrent, abrupt attacks of involuntary
  hyperkinetic movement — dystonia, chorea, athetosis, ballism, or a combination —
  occurring without loss of consciousness and, in the classic primary forms, against a
  completely normal interictal neurological examination. Because attacks are brief,
  stereotyped, and almost never witnessed in clinic, the disorders were historically
  dismissed as psychogenic or misdiagnosed as epilepsy; they are now understood as
  disorders of neuronal membrane excitability, synaptic-vesicle trafficking, and cerebral
  energy supply.

  The organising axis of the group is trigger to gene to treatment, and getting that
  mapping right is what makes the diagnosis actionable. Paroxysmal kinesigenic
  dyskinesia (PKD) is triggered by sudden voluntary movement, is caused mainly by
  loss-of-function variants in PRRT2 (with TMEM151A as a second locus), produces brief
  (under one minute) but often many-times-daily attacks, and is exquisitely responsive to
  low-dose carbamazepine or oxcarbazepine. Paroxysmal non-kinesigenic dyskinesia (PNKD)
  is triggered by alcohol, caffeine, emotional stress and fatigue, is caused by
  N-terminal variants in PNKD (MR-1), produces longer (minutes to hours) but far less
  frequent attacks, and responds poorly to drugs so that trigger avoidance is the
  mainstay. Paroxysmal exercise-induced dyskinesia (PED) is triggered by sustained
  exertion (and sometimes fasting), is most importantly caused by SLC2A1/GLUT1
  deficiency, and is ketogenic-diet-responsive — this is the treatable cause that must
  not be missed, and it is flagged biochemically by hypoglycorrhachia with a low
  CSF:blood glucose ratio. ADCY5 (characteristically with nocturnal exacerbation and
  perioral/facial involvement) and KCNMA1 (BK-channel gain of function, with absence
  epilepsy) broaden the genetic spectrum, and secondary/acquired paroxysmal dyskinesia
  follows multiple sclerosis, hypoparathyroidism, perinatal injury, transient ischaemia
  and other structural or metabolic insults.

  The historical fourth category, paroxysmal hypnogenic dyskinesia (PHD), is largely
  reclassified: most sleep-related dyskinetic attacks are now recognised as
  sleep-related hypermotor epilepsy (SHE, formerly nocturnal frontal lobe epilepsy),
  a focal epilepsy syndrome with genetic and structural causes. This entry models that
  reclassification explicitly rather than curating PHD as a dyskinesia (see the
  discussions block).
synonyms:
- Paroxysmal dyskinesias
- PxD
- Paroxysmal movement disorder
- Paroxysmal choreoathetosis
- Paroxysmal dystonic choreoathetosis
- Episodic dyskinesia
disease_term:
  preferred_term: paroxysmal dyskinesia
  term:
    id: MONDO:0015427
    label: paroxysmal dyskinesia
parents:
- Movement Disorder
- Paroxysmal Neurological Disorder
notes: >-
  Related dismech entries that this entry deliberately cross-references rather than
  duplicates: GLUT1_Deficiency_Syndrome (the full SLC2A1 phenotype including the
  classic infantile encephalopathy; PED/GLUT1DS2 is modelled here only as the
  paroxysmal-dyskinesia presentation), Benign_Familial_Infantile_Epilepsy (the
  PRRT2 seizure arm of the same allelic spectrum),
  Familial_Sleep_Related_Hypermotor_Epilepsy and DEPDC5-Related_Epilepsy (the
  entities that absorbed most of historical paroxysmal hypnogenic dyskinesia),
  Episodic_Ataxia (the cerebellar paroxysmal channelopathies that are the closest
  differential), and Dopa_Responsive_Dystonia / Myoclonus_Dystonia_Syndrome
  (non-paroxysmal genetic dystonias in the differential).

  Two deliberate modelling decisions. (1) Paroxysmal hypnogenic dyskinesia (PHD) is NOT
  listed as a subtype: this entry's position is that PHD is largely subsumed by
  sleep-related hypermotor epilepsy, so listing it under has_subtypes would assert the
  membership the entry argues against. It is instead handled as a differential diagnosis
  plus an explicit CONTROVERSY discussion that records the dissenting PRRT2-PHD evidence.
  (2) The ICCA subtype here overlaps deliberately with the ICCA subtype of
  Benign_Familial_Infantile_Epilepsy (same MONDO:0011178). ICCA is by definition the
  bridge between the two phenotypes of one PRRT2 allele, so it is visible from both
  sides; the epilepsy entry models the seizure arm, this entry models the dyskinesia arm
  and the age-dependent shift between them. Neither entry owns it exclusively.

  Scope caveat on classifications: the neurological-channelopathy classification is
  accurate for the PRRT2 and KCNMA1 arms but not for the PNKD (stress-response enzyme),
  SLC2A1 (transportopathy) or ADCY5 (cAMP signalling) arms. It is recorded because the
  channelopathy framing dominates the umbrella literature, not because it covers every
  member.

  Trigger-direction caveat: caffeine is a PNKD precipitant but has been reported to
  paradoxically REDUCE dyskinesia in ADCY5-related disease (a proposed adenosine A2A
  effect). The environmental EXACERBATES entry below therefore applies to PNKD, not
  universally across the group.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:30242089
      reference_title: "Unravelling of the paroxysmal dyskinesias."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Paroxysmal dyskinesias (PxD) refer to a rare group of clinically and genetically
        heterogeneous disorders presenting with recurrent attacks of abnormal movements,
        typically dystonia, chorea or a combination thereof, without loss of
        consciousness.
      explanation: >-
        Paroxysmal dyskinesias are hyperkinetic movement disorders of the central
        nervous system and belong to the neurologic Part.
  channelopathy_category:
    classification_value: neurological channelopathy
references:
- reference: PMID:20301400
  title: "Familial Paroxysmal Nonkinesigenic Dyskinesia."
  tags:
  - GeneReviews
- reference: PMID:20301603
  title: "Glucose Transporter Type 1 Deficiency Syndrome."
  tags:
  - GeneReviews
- reference: PMID:30242089
  title: "Unravelling of the paroxysmal dyskinesias."
- reference: PMID:26598494
  title: "The clinical and genetic heterogeneity of paroxysmal dyskinesias."
- reference: PMID:38091244
  title: "Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms."
has_subtypes:
- name: PKD
  display_name: Paroxysmal kinesigenic dyskinesia (PRRT2, TMEM151A)
  subtype_term:
    preferred_term: episodic kinesigenic dyskinesia
    term:
      id: MONDO:0044202
      label: episodic kinesigenic dyskinesia
  description: >-
    The commonest paroxysmal dyskinesia. Attacks of dystonia and/or choreoathetosis are
    triggered by sudden voluntary movement (rising from a chair, starting to walk,
    startle), typically last under one minute, and may occur many times a day, often
    preceded by a sensory aura in the affected limb. Onset is in childhood or early
    adolescence with a 2-4:1 male excess, and attacks usually decline in the third
    decade. Most cases carry heterozygous loss-of-function PRRT2 variants (recurrent
    c.649dupC); TMEM151A is a second locus in PRRT2-negative cases. Low-dose
    carbamazepine or oxcarbazepine is dramatically effective.
  genes:
  - preferred_term: PRRT2
    term:
      id: hgnc:30500
      label: PRRT2
  - preferred_term: TMEM151A
    term:
      id: hgnc:28497
      label: TMEM151A
  evidence:
  - reference: PMID:38091244
    reference_title: "Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Paroxysmal kinesigenic dyskinesia (PKD), the most common type of paroxysmal
      movement disorder, is characterized by sudden and brief attacks of choreoathetosis
      or dystonia triggered by sudden voluntary movements. PKD is mainly caused by
      mutations in the PRRT2 or TMEM151A gene.
    explanation: >-
      Defines the PKD subtype by its kinesigenic trigger and brief attack duration and
      names PRRT2 and TMEM151A as the two causative loci.
- name: PNKD
  display_name: Paroxysmal non-kinesigenic dyskinesia (PNKD/MR-1)
  subtype_term:
    preferred_term: paroxysmal nonkinesigenic dyskinesia
    term:
      id: MONDO:0700088
      label: paroxysmal nonkinesigenic dyskinesia
  description: >-
    Attacks of dystonia and choreoathetosis that arise spontaneously at rest or are
    precipitated by alcohol, coffee or tea, emotional stress, excitement and fatigue,
    but never by sudden movement. Attacks are much longer than in PKD (typically tens
    of minutes to hours) and correspondingly less frequent, sometimes only a few per
    year. Classic autosomal dominant PNKD is caused by the recurrent N-terminal
    p.Ala7Val and p.Ala9Val variants in PNKD (myofibrillogenesis regulator 1, MR-1).
    Pharmacological response is unreliable, so trigger avoidance is the mainstay.
  genes:
  - preferred_term: PNKD
    term:
      id: hgnc:9153
      label: PNKD
  evidence:
  - reference: PMID:15496428
    reference_title: "The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paroxysmal non-kinesigenic dyskinesia (PNKD) is characterized by spontaneous
      hyperkinetic attacks that are precipitated by alcohol, coffee, stress and fatigue.
    explanation: >-
      Establishes the defining non-kinesigenic trigger profile that separates PNKD from
      PKD.
- name: PED
  display_name: Paroxysmal exercise-induced dyskinesia (SLC2A1/GLUT1 deficiency)
  subtype_term:
    preferred_term: childhood onset GLUT1 deficiency syndrome 2
    term:
      id: MONDO:0012805
      label: childhood onset GLUT1 deficiency syndrome 2
  description: >-
    Attacks of leg-predominant dystonia and choreoathetosis provoked by prolonged
    exertion (and sometimes by fasting), relieved by rest or carbohydrate. The critical
    genotype is heterozygous SLC2A1 loss of function causing GLUT1 deficiency, which
    frequently co-segregates with generalised epilepsy. This is the treatable cause of
    paroxysmal dyskinesia: the ketogenic diet supplies ketone bodies that bypass the
    defective blood-brain-barrier glucose transporter. The biochemical clue is
    hypoglycorrhachia with a reduced CSF:blood glucose ratio in a normoglycaemic
    patient. The broader SLC2A1 phenotype is curated in GLUT1_Deficiency_Syndrome;
    only the paroxysmal-dyskinesia presentation is modelled here.
  genes:
  - preferred_term: SLC2A1
    term:
      id: hgnc:11005
      label: SLC2A1
  evidence:
  - reference: PMID:18577546
    reference_title: "Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, co-occurring PED and epilepsy can be due to autosomal dominant
      heterozygous SLC2A1 mutations, expanding the phenotypic spectrum associated with
      GLUT1 deficiency and providing a potential new treatment option for this clinical
      syndrome.
    explanation: >-
      Establishes SLC2A1/GLUT1 deficiency as the molecular cause of the PED subtype and
      flags its treatability.
  - reference: PMID:20301603
    reference_title: "Glucose Transporter Type 1 Deficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When first diagnosed in later childhood to adulthood (occasionally in a parent
      following the diagnosis of an affected child), the predominant clinical findings of
      Glut1DS are usually complex paroxysmal movement disorders, spasticity, ataxia,
      dystonia, speech difficulty, and intellectual disability.
    explanation: >-
      GeneReviews confirms that later-presenting GLUT1 deficiency is dominated by
      paroxysmal movement disorder, which is the presentation modelled in this entry.
- name: PNKD3
  display_name: Generalized epilepsy with paroxysmal dyskinesia (KCNMA1, PNKD3)
  subtype_term:
    preferred_term: generalized epilepsy-paroxysmal dyskinesia syndrome
    term:
      id: MONDO:0012276
      label: generalized epilepsy-paroxysmal dyskinesia syndrome
  description: >-
    Autosomal dominant co-occurrence of paroxysmal dyskinesia and generalised (usually
    absence) epilepsy in the same individual or family, caused by gain-of-function
    variants in KCNMA1 encoding the BK calcium-activated potassium channel alpha
    subunit (p.Asp434Gly is the index allele). This subtype makes the movement-disorder
    and epilepsy continuum explicit at the level of a single channel.
  genes:
  - preferred_term: KCNMA1
    term:
      id: hgnc:6284
      label: KCNMA1
  evidence:
  - reference: PMID:35286197
    reference_title: "Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We characterized a mouse model carrying a gain-of-function BK channelopathy D434G
      from a large family of patients with absence epilepsy and paroxysmal dyskinesia.
    explanation: >-
      Anchors the KCNMA1 D434G gain-of-function allele to the combined absence-epilepsy
      plus paroxysmal-dyskinesia human phenotype. Model-organism evidence; the human
      evidence for the same subtype is the item below.
  - reference: PMID:15937479
    reference_title: "Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a genetic locus associated with a human syndrome of coexistent
      generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a
      mutation of the alpha subunit of the BK channel causes this syndrome.
    explanation: >-
      Human genetic evidence establishing the PNKD3 syndrome and its KCNMA1 cause,
      independent of the mouse model.
- name: ADCY5
  display_name: ADCY5-related dyskinesia with orofacial involvement
  subtype_term:
    preferred_term: dyskinesia with orofacial involvement, autosomal dominant
    term:
      id: MONDO:0800028
      label: dyskinesia with orofacial involvement, autosomal dominant
  description: >-
    Childhood- or adolescent-onset mixed hyperkinetic disorder caused by gain-of-function
    ADCY5 variants, with paroxysmal choreiform, dystonic and myoclonic movements of the
    limbs, neck and face, characteristic perioral and periorbital involvement, nocturnal
    exacerbation, and frequent axial hypotonia. ADCY5 is the clearest single-gene
    demonstration that the trigger-based classification does not map one-to-one onto
    genotype: attacks may be kinesigenic, exercise-induced, non-kinesigenic or nocturnal
    in the same gene.
  genes:
  - preferred_term: ADCY5
    term:
      id: hgnc:236
      label: ADCY5
  evidence:
  - reference: PMID:26537056
    reference_title: "ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of
      hyperkinetic abnormal movements.
    explanation: >-
      Defines the ADCY5 subtype as a childhood-onset hyperkinetic disorder distinct from
      the trigger-defined classic subtypes.
- name: ICCA
  display_name: Infantile convulsions and choreoathetosis (PRRT2 pleiotropy)
  subtype_term:
    preferred_term: infantile convulsions and choreoathetosis
    term:
      id: MONDO:0011178
      label: infantile convulsions and choreoathetosis
  description: >-
    The bridging phenotype of the PRRT2 spectrum: benign familial infantile seizures in
    the first year of life followed, years later in the same individual or kindred, by
    kinesigenic dyskinesia. ICCA is the clearest demonstration that PRRT2
    haploinsufficiency produces an age-dependent shift in paroxysmal phenotype rather
    than two separate diseases.
  genes:
  - preferred_term: PRRT2
    term:
      id: hgnc:30500
      label: PRRT2
  evidence:
  - reference: PMID:22875091
    reference_title: "PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PRRT2 mutations are the major cause of PKD or ICCA, but they do not seem to be
      involved in the etiology of febrile convulsions and migraine.
    explanation: >-
      Establishes ICCA as a PRRT2-determined entity within the same allelic series as
      isolated PKD.
pathophysiology:
- name: PRRT2 and TMEM151A Loss of Function
  description: >-
    Heterozygous truncating variants in PRRT2 (the recurrent c.649dupC frameshift
    accounts for the majority of carriers) yield no stable protein, producing a
    haploinsufficient state at the presynaptic terminal. TMEM151A truncating and
    missense variants behave similarly, with patient transcript evidence supporting
    loss of function; TMEM151A accounts for a share of PRRT2-negative PKD. This is the
    molecular initiating lesion of the kinesigenic subtype.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: PRRT2
    term:
      id: hgnc:30500
      label: PRRT2
  - preferred_term: TMEM151A
    term:
      id: hgnc:28497
      label: TMEM151A
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  downstream:
  - target: Presynaptic Release Failure and Neuronal Hyperexcitability
    causal_link_type: DIRECT
  - target: Age-Dependent PRRT2 Phenotype Shift from Infantile Seizures to Kinesigenic Dyskinesia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Developmental change in the regional expression of, and functional dependence on, PRRT2 between infancy and later childhood
  evidence:
  - reference: PMID:22101681
    reference_title: "Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole-exome sequencing followed by Sanger sequencing, we identified three
      truncating mutations within PRRT2 (NM_145239.2) in eight Han Chinese families with
      histories of paroxysmal kinesigenic dyskinesia
    explanation: >-
      Original identification of truncating PRRT2 variants co-segregating with PKD.
  - reference: PMID:26598493
    reference_title: "The evolving spectrum of PRRT2-associated paroxysmal diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The vast majority of mutations lead to a truncated protein or no protein at all and
      thus to a haploinsufficient state.
    explanation: >-
      Establishes haploinsufficiency, rather than a dominant-negative or gain-of-function
      effect, as the operative molecular mechanism.
  - reference: PMID:38091244
    reference_title: "Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene.
    explanation: >-
      Supports treating PRRT2 and TMEM151A as the two loss-of-function loci of the same
      kinesigenic mechanism node.
- name: Presynaptic Release Failure and Neuronal Hyperexcitability
  description: >-
    PRRT2 is enriched at presynaptic terminals, where it interacts with the SNARE
    proteins SNAP-25 and syntaxin-1A, with synaptotagmin 1/2 calcium sensors, and with
    Nav1.2/Nav1.6 sodium channels and the Na+/K+ ATPase. Loss of PRRT2 desynchronises
    calcium-triggered vesicle fusion (reduced release probability and calcium
    sensitivity, increased asynchronous release, more docked vesicles at rest) while
    simultaneously increasing sodium-current density and lowering the action-potential
    threshold. PKD is therefore simultaneously a synaptopathy and a channelopathy: the
    lesion does not produce continuous dysfunction but a network that is stable at
    baseline and unstable when abruptly perturbed.
  biological_scale: CELLULAR
  role: central_effector
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Ion Channel and Synaptic Dysfunction"
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: ABNORMAL
  - preferred_term: calcium-ion regulated exocytosis
    term:
      id: GO:0017156
      label: calcium-ion regulated exocytosis
    modifier: DECREASED
  - preferred_term: regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: ABNORMAL
  - preferred_term: sodium ion transport
    term:
      id: GO:0006814
      label: sodium ion transport
    modifier: INCREASED
  downstream:
  - target: Cerebellar Spreading Depolarization and Circuit Instability
    causal_link_type: DIRECT
    hypothesis_groups:
    - cerebellar_origin_of_pkd
  - target: Trigger-Dependent Breach of the Motor Network Attack Threshold
    causal_link_type: DIRECT
  - target: Migraine
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Shared cortical and brainstem hyperexcitability with increased susceptibility to cortical spreading depolarization
  evidence:
  - reference: PMID:27052163
    reference_title: "PRRT2 Is a Key Component of the Ca(2+)-Dependent Neurotransmitter Release Machinery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PRRT2-silenced neurons exhibit a severe impairment of synchronous release,
      attributable to a sharp decrease in release probability and Ca(2+) sensitivity and
      associated with a marked increase of the asynchronous/synchronous release ratio.
      PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2.
    explanation: >-
      Directly demonstrates the presynaptic release defect and the SNARE/synaptotagmin
      interaction that make PKD a synaptopathy.
  - reference: PMID:38091244
    reference_title: "Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Based on abnormal ion channels and disturbed synaptic transmission in the absence
      of PRRT2, PKD may be channelopathy or synaptopathy, or both.
    explanation: >-
      Supports the dual channelopathy/synaptopathy framing of this node and justifies its
      conformance to the epilepsy excitation-inhibition module's ion-channel-and-synaptic
      dysfunction trigger.
  notes: >-
    Conformance rationale: this node declares
    epilepsy_excitation_inhibition_imbalance#Ion Channel and Synaptic Dysfunction
    because the PRRT2 lesion is literally an ion-channel-plus-synaptic-protein
    abnormality and because the very same PRRT2 alleles cause benign familial infantile
    epilepsy, so the excitation/inhibition-imbalance chain is not a metaphor here. The
    SLC2A1/GLUT1 arm of this entry deliberately does NOT declare module conformance: its
    lesion is a metabolic substrate-supply failure, not a primary channel or synaptic
    defect, even though epilepsy is a downstream consequence.
- name: Cerebellar Spreading Depolarization and Circuit Instability
  description: >-
    In PRRT2-deficient models the cerebellum, rather than the basal ganglia, emerges as
    the pivotal generator: granule-cell to Purkinje-cell circuits are hyperexcitable and
    dyskinetic episodes are tightly coupled to episodes of spreading depolarization in
    cerebellar cortex, which transiently disrupts cerebellar output to the deep nuclei
    and thalamus. The role of cortex and thalamus in PKD remains less well defined.
  biological_scale: TISSUE
  role: amplifier
  cell_types:
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  biological_processes:
  - preferred_term: action potential
    term:
      id: GO:0001508
      label: action potential
    modifier: ABNORMAL
  downstream:
  - target: Trigger-Dependent Breach of the Motor Network Attack Threshold
    causal_link_type: DIRECT
    hypothesis_groups:
    - cerebellar_origin_of_pkd
  evidence:
  - reference: PMID:38091244
    reference_title: "Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In addition, the cerebellum is regarded as the key pathogenic area. Spreading
      depolarization in the cerebellum is tightly associated with dyskinetic episodes.
    explanation: >-
      Identifies cerebellar spreading depolarization as the proximate circuit event
      linking the PRRT2 synaptic/channel lesion to a discrete attack.
- name: PNKD (MR-1) Dysfunction and Impaired Methylglyoxal Detoxification
  description: >-
    The recurrent p.Ala7Val and p.Ala9Val variants alter the N-terminal alpha helix of
    the brain-specific long isoform of PNKD (myofibrillogenesis regulator 1, MR-1),
    which is membrane-localised and homologous to hydroxyacylglutathione hydrolase. The
    homologous enzyme detoxifies methylglyoxal, a reactive dicarbonyl present in coffee
    and alcoholic drinks and generated as a by-product of oxidative stress — which
    supplies a direct chemical rationale for why exactly those exposures, plus stress
    and fatigue, precipitate PNKD attacks. Note this remains an inference from sequence
    homology plus trigger pharmacology; direct enzymatic proof in human neurons is not
    established.
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: PROVISIONAL
  genes:
  - preferred_term: PNKD
    term:
      id: hgnc:9153
      label: PNKD
  biological_processes:
  - preferred_term: methylglyoxal catabolic process
    term:
      id: GO:0051596
      label: methylglyoxal catabolic process
    modifier: DECREASED
  downstream:
  - target: Striatal Indirect-Pathway Medium Spiny Neuron Hypoactivity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Altered presynaptic transmission at corticostriatal synapses onto indirect-pathway neurons
    - Unresolved biochemical steps linking MR-1 dysfunction to the endocannabinoid abnormality
  evidence:
  - reference: PMID:15496428
    reference_title: "The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report mutations in the myofibrillogenesis regulator 1 (MR-1) gene causing PNKD
      in 50 individuals from eight families.
    explanation: >-
      Human genetic evidence establishing MR-1 as the PNKD locus.
  - reference: PMID:15496428
    reference_title: "The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway."
    supports: PARTIAL
    evidence_source: COMPUTATIONAL
    snippet: >-
      Bioinformatic analysis reveals that the MR-1 gene is homologous to the
      hydroxyacylglutathione hydrolase (HAGH) gene. HAGH functions in a pathway to
      detoxify methylglyoxal, a compound present in coffee and alcoholic beverages and
      produced as a by-product of oxidative stress. Our results suggest a mechanism
      whereby alcohol, coffee and stress may act as precipitants of attacks in PNKD.
    explanation: >-
      The methylglyoxal-detoxification mechanism rests on sequence homology plus trigger
      pharmacology, not on a measured enzymatic assay. Recorded as COMPUTATIONAL and
      PARTIAL because the authors themselves frame it as a suggested mechanism.
  - reference: PMID:15262732
    reference_title: "Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations were absent in control subjects and caused substitutions of valine
      for alanine at amino acid positions 7 and 9. The substitutions disturb interspecies
      conserved residues and are predicted to alter the MR-1 gene's amino-terminal alpha
      helix.
    explanation: >-
      Independent identification of the same recurrent N-terminal MR-1 substitutions in
      PNKD kindreds.
- name: Striatal Indirect-Pathway Medium Spiny Neuron Hypoactivity
  description: >-
    In PNKD transgenic mice, caffeine and alcohol provoke dyskinetic attacks that
    coincide with a loss of firing in optically identified indirect-pathway striatal
    medium spiny neurons (iMSNs). Chemogenetic silencing of iMSNs is sufficient to
    trigger attacks, and the firing loss is attributable to aberrant
    endocannabinoid-mediated suppression of glutamatergic input. This inverts the
    classical dyskinesia model (direct-pathway hyperactivity) and places the causal
    lesion in indirect-pathway hypoactivity. The evidence is mouse-only; no human
    biomarker corresponds to it (see the discussions block).
  biological_scale: CELLULAR
  role: central_effector
  cell_types:
  - preferred_term: indirect pathway medium spiny neuron
    term:
      id: CL:4023029
      label: indirect pathway medium spiny neuron
  locations:
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  biological_processes:
  - preferred_term: action potential
    term:
      id: GO:0001508
      label: action potential
    modifier: DECREASED
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: DECREASED
  downstream:
  - target: Trigger-Dependent Breach of the Motor Network Attack Threshold
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35165171
    reference_title: "Striatal Indirect Pathway Dysfunction Underlies Motor Deficits in a Mouse Model of Paroxysmal Dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using optically identified striatal single-unit recordings in freely moving PNKD
      mice, we found a loss of iMSN firing during dyskinesia bouts. Further, chemogenetic
      inhibition of iMSNs triggered dyskinetic episodes in PNKD mice.
    explanation: >-
      Provides cell-type-resolved causal evidence that indirect-pathway hypoactivity
      generates the PNKD attack.
  - reference: PMID:35165171
    reference_title: "Striatal Indirect Pathway Dysfunction Underlies Motor Deficits in a Mouse Model of Paroxysmal Dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, we found that these decreases in iMSN firing are likely because of
      aberrant endocannabinoid-mediated suppression of glutamatergic inputs.
    explanation: >-
      Identifies the endocannabinoid-dependent synaptic mechanism upstream of the iMSN
      firing loss.
- name: GLUT1 Haploinsufficiency and Reduced Blood-Brain-Barrier Glucose Transport
  description: >-
    Heterozygous SLC2A1 missense, frameshift, splice and deletion variants reduce the
    glucose-transport capacity of GLUT1 at the brain microvascular endothelium, the
    obligatory route by which glucose — the brain's principal fuel — crosses the
    blood-brain barrier. Reduced uptake by mutant transporters is directly demonstrable
    in Xenopus oocytes, and the resulting transport failure is visible clinically as
    hypoglycorrhachia with a low CSF:blood glucose ratio in a normoglycaemic patient.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: SLC2A1
    term:
      id: hgnc:11005
      label: SLC2A1
  cell_types:
  - preferred_term: brain microvascular endothelial cell
    term:
      id: CL:2000044
      label: brain microvascular endothelial cell
  molecular_functions:
  - preferred_term: D-glucose transmembrane transporter activity
    term:
      id: GO:0055056
      label: D-glucose transmembrane transporter activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: D-glucose transmembrane transport
    term:
      id: GO:1904659
      label: D-glucose transmembrane transport
    modifier: DECREASED
  - preferred_term: transport across blood-brain barrier
    term:
      id: GO:0150104
      label: transport across blood-brain barrier
    modifier: DECREASED
  downstream:
  - target: Exertion- and Fasting-Unmasked Corticostriatal Energy Failure
    causal_link_type: DIRECT
  - target: Hypoglycorrhachia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:18577546
    reference_title: "Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients
    explanation: >-
      The biochemical signature of reduced blood-brain-barrier glucose transport measured
      directly in patients with PED.
  - reference: PMID:18577546
    reference_title: "Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      a reduced glucose uptake by mutated transporters compared with the wild-type as
      determined in Xenopus oocytes confirmed a pathogenic role of these mutations
    explanation: >-
      Heterologous-expression assay demonstrating that the patient variants directly
      reduce transporter function. Split from the patient CSF finding so each evidence
      item carries a single evidence_source.
- name: Exertion- and Fasting-Unmasked Corticostriatal Energy Failure
  description: >-
    A partially reduced glucose-transport reserve is sufficient at rest but becomes
    limiting when cerebral demand rises with sustained exertion or when substrate supply
    falls with fasting. Functional imaging in SLC2A1-related PED implicates altered
    glucose metabolism specifically in the corticostriate pathways (and in frontal
    cortex for the accompanying seizures), giving an energetic rather than a
    channel-based explanation for why the trigger is prolonged exercise and why rest or
    carbohydrate terminates the attack. This is the node the ketogenic diet targets, by
    supplying ketone bodies as a GLUT1-independent fuel.
  biological_scale: TISSUE
  role: mediator
  locations:
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  downstream:
  - target: Trigger-Dependent Breach of the Motor Network Attack Threshold
    causal_link_type: DIRECT
  - target: Gait Disturbance During Attacks
    causal_link_type: DIRECT
  - target: Seizures
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:18577546
    reference_title: "Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional imaging studies implicated alterations in glucose metabolism in the
      corticostriate pathways in the pathophysiology of PED and in the frontal lobe
      cortex in the pathophysiology of epileptic seizures.
    explanation: >-
      Localises the metabolic failure to the corticostriatal circuit for the movement
      phenotype and to frontal cortex for the epilepsy phenotype.
  notes: >-
    Deliberately NOT declared as conforming to
    epilepsy_excitation_inhibition_imbalance. Although GLUT1 deficiency causes
    epilepsy, the primary lesion here is a metabolic substrate-transport failure, not an
    ion-channel or synaptic-protein abnormality, so claiming conformance to the module's
    ion-channel/synaptic trigger node would misrepresent the mechanism.
- name: KCNMA1 BK-Channel Gain of Function
  description: >-
    Gain-of-function variants in KCNMA1 (p.Asp434Gly, p.Asn999Ser) increase
    calcium-activated BK potassium current, accelerating action-potential repolarisation
    and thereby permitting faster repetitive firing. In the D434G knock-in mouse this
    produces hyperexcitability of cortical pyramidal neurons and cerebellar Purkinje
    cells, and the animals recapitulate the human combination of absence epilepsy with
    dyskinesia; BK blockade with paxilline reverses both. Variant direction of effect,
    not merely the gene name, determines the mechanism: in heterologous cells p.Asn999Ser
    and p.Asp434Gly are gain-of-function while p.His444Gln is loss-of-function.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: KCNMA1
    term:
      id: hgnc:6284
      label: KCNMA1
  molecular_functions:
  - preferred_term: calcium-activated potassium channel activity
    term:
      id: GO:0015269
      label: calcium-activated potassium channel activity
    modifier: INCREASED
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  downstream:
  - target: Trigger-Dependent Breach of the Motor Network Attack Threshold
    causal_link_type: DIRECT
  - target: Absence Seizures
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35286197
    reference_title: "Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The cortical pyramidal neurons and cerebellar Purkinje cells from the BK-D434G mice
      show hyperexcitability, which likely contributes to the pathogenesis of absence
      seizures and paroxysmal dyskinesia.
    explanation: >-
      Establishes BK gain of function as a hyperexcitability mechanism producing both the
      dyskinesia and the absence epilepsy of PNKD3.
  - reference: PMID:35286197
    reference_title: "Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pharmacological inhibition of BK channels suppresses neuronal hyperactivity and
      mitigates absence seizure and the locomotor defects.
    explanation: >-
      Pharmacological reversal by a BK blocker supports the gain-of-function direction of
      effect as causal rather than incidental. The blocker used, paxilline, is a research
      tool and not a human therapy.
  - reference: PMID:35819138
    reference_title: "BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In heterologous cells, BKN999S and BKD434G channels displayed gain-of-function (GOF)
      properties, whereas BKH444Q channels showed loss-of-function (LOF) properties.
    explanation: >-
      Source for the p.Asn999Ser gain-of-function allele and for the statement that
      loss-of-function KCNMA1 alleles (p.His444Gln) behave differently in the same assay.
  - reference: PMID:15937479
    reference_title: "Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose that enhancement of BK channels in vivo leads to increased excitability
      by inducing rapid repolarization of action potentials, resulting in generalized
      epilepsy and paroxysmal dyskinesia by allowing neurons to fire at a faster rate.
    explanation: >-
      States the faster-repolarisation-to-faster-firing mechanism curated in this node,
      from the paper that identified the human KCNMA1 syndrome.
- name: ADCY5 Striatal cAMP Signalling Gain of Function
  description: >-
    Gain-of-function variants in ADCY5, the adenylate cyclase isoform enriched in
    striatal medium spiny neurons, raise cAMP production downstream of dopamine and
    adenosine receptors and produce a mixed hyperkinetic disorder — dystonia, chorea and
    myoclonus with characteristic facial/perioral involvement — that fluctuates and
    worsens paroxysmally, notably at night. Recurrent variants at residues 418 and 726
    dominate, and somatic mosaicism attenuates severity. Because ADCY5 attacks may be
    kinesigenic, exercise-induced, non-kinesigenic or nocturnal within one gene, ADCY5 is
    the clearest single-gene demonstration that trigger-based classification does not map
    one-to-one onto genotype.
  biological_scale: MOLECULAR
  role: trigger
  genes:
  - preferred_term: ADCY5
    term:
      id: hgnc:236
      label: ADCY5
  molecular_functions:
  - preferred_term: adenylate cyclase activity
    term:
      id: GO:0004016
      label: adenylate cyclase activity
    modifier: INCREASED
  biological_processes:
  - preferred_term: cAMP biosynthetic process
    term:
      id: GO:0006171
      label: cAMP biosynthetic process
    modifier: INCREASED
  cell_types:
  - preferred_term: medium spiny neuron
    term:
      id: CL:1001474
      label: medium spiny neuron
  locations:
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  downstream:
  - target: Trigger-Dependent Breach of the Motor Network Attack Threshold
    causal_link_type: DIRECT
  - target: Orofacial Dyskinesia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:26537056
    reference_title: "ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea,
      and myoclonus, often with facial involvement. The movements are sometimes painful
      and show episodic worsening on a fluctuating background.
    explanation: >-
      Documents the mixed hyperkinetic phenomenology with facial involvement and episodic
      exacerbation that distinguishes ADCY5-related dyskinesia.
  - reference: PMID:26537056
    reference_title: "ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1,
      produce a moderate to severe disorder with axial hypotonia, limb hypertonia,
      paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent
      facial dyskinesia.
    explanation: >-
      Anchors the characteristic nocturnal exacerbation and perioral/facial dyskinesia to
      the recurrent ADCY5 residue-418 alleles.
- name: Secondary and Acquired Causes of Paroxysmal Dyskinesia
  description: >-
    Paroxysmal dyskinesia is not always genetic. Acquired causes act by imposing a focal
    or diffuse insult on the same motor circuits: demyelinating lesions in multiple
    sclerosis (classically producing paroxysmal tonic spasms that are the acquired
    mimic of PKD, likewise carbamazepine-responsive), hypoparathyroidism and other
    metabolic derangements (often with basal-ganglia calcification), perinatal
    hypoxic-ischaemic injury, transient cerebral ischaemia, stroke, trauma, encephalitis
    and autoimmune disease, structural basal-ganglia lesions, and drugs or toxins.
    Adult onset, inconsistent triggers, evolving phenomenology, or any abnormality on
    interictal examination should prompt a search for a secondary cause.
  biological_scale: ORGANISM
  role: trigger
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  downstream:
  - target: Trigger-Dependent Breach of the Motor Network Attack Threshold
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Focal demyelination, basal-ganglia calcification, ischaemic damage or inflammation
    - Perturbed excitability of the same basal-ganglia-thalamo-cortical and cerebellar circuits that the genetic lesions destabilise
  evidence:
  - reference: PMID:32443735
    reference_title: "Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From an etiological point of view, both primary (genetic) and secondary (acquired)
      causes of PMDs are known.
    explanation: >-
      Establishes that acquired aetiologies are a recognised and distinct arm of the
      paroxysmal movement disorder group.
  - reference: PMID:10323309
    reference_title: "The paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tonic spasms in multiple sclerosis and Sandiffers syndrome producing intermittent
      torticollis in infants and children are other paroxysmal movement disorders.
    explanation: >-
      Names multiple sclerosis paroxysmal tonic spasms as an acquired paroxysmal movement
      disorder within the same clinical group.
- name: Trigger-Dependent Breach of the Motor Network Attack Threshold
  description: >-
    The convergence node of the entry. Whatever the upstream lesion — presynaptic release
    failure, striatal indirect-pathway hypoactivity, corticostriatal energy failure, BK
    or cAMP dysregulation, or an acquired structural insult — the result is the same: a
    basal-ganglia-thalamo-cortical and cerebello-thalamic motor network that behaves
    normally at baseline but has a reduced margin before a discrete, self-limited
    episode of aberrant motor output. The trigger (sudden movement, stimulant, stress,
    exertion, sleep state) supplies the perturbation that breaches the margin. This
    trigger-threshold architecture is what explains the two defining features of the
    group: attacks are stereotyped and provoked, and the examination between them is
    normal.
  biological_scale: TISSUE
  role: central_effector
  locations:
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  biological_processes:
  - preferred_term: regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: ABNORMAL
  downstream:
  - target: Paroxysmal Dyskinetic Attacks
    causal_link_type: DIRECT
  - target: Paroxysmal Dystonia
    causal_link_type: DIRECT
  - target: Paroxysmal Choreoathetosis
    causal_link_type: DIRECT
  - target: Hemiballismus During Attacks
    causal_link_type: DIRECT
  - target: Sensory Aura Preceding Attacks
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30242089
    reference_title: "Unravelling of the paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classically, PxD have been categorised according to their triggers and duration of
      the attacks, but increasing evidence suggests that there is a certain degree of
      clinical and genetic overlap and challenges the concept that one phenotype is
      attributable to one single aetiology.
    explanation: >-
      Supports modelling the attack as a shared trigger-dependent convergence point that
      several distinct genotypes reach, rather than as a phenotype uniquely determined by
      one gene.
- name: Age-Dependent PRRT2 Phenotype Shift from Infantile Seizures to Kinesigenic Dyskinesia
  description: >-
    The single most instructive feature of PRRT2 biology: one haploinsufficient allele
    produces benign familial infantile epilepsy in the first year of life, kinesigenic
    dyskinesia from later childhood, or both sequentially in the same person (the ICCA
    syndrome), with hemiplegic migraine and episodic ataxia at the phenotypic margins.
    Across 1444 published carriers, benign familial infantile epilepsy (41.7%), PKD
    (38.7%) and ICCA (14.3%) account for almost the entire spectrum. Penetrance depends
    on which phenotype is counted: about 61% for PKD alone, but nearly complete once
    infantile convulsions are included. Curatorially this means seizures and dyskinesia
    must be modelled as age-dependent expressions of one lesion, not as comorbidity.
  biological_scale: ORGANISM
  role: consequence
  genes:
  - preferred_term: PRRT2
    term:
      id: hgnc:30500
      label: PRRT2
  downstream:
  - target: Benign Infantile Seizures
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:26598493
    reference_title: "The evolving spectrum of PRRT2-associated paroxysmal diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Benign familial infantile epilepsy (41.7%; n = 602), paroxysmal kinesigenic
      dyskinesia (38.7%; n = 560) and infantile convulsions and choreoathetosis (14.3%; n
      = 206) constitute the vast majority of PRRT2-associated diseases
    explanation: >-
      Quantifies the pleiotropy across a 1444-patient review, showing epilepsy and
      dyskinesia as roughly co-equal expressions of the same gene.
  - reference: PMID:22875091
    reference_title: "PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The estimated penetrance of PRRT2 mutations was 61%, if only the PKD phenotype was
      considered; however, if infantile convulsions were also taken into account, the
      penetrance was nearly complete.
    explanation: >-
      Shows that the apparent incomplete penetrance of PKD is largely an artefact of
      ignoring the infantile-seizure expression of the same allele.
phenotypes:
- category: Neurologic
  name: Paroxysmal Dyskinetic Attacks
  description: >-
    The defining manifestation: recurrent, abrupt, self-limited bouts of involuntary
    hyperkinetic movement — dystonia, chorea, athetosis, ballism or a mixture —
    occurring without loss of consciousness and without postictal confusion.
  phenotype_term:
    preferred_term: Paroxysmal dyskinesia
    term:
      id: HP:0007166
      label: Paroxysmal dyskinesia
    temporality: RECURRENT
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:30242089
    reference_title: "Unravelling of the paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paroxysmal dyskinesias (PxD) refer to a rare group of clinically and genetically
      heterogeneous disorders presenting with recurrent attacks of abnormal movements,
      typically dystonia, chorea or a combination thereof, without loss of
      consciousness.
    explanation: >-
      Directly states the obligate, defining phenotype including preservation of
      consciousness.
- category: Neurologic
  name: Paroxysmal Dystonia
  description: >-
    Episodic dystonic posturing of limbs, trunk or face during attacks, with no dystonia
    between episodes. In PED the dystonia is characteristically leg-predominant and
    follows sustained walking or running.
  phenotype_term:
    preferred_term: Paroxysmal dystonia
    term:
      id: HP:0002268
      label: Paroxysmal dystonia
    temporality: RECURRENT
  notes: >-
    No FrequencyEnum band is asserted. Dystonia is one of two alternating core attack
    phenomenologies rather than a separately enumerable feature, and no cited source
    reports a band-mappable proportion across the umbrella group.
  evidence:
  - reference: PMID:10323309
    reference_title: "The paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paroxysmal exercise induced dystonia (PED) is a rare disorder manifesting as
      episodes of dystonia mostly affecting the feet induced by continuous exercise like
      walking or running.
    explanation: >-
      Documents episodic dystonia as the attack phenomenology, and its leg/foot
      predominance in the exercise-induced subtype.
  - reference: PMID:20301400
    reference_title: "Familial Paroxysmal Nonkinesigenic Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Attacks involve dystonic posturing with choreic and ballistic movements, may be
      accompanied by a preceding aura, occur while the individual is awake, and are not
      associated with seizures.
    explanation: >-
      GeneReviews confirms dystonic posturing as the core attack phenomenology in the
      non-kinesigenic subtype as well.
- category: Neurologic
  name: Paroxysmal Choreoathetosis
  description: >-
    Episodic choreiform and athetoid movements, the phenomenology that gave PKD and PNKD
    their historical names (paroxysmal kinesigenic choreoathetosis and paroxysmal
    dystonic choreoathetosis).
  phenotype_term:
    preferred_term: Paroxysmal choreoathetosis
    term:
      id: HP:0007098
      label: Paroxysmal choreoathetosis
    temporality: RECURRENT
  notes: >-
    No FrequencyEnum band is asserted: the cited sources state that attacks comprise
    choreoathetosis OR dystonia without giving a band-mappable proportion.
  evidence:
  - reference: PMID:38091244
    reference_title: "Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Paroxysmal kinesigenic dyskinesia (PKD), the most common type of paroxysmal
      movement disorder, is characterized by sudden and brief attacks of choreoathetosis
      or dystonia triggered by sudden voluntary movements.
    explanation: >-
      Names choreoathetosis alongside dystonia as the core attack phenomenology of the
      commonest subtype.
- category: Neurologic
  name: Hemiballismus During Attacks
  description: >-
    Large-amplitude proximal flinging movements of one side of the body, an occasional
    but characteristic component of the attack repertoire alongside chorea and dystonia.
  phenotype_term:
    preferred_term: Hemiballismus
    term:
      id: HP:0100248
      label: Hemiballismus
    temporality: TRANSIENT
  notes: >-
    No FrequencyEnum band is asserted: the sources state that ballism "can occur" and
    that attacks "involve dystonic posturing with choreic and ballistic movements",
    neither of which maps to a frequency band.
  evidence:
  - reference: PMID:29276650
    reference_title: "Paroxysmal Kinesigenic Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other hyperkinesias that can occur in PKD patients include chorea and/or ballism.
    explanation: >-
      Documents ballism as part of the attack repertoire in PKD.
  - reference: PMID:20301400
    reference_title: "Familial Paroxysmal Nonkinesigenic Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Attacks involve dystonic posturing with choreic and ballistic movements
    explanation: >-
      GeneReviews confirms ballistic movements as part of the attack repertoire in PNKD.
- category: Neurologic
  name: Sensory Aura Preceding Attacks
  description: >-
    A premonitory sensory sensation — paraesthesia, tingling, tension or stiffness — in
    the limb about to be affected, reported by most patients with PKD and a useful
    positive diagnostic clue that distinguishes an attack from a functional movement
    disorder or a tic.
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
    temporality: TRANSIENT
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:29276650
    reference_title: "Paroxysmal Kinesigenic Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aura-like symptoms (paresthesias and stiffness in the affected limb) before the
      attacks, as described in this case, are very common.
    explanation: >-
      Establishes premonitory paraesthesia in the affected limb as a feature of PKD
      attacks. The band VERY_FREQUENT maps the source's qualitative term "very common"
      per the literature-term-to-enum mapping in docs/frequency-evidence-guidelines.md.
  - reference: PMID:20301400
    reference_title: "Familial Paroxysmal Nonkinesigenic Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      may be accompanied by a preceding aura
    explanation: >-
      GeneReviews confirms a preceding aura in the non-kinesigenic subtype too, though
      without a frequency qualifier.
- category: Neurologic
  name: Benign Infantile Seizures
  subtype: ICCA
  description: >-
    Afebrile focal or generalised seizures clustering in the first year of life, with
    normal development and spontaneous remission, occurring in PRRT2 carriers who later
    develop kinesigenic dyskinesia (the ICCA sequence). Curated here as the earlier
    expression of the same allele, not as a comorbid epilepsy.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    onset:
      onset_category: INFANTILE
  frequency: OBLIGATE
  notes: >-
    The band is OBLIGATE, not a partial frequency, because this phenotype is scoped to
    the ICCA subtype (subtype: ICCA), in which infantile seizures are definitionally
    required: MONDO:0011178 defines infantile convulsions and choreoathetosis as
    "a neurological condition characterized by the occurrence of seizures during the
    first year of life ... and choreoathetotic dyskinetic attacks during childhood or
    adolescence". Across unselected PRRT2 carriers, by contrast, infantile seizures are
    present in roughly 56% (BFIE 41.7% plus ICCA 14.3% of 1444 published carriers,
    PMID:26598493), which is the figure that would apply at gene rather than subtype
    level.
  evidence:
  - reference: PMID:22875091
    reference_title: "PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To describe the phenotypes and penetrance of paroxysmal kinesigenic dyskinesia
      (PKD), a movement disorder characterized by attacks of involuntary movements
      occurring after sudden movements, infantile convulsion and choreoathetosis (ICCA)
      syndrome, and benign familial infantile convulsions (BFIC), caused by PRRT2
      mutations.
    explanation: >-
      Places benign infantile convulsions inside the PRRT2 phenotype set that includes
      PKD.
- category: Neurologic
  name: Seizures
  subtype: PED
  description: >-
    Predominantly primary generalised seizures co-occurring with exercise-induced
    dyskinesia in SLC2A1/GLUT1 deficiency; the combination of PED plus epilepsy in one
    family is itself a strong pointer to SLC2A1.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  notes: >-
    No FrequencyEnum band is asserted. The source cohort was ascertained as PED
    co-occurring with epilepsy, so the apparent frequency is 100% by construction and
    cannot be read as the seizure frequency among unselected SLC2A1-related PED.
  evidence:
  - reference: PMID:18577546
    reference_title: "Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PED was characterized by choreoathetosis, dystonia or both, affecting mainly the
      legs. Predominant epileptic seizure types were primary generalized.
    explanation: >-
      Documents co-occurring primary generalised epilepsy in the SLC2A1-related PED
      kindreds.
- category: Neurologic
  name: Absence Seizures
  subtype: PNKD3
  description: >-
    Generalised non-motor (absence) seizures co-segregating with paroxysmal dyskinesia
    in KCNMA1 gain-of-function families, recapitulated in the D434G knock-in mouse.
  phenotype_term:
    preferred_term: Generalized non-motor (absence) seizure
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
  evidence:
  - reference: PMID:35286197
    reference_title: "Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We characterized a mouse model carrying a gain-of-function BK channelopathy D434G
      from a large family of patients with absence epilepsy and paroxysmal dyskinesia.
    explanation: >-
      Links absence epilepsy to the KCNMA1 D434G family from which the model derives.
      Model-organism evidence; the human evidence is the item below. No frequency band is
      asserted because the sources describe single kindreds.
  - reference: PMID:15937479
    reference_title: "Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a genetic locus associated with a human syndrome of coexistent
      generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22
    explanation: >-
      Human evidence that generalised epilepsy co-occurs with paroxysmal dyskinesia in the
      KCNMA1 syndrome.
- category: Neurologic
  name: Gait Disturbance During Attacks
  subtype: PED
  description: >-
    Loss of normal walking during exercise-induced attacks — the presenting complaint in
    many PED patients, with episodes lasting minutes to hours and relieved by rest or
    carbohydrate.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
    temporality: TRANSIENT
  evidence:
  - reference: PMID:27351150
    reference_title: "Paroxysmal Exercise-induced Dyskinesias Caused by GLUT1 Deficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At age 16 years, she again began to have paroxysmal gait disturbances lasting from
      a few minutes to several hours. The episodes occurred several times in a month.
      They were triggered by prolonged exercise or fasting, and could be relieved by
      carbohydrate intake or rest.
    explanation: >-
      Illustrates the exercise/fasting-triggered gait disturbance and its relief by
      carbohydrate, the clinical signature of the GLUT1 energy-supply mechanism. This is
      a single case report, so no frequency band is asserted.
- category: Neurologic
  name: Orofacial Dyskinesia
  subtype: ADCY5
  description: >-
    Perioral and facial involuntary movements, characteristic of ADCY5-related dyskinesia
    and unusual in PRRT2-related PKD; together with nocturnal exacerbation this is the
    main clinical clue that redirects testing to ADCY5.
  phenotype_term:
    preferred_term: Orofacial dyskinesia
    term:
      id: HP:0002310
      label: Orofacial dyskinesia
  notes: >-
    No FrequencyEnum band is asserted: the source says facial involvement occurs "often"
    within ADCY5-related dyskinesia specifically, and no cited source quantifies the
    ADCY5 share of the umbrella group, so neither a subtype-level nor an umbrella-level
    band can be justified.
  evidence:
  - reference: PMID:26537056
    reference_title: "ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea,
      and myoclonus, often with facial involvement.
    explanation: >-
      Documents facial involvement as a recurrent feature of ADCY5-related dyskinesia.
- category: Neurologic
  name: Migraine
  description: >-
    Migraine, including hemiplegic migraine, is over-represented in PRRT2 carriers and
    in cohorts screened across the three classic paroxysmal dyskinesia genes, reflecting
    shared susceptibility to cortical spreading depolarization. Note that formal
    co-segregation of PRRT2 alleles with migraine has been challenged, so this is a
    phenotypic association rather than a demonstrated Mendelian consequence.
  phenotype_term:
    preferred_term: Migraine
    term:
      id: HP:0002076
      label: Migraine
  evidence:
  - reference: PMID:26598494
    reference_title: "The clinical and genetic heterogeneity of paroxysmal dyskinesias."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotypes associated with PRRT2 mutations included a high frequency of migraine
      and hemiplegic migraine.
    explanation: >-
      Supports the association at cohort level. Marked PARTIAL because PMID:22875091
      reports that PRRT2 mutations did not cosegregate with migraine in their families;
      no frequency band is asserted for that reason.
biochemical:
- name: Hypoglycorrhachia
  subtype: PED
  notes: >-
    Low cerebrospinal fluid glucose with a reduced CSF:blood glucose ratio measured after
    a fast, in the presence of normal blood glucose, is the biochemical fingerprint of
    GLUT1 deficiency and therefore the single most important bedside test for the
    treatable cause of paroxysmal dyskinesia. In PED cohorts the median CSF/blood glucose
    ratio is around 0.52 against a normal lower limit above 0.60; note that the reduction
    can be subtle in mild GLUT1 phenotypes (ratios of 0.54 have been reported in
    genetically confirmed cases), so a borderline ratio does not exclude the diagnosis
    and SLC2A1 sequencing should follow clinical suspicion.
  presence: PRESENT
  biomarker_term:
    preferred_term: Hypoglycorrhachia
    term:
      id: HP:0011972
      label: Hypoglycorrhachia
  specificity: >-
    Highly specific for GLUT1 deficiency among the paroxysmal dyskinesias; not a feature
    of PRRT2, PNKD, KCNMA1 or ADCY5 disease. Must be interpreted against a simultaneous
    normal blood glucose to exclude systemic hypoglycaemia and against CSF pleocytosis
    to exclude meningitis.
  evidence:
  - reference: PMID:18577546
    reference_title: "Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients and a
      reduced glucose uptake by mutated transporters compared with the wild-type as
      determined in Xenopus oocytes confirmed a pathogenic role of these mutations.
    explanation: >-
      Provides the quantitative CSF:blood glucose ratio in a genetically confirmed PED
      cohort together with the normal reference threshold.
  - reference: PMID:27351150
    reference_title: "Paroxysmal Exercise-induced Dyskinesias Caused by GLUT1 Deficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cerebrospinal fluid to blood glucose ratio, obtained after 10 hours of fasting,
      was slightly decreased (0.54, Normal>0.59).
    explanation: >-
      Shows that the ratio may be only marginally reduced in mild GLUT1 phenotypes, which
      is why a borderline value must not be used to exclude the diagnosis.
genetic:
- name: PRRT2
  subtype: PKD
  gene_term:
    preferred_term: PRRT2
    term:
      id: hgnc:30500
      label: PRRT2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    Heterozygous loss-of-function variants at 16p11.2; the recurrent c.649dupC
    (p.Arg217Profs*8) frameshift dominates. Biallelic variants produce a more severe
    phenotype with epilepsy, ataxia and intellectual disability, and 16p11.2 deletions
    encompassing PRRT2 are a structural cause. Detection rate is far higher in familial
    than sporadic PKD.
  evidence:
  - reference: PMID:22744660
    reference_title: "PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations introducing premature termination codons were identified in 22 of 34
      patients including 13 of 14 families and 9 of 20 patients with sporadic cases.
    explanation: >-
      Quantifies PRRT2 as the major cause of PKD in an independent European cohort, with
      the familial/sporadic split.
  case_fractions:
  - population: European PKD/ICCA referral cohort, familial cases
    case_fraction_percent: 92.9
    cohort_size: 14
    notes: Familial PKD families with a PRRT2 premature termination codon (13 of 14).
    evidence:
    - reference: PMID:22744660
      reference_title: "PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutations introducing premature termination codons were identified in 22 of 34
        patients including 13 of 14 families and 9 of 20 patients with sporadic cases.
      explanation: Source for the familial PRRT2 detection fraction.
  - population: European PKD/ICCA referral cohort, sporadic cases
    case_fraction_percent: 45.0
    cohort_size: 20
    notes: Sporadic PKD cases with a PRRT2 premature termination codon (9 of 20).
    evidence:
    - reference: PMID:22744660
      reference_title: "PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutations introducing premature termination codons were identified in 22 of 34
        patients including 13 of 14 families and 9 of 20 patients with sporadic cases.
      explanation: Source for the sporadic PRRT2 detection fraction.
- name: TMEM151A
  subtype: PKD
  gene_term:
    preferred_term: TMEM151A
    term:
      id: hgnc:28497
      label: TMEM151A
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    Second PKD locus at 11q13.2, identified in PRRT2-negative cases. Truncating,
    missense and in-frame deletion variants have been reported and the available
    transcript evidence supports loss of function; penetrance is lower than for PRRT2 and
    the protein's normal function remains poorly defined.
  evidence:
  - reference: PMID:38091244
    reference_title: "Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene.
    explanation: >-
      Review naming TMEM151A alongside PRRT2 as the two described causative genes for
      PKD.
- name: PNKD
  subtype: PNKD
  gene_term:
    preferred_term: PNKD
    term:
      id: hgnc:9153
      label: PNKD
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    Also known as MR-1 (myofibrillogenesis regulator 1) at 2q35. Nearly all classic PNKD
    is caused by one of two recurrent N-terminal missense substitutions, p.Ala7Val and
    p.Ala9Val, which affect only the brain-specific long isoform.
  evidence:
  - reference: PMID:15496428
    reference_title: "The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report mutations in the myofibrillogenesis regulator 1 (MR-1) gene causing PNKD
      in 50 individuals from eight families.
    explanation: >-
      Original gene identification across eight PNKD kindreds.
- name: SLC2A1
  subtype: PED
  gene_term:
    preferred_term: SLC2A1
    term:
      id: hgnc:11005
      label: SLC2A1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    Heterozygous missense and frameshift variants segregate with PED plus epilepsy; many
    cases are de novo. Deletion/duplication analysis is required because whole- or
    partial-gene deletions occur. Identifying SLC2A1 changes management immediately
    because it makes the disorder ketogenic-diet-responsive.
  evidence:
  - reference: PMID:18577546
    reference_title: "Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on a whole genome linkage analysis we screened SLC2A1, encoding the glucose
      transporter of the blood-brain-barrier, GLUT1 and identified heterozygous missense
      and frameshift mutations segregating in this and three other nuclear families with
      a similar phenotype.
    explanation: >-
      Establishes SLC2A1 as the PED locus with segregating heterozygous variants in four
      families.
  case_fractions:
  - population: UK and international paroxysmal dyskinesia referral cohort (145 families)
    case_fraction_percent: 10.0
    cohort_size: 145
    notes: >-
      SLC2A1 mutations were identified in 10% of paroxysmal movement disorder patients in
      a study screening PRRT2, SLC2A1 and PNKD across all subtypes.
    evidence:
    - reference: PMID:26598494
      reference_title: "The clinical and genetic heterogeneity of paroxysmal dyskinesias."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        PRRT2 mutations were identified in 35% of patients, SLC2A1 mutations in 10%, PNKD
        in 2%.
      explanation: Source for the SLC2A1 share of a mixed paroxysmal dyskinesia cohort.
- name: KCNMA1
  subtype: PNKD3
  gene_term:
    preferred_term: KCNMA1
    term:
      id: hgnc:6284
      label: KCNMA1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    Gain-of-function alleles (p.Asp434Gly, p.Asn999Ser) increase BK current and cause
    paroxysmal dyskinesia with or without epilepsy; the p.His444Gln allele is
    loss-of-function in the same heterologous assay, so the direction of the variant
    effect must be established before mechanistic or therapeutic inference.
  evidence:
  - reference: PMID:35286197
    reference_title: "Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A growing number of gain-of-function (GOF) BK channelopathies have been identified
      in patients with epilepsy and movement disorders.
    explanation: >-
      Establishes gain-of-function KCNMA1/BK channelopathy as a recognised cause of
      combined epilepsy and movement disorder in patients.
  - reference: PMID:15937479
    reference_title: "Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a genetic locus associated with a human syndrome of coexistent
      generalized epilepsy and paroxysmal dyskinesia on chromosome 10q22 and show that a
      mutation of the alpha subunit of the BK channel causes this syndrome.
    explanation: >-
      Original human gene identification for the combined generalised-epilepsy plus
      paroxysmal-dyskinesia syndrome.
  - reference: PMID:35819138
    reference_title: "BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, genetic screening identified heterozygous KCNMA1 variants in a subset of
      patients with debilitating paroxysmal non-kinesigenic dyskinesia, presenting with or
      without epilepsy (PNKD3).
    explanation: >-
      Confirms in patients that heterozygous KCNMA1 variants cause PNKD3 with or without
      epilepsy. Source also for the differing direction of effect between alleles.
- name: ADCY5
  subtype: ADCY5
  gene_term:
    preferred_term: ADCY5
    term:
      id: hgnc:236
      label: ADCY5
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE_AND_SOMATIC
  presence: PRESENT
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    Recurrent gain-of-function variants at residues 418 (p.Arg418Trp, p.Arg418Gln) and
    726 (p.Ala726Thr); most severe cases are de novo. Somatic mosaicism contributes to
    phenotypic variability and has been reported in less severely affected individuals,
    so a mildly affected transmitting parent does not exclude ADCY5. (The cited source
    supports mosaicism as a contributor to variability; the direction of effect is a
    reported observation rather than a quantified association.)
  evidence:
  - reference: PMID:26537056
    reference_title: "ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genotype-specific correlations and mosaicism play important roles in the phenotypic
      variability. Recurrent mutations suggest particular functional importance of
      residues 418 and 726 in disease pathogenesis.
    explanation: >-
      Documents the recurrent residues and the role of mosaicism in ADCY5-related
      dyskinesia.
inheritance:
- name: Autosomal dominant with incomplete, phenotype-dependent penetrance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  penetrance_percentage: "61"
  expressivity: VARIABLE
  description: >-
    The primary paroxysmal dyskinesias are predominantly autosomal dominant (PRRT2,
    TMEM151A, PNKD, SLC2A1, KCNMA1, ADCY5). Reported penetrance depends critically on
    which phenotype is counted: for PRRT2 it is about 61% when only PKD is scored but
    nearly complete when infantile convulsions are also counted. Expressivity is highly
    variable within a single kindred — the same PRRT2 allele may produce isolated
    infantile seizures, isolated kinesigenic dyskinesia, both sequentially (ICCA),
    hemiplegic migraine, episodic ataxia, or nothing at all. Autosomal recessive and de
    novo mechanisms occur, particularly for SLC2A1 (frequently de novo), biallelic
    PRRT2, and the metabolic PED mimics.
  evidence:
  - reference: PMID:22875091
    reference_title: "PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The estimated penetrance of PRRT2 mutations was 61%, if only the PKD phenotype was
      considered; however, if infantile convulsions were also taken into account, the
      penetrance was nearly complete.
    explanation: >-
      Direct source for the penetrance figure and for the observation that it is
      phenotype-definition dependent.
prevalence:
- subtype: PKD
  population: General population
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.67
  notes: >-
    Reported as approximately 1 in 150,000, i.e. about 6.7 per million or 0.67 per
    100,000. PKD is the commonest of the paroxysmal dyskinesias, so this is an upper
    bound for the individual subtypes; reliable population estimates for PNKD, PED and
    the umbrella group are not available.
  evidence:
  - reference: PMID:38091244
    reference_title: "Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the general population, PKD is rare, with the prevalence estimated at 1:150,000
    explanation: >-
      Source for the PKD population prevalence estimate normalised here to cases per
      100,000.
epidemiology:
- name: Male predominance and childhood onset
  description: >-
    PKD shows a consistent male excess of roughly 2-4:1 and typically begins in childhood
    or early adolescence, with attack frequency declining in adulthood. The reason for
    the sex bias is unresolved. In a systematic review of 605 paediatric patients the
    mean age at onset was 5.99 years and PKD was the commonest subtype.
  evidence:
  - reference: PMID:38091244
    reference_title: "Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Male patients are far more numerous than female patients, with a ratio of 2-4:1
    explanation: >-
      Source for the male predominance of PKD.
  - reference: PMID:40943684
    reference_title: "Paroxysmal Dyskinesias in Paediatric Age: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We included 112 studies encompassing 605 paediatric patients. The most common
      subtype was Paroxistic Kinesigenic Dyskinesia (PKD). Male sex was more frequently
      reported. The mean onset age was 5.99 years.
    explanation: >-
      Independent systematic review confirming PKD predominance, male excess and
      early-childhood onset. Note these are literature-level, referral-biased figures,
      not population statistics.
environmental:
- name: Sudden Voluntary Movement or Startle
  description: >-
    The defining precipitant of PKD: rising from a chair, initiating gait, being startled
    or making any abrupt voluntary movement provokes an attack within seconds. The
    trigger is so specific that its presence is one of the formal diagnostic criteria.
  effect: EXACERBATES
  evidence:
  - reference: PMID:15623687
    reference_title: "Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The authors propose the following diagnostic criteria for idiopathic PKD based on
      this phenotype: identified trigger for the attacks (sudden movements), short
      duration of attacks (<1 minute), lack of loss of consciousness or pain during
      attacks, antiepileptic drug responsiveness, exclusion of other organic diseases
    explanation: >-
      Formalises the kinesigenic trigger as a diagnostic criterion for PKD.
- name: Caffeine and Alcohol
  description: >-
    Coffee, tea and alcohol are the reproducible precipitants of PNKD attacks and are
    also the exposures whose shared chemistry (methylglyoxal content) motivated the
    stress-response-pathway hypothesis of MR-1 function. Avoiding them is the principal
    intervention in PNKD.
  effect: EXACERBATES
  chemicals:
  - caffeine
  - ethanol
  evidence:
  - reference: PMID:15496428
    reference_title: "The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HAGH functions in a pathway to detoxify methylglyoxal, a compound present in coffee
      and alcoholic beverages and produced as a by-product of oxidative stress. Our
      results suggest a mechanism whereby alcohol, coffee and stress may act as
      precipitants of attacks in PNKD.
    explanation: >-
      Documents caffeine and alcohol as precipitants and supplies the chemical rationale
      linking them to the causal gene.
- name: Prolonged Exertion and Fasting
  description: >-
    Sustained exercise and, less commonly, fasting precipitate PED attacks by pushing
    cerebral glucose demand beyond the reduced GLUT1 transport reserve. Rest and
    carbohydrate intake terminate attacks, which is itself a useful diagnostic manoeuvre.
  effect: EXACERBATES
  evidence:
  - reference: PMID:27351150
    reference_title: "Paroxysmal Exercise-induced Dyskinesias Caused by GLUT1 Deficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They were triggered by prolonged exercise or fasting, and could be relieved by
      carbohydrate intake or rest.
    explanation: >-
      Documents exertion and fasting as the triggers and carbohydrate/rest as the relief,
      consistent with the energy-supply mechanism.
treatments:
- name: Low-Dose Carbamazepine
  description: >-
    First-line and often dramatically effective treatment for PKD, frequently at doses
    well below those used for epilepsy. Response is so characteristic that antiepileptic
    drug responsiveness is one of the formal PKD diagnostic criteria, and a PRRT2
    mutation predicts near-complete abolition of attacks. Monitor for rash, hyponatraemia,
    sedation, hepatic and haematological toxicity and drug interactions; HLA-B*15:02
    screening is indicated in at-risk ancestries because carbamazepine can precipitate
    Stevens-Johnson syndrome and toxic epidermal necrolysis.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carbamazepine
      term:
        id: CHEBI:3387
        label: carbamazepine
  target_mechanisms:
  - target: Presynaptic Release Failure and Neuronal Hyperexcitability
    treatment_effect: INHIBITS
    description: >-
      Use-dependent sodium-channel blockade counteracts the lowered action-potential
      threshold and increased sodium-current density produced by PRRT2 loss, restoring
      the margin between baseline and attack.
  target_phenotypes:
  - preferred_term: Paroxysmal dyskinesia
    term:
      id: HP:0007166
      label: Paroxysmal dyskinesia
  evidence:
  - reference: PMID:24661410
    reference_title: "Genotype-phenotype correlation in a cohort of paroxysmal kinesigenic dyskinesia cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, the presence of PRRT2 mutations also predicted a good response to
      carbamazepine therapy, especially at low dose.
    explanation: >-
      Establishes both the efficacy and the low-dose requirement, and links response to
      PRRT2 genotype.
  - reference: PMID:24661410
    reference_title: "Genotype-phenotype correlation in a cohort of paroxysmal kinesigenic dyskinesia cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the follow-up study revealed that p.R217Pfs 8-positive patients showed dramatic
      improvement with complete abolition of dyskinetic episodes with carbamazepine
      treatment, while only 7 of the 18 patients without PRRT2 mutations showed a response
      to the antiepileptic drug.
    explanation: >-
      Quantifies the genotype-stratified response: complete abolition in PRRT2 carriers
      versus 7 of 18 in non-carriers.
  - reference: PMID:10323309
    reference_title: "The paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Antiepileptic drugs particularly carbamazepine are very helpful in a large
      proportion of cases.
    explanation: >-
      Independent confirmation of carbamazepine efficacy in PKD across a review of the
      clinical literature.
- name: Oxcarbazepine
  description: >-
    Structural analogue of carbamazepine used as an equally effective alternative in PKD,
    particularly where carbamazepine is not tolerated. It has been used successfully after
    carbamazepine-induced Stevens-Johnson syndrome, although cross-reactivity is possible
    and reintroduction requires caution.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: oxcarbazepine
      term:
        id: CHEBI:7824
        label: oxcarbazepine
  target_mechanisms:
  - target: Presynaptic Release Failure and Neuronal Hyperexcitability
    treatment_effect: INHIBITS
    description: >-
      Sodium-channel blockade, as for carbamazepine.
  evidence:
  - reference: PMID:40943684
    reference_title: "Paroxysmal Dyskinesias in Paediatric Age: A Systematic Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Antiseizure drugs-particularly sodium channel blockers such as carbamazepine and
      oxcarbazepine-were the most frequently reported treatment, with complete efficacy
      documented in 59.7% of the studies describing their use.
    explanation: >-
      Systematic review evidence that sodium-channel blockers including oxcarbazepine are
      the mainstay and frequently produce complete efficacy.
- name: Ketogenic Diet
  description: >-
    Disease-directed therapy for SLC2A1/GLUT1-related PED, and the reason GLUT1 deficiency
    must not be missed. Ketone bodies enter the brain via monocarboxylate transporters,
    bypassing the defective GLUT1 route entirely and restoring cerebral fuel supply, so
    the diet treats the mechanism rather than the symptom. Modified Atkins and other
    ketogenic formulations are used where the classic diet is not tolerated; management
    requires a specialist ketogenic team.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Ketogenic Diet
    term:
      id: NCIT:C173168
      label: Ketogenic Diet
  target_mechanisms:
  - target: Exertion- and Fasting-Unmasked Corticostriatal Energy Failure
    treatment_effect: INHIBITS
    description: >-
      Supplies ketone bodies as a GLUT1-independent cerebral fuel, replenishing the energy
      reserve that exertion and fasting deplete.
  target_phenotypes:
  - preferred_term: Paroxysmal dyskinesia
    term:
      id: HP:0007166
      label: Paroxysmal dyskinesia
  evidence:
  - reference: PMID:18577546
    reference_title: "Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three patients were successfully treated with a ketogenic diet.
    explanation: >-
      Direct clinical evidence of ketogenic-diet response in genetically confirmed
      SLC2A1-related PED.
  - reference: PMID:27351150
    reference_title: "Paroxysmal Exercise-induced Dyskinesias Caused by GLUT1 Deficiency Syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Proper identification of the paroxysmal events and early diagnosis is important
      since the disease is potentially treatable.
    explanation: >-
      Supports the clinical imperative of early recognition because the GLUT1 form is
      treatable. Marked PARTIAL because this source does not itself mention the ketogenic
      diet; it establishes treatability, not the specific therapy.
  - reference: PMID:20301603
    reference_title: "Glucose Transporter Type 1 Deficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Targeted therapy: Age-specific KDTs primarily provide a supplemental fuel, namely,
      ketone bodies, for brain energy metabolism.
    explanation: >-
      GeneReviews states the targeted mechanism of ketogenic dietary therapy curated in
      this treatment node.
  - reference: PMID:20301603
    reference_title: "Glucose Transporter Type 1 Deficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typically, the earlier the treatment the better the long-term clinical outcome.
    explanation: >-
      GeneReviews basis for the entry's emphasis that GLUT1 deficiency is the treatable
      cause that must not be missed and that delay costs outcome.
- name: Trigger Avoidance and Lifestyle Modification
  description: >-
    The mainstay in PNKD, where drug response is unreliable: systematic avoidance of
    coffee, tea, alcohol, sleep deprivation and, so far as possible, emotional stress.
    In PED, pacing of exertion and avoidance of fasting reduce attack burden alongside
    the ketogenic diet. Structured counselling about identified personal triggers,
    together with fall precautions and school or workplace accommodation, addresses much
    of the disability even when no drug is effective.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Lifestyle Therapy
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  notes: >-
    Term-binding note: MAXO:0000053 (therapeutic avoidance of environmental exposure) is
    the semantically exact term, but the TreatmentActionTerm dynamic enum is rooted at
    NCIT:C25218 and rejects MAXO identifiers (dismech issue #7524), so the NCIT
    Lifestyle Therapy term is used instead. Its NCIT definition explicitly covers
    "behavioral and dietary modifications, exercise, stress management, and addiction
    control", which matches the intervention curated here.
  evidence:
  - reference: PMID:15496428
    reference_title: "The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paroxysmal non-kinesigenic dyskinesia (PNKD) is characterized by spontaneous
      hyperkinetic attacks that are precipitated by alcohol, coffee, stress and fatigue.
    explanation: >-
      Identifies the modifiable precipitants that trigger avoidance targets. Marked
      PARTIAL because this establishes the triggers rather than trialling the avoidance
      strategy.
  - reference: PMID:20301400
    reference_title: "Familial Paroxysmal Nonkinesigenic Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of manifestations: Avoid triggers (e.g., caffeine, alcohol, excitement,
      stress, fatigue). Response to pharmacologic treatment is poor; clonazepam or
      diazepam can be effective in some individuals.
    explanation: >-
      GeneReviews management recommendation stating both that trigger avoidance is the
      first-line intervention and that pharmacological response in PNKD is poor, which is
      the entry's rationale for making avoidance the mainstay of this subtype.
- name: Genetic Counselling and Cascade Testing
  description: >-
    Molecular diagnosis changes management (sodium-channel blocker for PRRT2/TMEM151A,
    ketogenic diet for SLC2A1) and changes counselling. Because penetrance is incomplete
    and phenotype-dependent, an unaffected carrier does not refute pathogenicity, and
    families must be counselled that the same allele may present as infantile seizures in
    one member and kinesigenic dyskinesia in another. Cascade testing is appropriate once
    a familial variant is identified.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:22875091
    reference_title: "PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of PRRT2 as a major gene for the PKD-ICCA-BFIC spectrum allows
      better disease classification, molecular confirmation of the clinical diagnosis,
      and genetic testing and counseling.
    explanation: >-
      States the counselling and diagnostic-confirmation value of molecular diagnosis in
      this spectrum.
  - reference: PMID:20301400
    reference_title: "Familial Paroxysmal Nonkinesigenic Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Offspring of an affected individual have a 50% chance of inheriting the PNKD
      pathogenic variant. Once the PNKD pathogenic variant has been identified in an
      affected family member, prenatal and preimplantation genetic testing are possible.
    explanation: >-
      GeneReviews genetic-counselling content: the autosomal dominant 50% transmission
      risk and the reproductive options that cascade testing enables.
- name: Deep Brain Stimulation
  description: >-
    Reserved for severe, medication-refractory hyperkinetic disease, principally in the
    pleiotropic genotypes (ADCY5, GNAO1) rather than in classic PKD, PNKD or PED. Globus
    pallidus internus is the usual target. Evidence is limited to case reports and small
    series, so this is recorded as a practice-level option rather than an established
    standard.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Deep Brain Stimulation
    term:
      id: NCIT:C21024
      label: Deep Brain Stimulation
  notes: >-
    Deliberately curated without an efficacy evidence item because no controlled or
    cohort evidence for deep brain stimulation in paroxysmal dyskinesia was identified
    during curation; the supporting citation below only establishes the clinical severity
    that motivates considering it. Term-binding caveat: NCIT:C21024 is the only Deep
    Brain Stimulation term in NCIT and is reachable from NCIT:C25218, but its NCIT
    definition frames DBS as electroanalgesia for chronic pain. The intervention curated
    here is pallidal DBS for refractory hyperkinesia; the identifier is used for its
    label, not its definition.
  evidence:
  - reference: PMID:26537056
    reference_title: "ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In one family, a p.M1029K mutation in the C2 domain causes severe dystonia,
      hypotonia, and chorea.
    explanation: >-
      Documents the severe refractory ADCY5 phenotype in which deep brain stimulation is
      considered. Marked PARTIAL: this supports the clinical context, not efficacy.
diagnosis:
- name: Attack history with video documentation
  description: >-
    Diagnosis is fundamentally historical. Document attack phenomenology, preservation of
    awareness, the trigger, duration, frequency, body distribution, presence of a sensory
    aura, family history, the interictal examination, and treatment response. Because
    attacks are brief and almost never occur in clinic, smartphone video recorded by the
    family is the highest-yield single investigation and is what most often converts a
    suspected functional disorder into a recognised paroxysmal dyskinesia.
  presence: PRESENT
  evidence:
  - reference: PMID:15623687
    reference_title: "Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of idiopathic paroxysmal kinesigenic dyskinesia (PKD) can be made
      based on historical features.
    explanation: >-
      Establishes that the diagnosis rests on history rather than on an investigation.
- name: Interictal EEG and brain MRI
  description: >-
    Interictal EEG and brain MRI are typically normal in primary paroxysmal dyskinesia and
    are performed to exclude alternatives rather than to confirm the diagnosis. Video-EEG
    is specifically indicated where awareness is impaired, where attacks are sleep-related
    (to separate paroxysmal dyskinesia from sleep-related hypermotor epilepsy), or where
    the semiology is atypical. MRI is mandatory for adult onset, focal deficit,
    progressive course or any interictal abnormality.
  presence: ABSENT
  evidence:
  - reference: PMID:29276650
    reference_title: "Paroxysmal Kinesigenic Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy was suspected first; however, repeat investigations with
      electroencephalography and neuroimaging were normal.
    explanation: >-
      Illustrates the normal EEG and imaging that characterise primary paroxysmal
      dyskinesia and the epilepsy misdiagnosis that precedes recognition.
- name: Paired fasting CSF and blood glucose
  description: >-
    In any patient with exercise- or fasting-triggered attacks, or with paroxysmal
    dyskinesia plus epilepsy, measure CSF glucose with a simultaneous blood glucose after
    a fast and calculate the CSF:blood ratio. A ratio below about 0.60 in a normoglycaemic
    patient indicates GLUT1 deficiency and should be followed by SLC2A1 sequencing plus
    deletion/duplication analysis. This is the highest-value targeted test in the whole
    group because it identifies the ketogenic-diet-responsive cause.
  presence: PRESENT
  evidence:
  - reference: PMID:18577546
    reference_title: "Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients
    explanation: >-
      Provides the diagnostic threshold and the observed patient values.
  - reference: PMID:20301603
    reference_title: "Glucose Transporter Type 1 Deficiency Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Glut1DS is established in a proband with suggestive clinical
      findings, hypoglycorrhachia documented by lumbar puncture, and a (usually)
      heterozygous pathogenic variant in SLC2A1 identified by molecular genetic testing.
    explanation: >-
      GeneReviews diagnostic algorithm: hypoglycorrhachia on lumbar puncture followed by
      SLC2A1 molecular testing, which is the pathway curated here.
- name: Multigene panel or exome sequencing
  description: >-
    Because treatment is genotype-directed rather than phenomenology-directed, molecular
    testing is not merely confirmatory. A paroxysmal movement disorder panel should
    include at minimum PRRT2, TMEM151A, PNKD, SLC2A1, KCNMA1, ADCY5, GNAO1, SCN8A, KCNA1,
    CACNA1A and ATP1A3, with deletion/duplication analysis covering 16p11.2 and SLC2A1.
    Trio exome or genome sequencing is appropriate for panel-negative or developmentally
    complex cases. Reported diagnostic yields vary widely with ascertainment.
  presence: PRESENT
  evidence:
  - reference: PMID:26598494
    reference_title: "The clinical and genetic heterogeneity of paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with paroxysmal movement disorders 68 families had mutations (47%) out
      of 145 patients.
    explanation: >-
      Quantifies the diagnostic yield of screening the three principal genes across a
      large paroxysmal dyskinesia cohort.
definitions:
- name: Bruno diagnostic criteria for idiopathic paroxysmal kinesigenic dyskinesia
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    The consensus clinical criteria for idiopathic PKD, derived from review of 121
    affected individuals: an identified kinesigenic trigger (sudden movements); short
    attack duration, under one minute; no loss of consciousness and no pain during
    attacks; responsiveness to antiepileptic drugs; exclusion of other organic disease,
    with a normal neurological examination; and age at onset between 1 and 20 years where
    there is no family history (applied less stringently in familial cases).
  scope: >-
    Clinical recognition of idiopathic PKD; the criteria were designed to homogenise
    cohorts for gene discovery and remain the reference case definition.
  inclusion_criteria:
  - preferred_term: Identified kinesigenic trigger (sudden voluntary movement)
    term:
      id: HP:0025228
      label: Triggered by sudden movement
  - preferred_term: Attack duration under one minute
  - preferred_term: Preserved consciousness and absence of pain during attacks
  - preferred_term: Responsiveness to antiepileptic drugs
  - preferred_term: Age at onset between 1 and 20 years when there is no family history
  exclusion_criteria:
  - preferred_term: Other organic disease accounting for the attacks
  notes: >-
    The authors themselves note that these criteria are not universally satisfied: a clear
    kinesigenic trigger was not elicited in every case, antiepileptic response was not
    universal, and some infants had attacks during sleep. A separate infantile-onset group
    with different characteristics was identified.
  evidence:
  - reference: PMID:15623687
    reference_title: "Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The authors propose the following diagnostic criteria for idiopathic PKD based on
      this phenotype: identified trigger for the attacks (sudden movements), short
      duration of attacks (<1 minute), lack of loss of consciousness or pain during
      attacks, antiepileptic drug responsiveness, exclusion of other organic diseases, and
      age at onset between 1 and 20 years if there is no family history
    explanation: >-
      Verbatim statement of the criteria set curated here.
  - reference: PMID:15623687
    reference_title: "Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A clear kinesigenic trigger was not elicited in all cases, antiepileptic response
      was not universal, and some infants had attacks while asleep.
    explanation: >-
      Records the authors' own caveats limiting the sensitivity of the criteria.
differential_diagnoses:
- name: Focal epilepsy, including sleep-related hypermotor epilepsy
  disease_term:
    preferred_term: sleep-related hypermotor epilepsy
    term:
      id: MONDO:0100631
      label: sleep-related hypermotor epilepsy
  description: >-
    The single most important and most frequent misdiagnosis in both directions. PKD is
    often misdiagnosed clinically as epilepsy, while most historically diagnosed
    paroxysmal hypnogenic dyskinesia is in fact sleep-related hypermotor epilepsy (SHE),
    formerly nocturnal frontal lobe epilepsy. Curated as an entry-level differential
    precisely because the boundary defines the scope of this entry.
  distinguishing_features:
  - "Paroxysmal dyskinesia: consciousness is fully preserved with no postictal confusion"
  - "Paroxysmal dyskinesia: stereotyped external trigger (sudden movement, caffeine, exertion) with normal ictal and interictal EEG"
  - "Paroxysmal dyskinesia: dystonic or choreic semiology rather than tonic-hypermotor"
  - "SHE: attacks arise out of sleep in clusters, are hypermotor or asymmetric-tonic, may show ictal fear or vocalisation, and may secondarily generalise"
  - "SHE: video-EEG documentation is the definitive discriminator"
  - "Caveat: some short-attack hypnogenic cases do carry PRRT2 variants, so the boundary is probabilistic"
  evidence:
  - reference: PMID:22101681
    reference_title: "Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal movement
      disorder and is often misdiagnosed clinically as epilepsy.
    explanation: >-
      Documents epilepsy as the commonest misdiagnosis of PKD.
  - reference: PMID:27164717
    reference_title: "Definition and diagnostic criteria of sleep-related hypermotor epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnostic criteria were developed with 3 levels of certainty: witnessed (possible)
      SHE, video-documented (clinical) SHE, and video-EEG-documented (confirmed) SHE.
    explanation: >-
      Provides the graded video-EEG-anchored criteria that separate SHE from a nocturnal
      dyskinesia.
- name: Episodic ataxia type 1
  disease_term:
    preferred_term: episodic ataxia type 1
    term:
      id: MONDO:0008047
      label: episodic ataxia type 1
  description: >-
    KCNA1 (Kv1.1) channelopathy producing brief attacks that, like PKD, are triggered by
    startle or sudden movement and last seconds to minutes; both are treated with
    antiepileptic drugs. Curated in dismech as Episodic_Ataxia.
  distinguishing_features:
  - EA1 attacks are cerebellar (ataxia, dysarthria, tremor) rather than dyskinetic
  - "Interictal examination in EA1 is NOT normal: continuous myokymia (fine muscle rippling, often periorbital or in the hands) is present between attacks"
  - KCNA1 variants have been reported occasionally in PKD cohorts, so genetic overlap exists
  evidence:
  - reference: PMID:26598494
    reference_title: "The clinical and genetic heterogeneity of paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We analysed all three genes (the whole coding regions of SLC2A1 and PRRT2 and exons
      one and two of PNKD) in a series of 145 families with paroxysmal dyskinesias as well
      as in a series of 53 patients with familial episodic ataxia and hemiplegic migraine
    explanation: >-
      Shows that episodic ataxia is routinely screened alongside paroxysmal dyskinesia
      because the two groups are clinically and genetically adjacent.
- name: Episodic ataxia type 2
  disease_term:
    preferred_term: episodic ataxia type 2
    term:
      id: MONDO:0007163
      label: episodic ataxia type 2
  description: >-
    CACNA1A (Cav2.1) channelopathy with attacks of ataxia and vertigo triggered by stress
    or exertion — the same trigger profile as PNKD and PED respectively.
  distinguishing_features:
  - EA2 attacks last hours and are cerebellar rather than hyperkinetic
  - Interictal nystagmus is usually present in EA2
  - EA2 attacks respond to acetazolamide rather than to carbamazepine or the ketogenic diet
  - Progressive interictal cerebellar signs develop in many EA2 patients, which does not occur in primary paroxysmal dyskinesia
  evidence:
  - reference: PMID:32443735
    reference_title: "Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal
      dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement
      disorders, while attacks of cerebellar dysfunction are the hallmark of episodic
      ataxias (EAs).
    explanation: >-
      States the phenomenological criterion (hyperkinetic versus cerebellar) that
      separates the two groups.
- name: Functional (psychogenic) movement disorder
  disease_term:
    preferred_term: conversion disorder
    term:
      id: MONDO:0002104
      label: conversion disorder
  description: >-
    Historically the default label for paroxysmal dyskinesia, and still a frequent
    misdiagnosis, because attacks are unwitnessed, bizarre-looking, emotionally
    precipitated, and accompanied by entirely normal examination and investigations.
    Getting this wrong denies patients a treatment that often abolishes the disorder
    outright.
  distinguishing_features:
  - "Favours paroxysmal dyskinesia: a highly consistent and specific trigger and a stereotyped sensory aura in the limb about to be involved"
  - "Favours paroxysmal dyskinesia: stereotyped short attack duration, positive family history, and dramatic response to low-dose carbamazepine"
  - "Favours a functional disorder: variable and distractible phenomenology, entrainment, incongruent triggers, and absence of a consistent aura"
  - "Trap: normal EEG and MRI do NOT favour a functional diagnosis, since they are also normal in primary paroxysmal dyskinesia"
  evidence:
  - reference: PMID:29276650
    reference_title: "Paroxysmal Kinesigenic Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient's presentation was previously misinterpreted as Tourette's syndrome
      despite the absence of vocal tics.
    explanation: >-
      A worked example of the diagnostic-delay problem: a PKD patient carried an incorrect
      hyperkinetic-disorder label for years before the correct diagnosis and an effective
      treatment.
- name: Primary (non-paroxysmal) dystonia
  disease_term:
    preferred_term: dystonic disorder
    term:
      id: MONDO:0003441
      label: dystonic disorder
  description: >-
    Isolated genetic and idiopathic dystonias (including dopa-responsive dystonia and
    myoclonus-dystonia, both curated in dismech) share the dystonic phenomenology but not
    the episodic architecture.
  distinguishing_features:
  - Primary dystonia is continuous or task-specific and persists between episodes, whereas paroxysmal dyskinesia has a completely normal interictal examination
  - Dopa-responsive dystonia shows marked diurnal fluctuation that can be mistaken for paroxysmality, but responds to levodopa
  - Dopa-responsive dystonia worsens through the day rather than being movement-triggered, and does not remit completely between episodes
  evidence:
  - reference: PMID:30242089
    reference_title: "Unravelling of the paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we review the increasing spectrum of genetic conditions, as well as of other
      non-genetic disorders, that might present with PxD, provide criteria for case
      definition and propose a diagnostic workup to reach a definitive diagnosis, on which
      treatment is heavily dependent.
    explanation: >-
      Supports the need for explicit case definition to separate paroxysmal from
      continuous movement disorders, and the treatment consequences of getting it right.
- name: Hypoparathyroidism with basal ganglia calcification
  disease_term:
    preferred_term: hypoparathyroidism
    term:
      id: MONDO:0001220
      label: hypoparathyroidism
  description: >-
    A classic secondary cause: hypocalcaemia with basal-ganglia calcification can produce
    paroxysmal kinesigenic or exertion-induced dyskinesia that is phenotypically
    indistinguishable from the primary forms and remits on correction of calcium.
  distinguishing_features:
  - Later or adult onset with absent family history
  - Associated tetany, paraesthesia, cataract or seizures
  - Low serum calcium with raised phosphate, and bilateral basal-ganglia calcification on CT
  - Treatment is calcium and vitamin D replacement rather than a sodium-channel blocker, so serum calcium should be checked in any atypical case
  evidence:
  - reference: PMID:32443735
    reference_title: "Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From an etiological point of view, both primary (genetic) and secondary (acquired)
      causes of PMDs are known.
    explanation: >-
      Supports the existence of acquired and metabolic causes requiring exclusion. Marked
      PARTIAL because this citation establishes the category rather than the specific
      hypoparathyroidism association.
- name: Multiple sclerosis with paroxysmal tonic spasms
  disease_term:
    preferred_term: multiple sclerosis
    term:
      id: MONDO:0005301
      label: multiple sclerosis
  description: >-
    Demyelinating lesions, characteristically in the posterior limb of the internal
    capsule or brainstem, produce brief stereotyped painful tonic spasms often triggered
    by movement — the closest acquired mimic of PKD, and likewise
    carbamazepine-responsive.
  distinguishing_features:
  - Attacks are typically painful, and pain is an exclusion criterion for idiopathic PKD
  - Onset is in adulthood with no family history
  - Other neurological signs or a prior demyelinating episode are usually present
  - MRI shows demyelinating lesions rather than being normal
  evidence:
  - reference: PMID:10323309
    reference_title: "The paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tonic spasms in multiple sclerosis and Sandiffers syndrome producing intermittent
      torticollis in infants and children are other paroxysmal movement disorders.
    explanation: >-
      Places multiple sclerosis tonic spasms within the paroxysmal movement disorder
      differential.
clinical_trials:
- name: NCT04023656
  status: UNKNOWN
  description: >-
    Korean prospective observational registry following adults with paroxysmal kinesigenic
    choreoathetosis to establish long-term prognosis (remission, degree of improvement,
    worsening, and medication requirement). Relevant because the natural history of PKD
    into adulthood — the reported decline in attack frequency in the third decade — rests
    almost entirely on retrospective series.
  target_phenotypes:
  - preferred_term: Paroxysmal dyskinesia
    term:
      id: HP:0007166
      label: Paroxysmal dyskinesia
  evidence:
  - reference: clinicaltrials:NCT04023656
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The aim of this study is to assess the prognosis of paroxysmal kinesigenic
      choreoathetosis (PKC) in Korean.
    explanation: >-
      Confirms the registry's prognostic objective in PKD.
- name: NCT06701851
  status: RECRUITING
  description: >-
    French mechanistic imaging study (ancillary to AMEDYST) using real-time functional
    imaging in PRRT2 patients who can voluntarily provoke and control their attacks, to
    test the striatum-cerebellum reciprocal-influence model of the attack. Directly
    interrogates the cerebellar-origin hypothesis recorded in this entry's
    mechanistic_hypotheses block. It is mechanistic, not therapeutic.
  target_phenotypes:
  - preferred_term: Paroxysmal dyskinesia
    term:
      id: HP:0007166
      label: Paroxysmal dyskinesia
  evidence:
  - reference: clinicaltrials:NCT06701851
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the pathological role of the reciprocal influence between the striatum and the
      cerebellum in paroxysmal dyskinesia episodes
    explanation: >-
      States the striatum-cerebellum question that this trial is designed to resolve,
      which is the open question recorded in mechanistic_hypotheses.
mechanistic_hypotheses:
- hypothesis_group_id: cerebellar_origin_of_pkd
  hypothesis_label: Cerebellar rather than basal-ganglia origin of the PKD attack
  status: EMERGING
  description: >-
    The traditional assumption that paroxysmal dyskinesia is a basal-ganglia disorder is
    under revision for PKD specifically. Work in PRRT2-deficient models points to the
    cerebellum as the pivotal generator, with dyskinetic episodes tightly coupled to
    spreading depolarization in cerebellar cortex, while the contribution of cortex,
    thalamus and striatum is comparatively unresolved. The competing and complementary
    view remains that the basal-ganglia-thalamo-cortical loop generates the motor output.
    This matters practically because it predicts different neuromodulation targets.
  applies_to_subtypes:
  - PKD
  evidence:
  - reference: PMID:38091244
    reference_title: "Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Whereas, in PKD, other than the cerebellum, the role of the cerebrum including the
      cortex and thalamus needs to be further investigated.
    explanation: >-
      States both the cerebellar-primacy position and the explicit acknowledgement that
      the cerebral contribution is unresolved.
discussions:
- discussion_id: phd_nosology
  kind: CONTROVERSY
  prompt: >-
    Is paroxysmal hypnogenic dyskinesia (PHD) a genuine fourth subtype of paroxysmal
    dyskinesia, or is it entirely subsumed by sleep-related hypermotor epilepsy?
  status: OPEN
  attaches_to:
  - "pathophysiology#Trigger-Dependent Breach of the Motor Network Attack Threshold"
  rationale: >-
    The dominant position, formalised by the 2016 consensus that renamed nocturnal frontal
    lobe epilepsy as sleep-related hypermotor epilepsy, is that sleep-related dyskinetic
    attacks are epileptic seizures with hypermotor semiology. This entry follows that
    position and does not curate PHD as a mechanistically distinct dyskinesia. However, a
    2016 screening study of 11 PHD patients found PRRT2 variants in 2 patients with
    typical (short-attack) PHD and no variants in any of the epilepsy genes screened, and
    its authors concluded the opposite — that PHD is a subtype of paroxysmal dyskinesia
    rather than NFLE. The honest reading is that the PHD label historically pooled two
    populations: a majority with genetic focal epilepsy and a minority with short-attack
    PRRT2-related dyskinesia occurring in sleep. Video-EEG is the discriminator, and the
    label itself should be retired in favour of the specific diagnosis.
  proposed_experiments:
  - experiment_id: phd_video_eeg_genotype_cohort
    name: Prospective video-EEG plus broad panel sequencing in sleep-related paroxysmal motor attacks
    description: >-
      Recruit an unselected cohort of patients with sleep-related paroxysmal motor
      attacks, obtain video-EEG on all, and sequence PRRT2, TMEM151A, CHRNA4, CHRNB2,
      CHRNA2, KCNT1 and DEPDC5. Report the proportion with an ictal epileptiform
      correlate, stratified by genotype and by attack duration.
    decision_criterion: >-
      If PRRT2-positive sleep-related cases consistently lack an ictal epileptiform
      correlate, a residual non-epileptic PHD population is supported; if they show one,
      PHD is fully subsumed by SHE.
  - experiment_id: phd_prrt2_treatment_profile
    name: Treatment-response and semiology profiling of PRRT2-positive sleep-related attacks
    description: >-
      Determine whether PRRT2-positive sleep-related cases show the
      carbamazepine-responsive, aura-preceded, short-attack profile of waking PKD or the
      clustered hypermotor profile of SHE.
  evidence:
  - reference: PMID:27123484
    reference_title: "Paroxysmal hypnogenic dyskinesia is associated with mutations in the PRRT2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study identified PRRT2 mutations in PHD, extending the phenotypic
      spectrum of PRRT2 and supporting the classification of PHD as a subtype of paroxysmal
      dyskinesia but not NFLE.
    explanation: >-
      The minority position, with direct genetic evidence, that must be represented rather
      than suppressed.
  - reference: PMID:27164717
    reference_title: "Definition and diagnostic criteria of sleep-related hypermotor epilepsy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It was recommended that the name be changed to sleep-related hypermotor epilepsy
      (SHE), reflecting evidence that the attacks are associated with sleep rather than
      time of day, the seizures may arise from extrafrontal sites, and the motor aspects of
      the seizures are characteristic.
    explanation: >-
      The consensus position that sleep-related hypermotor attacks are epileptic; recorded
      as REFUTE with respect to the proposition that PHD is a distinct dyskinesia.
- discussion_id: pnkd_imsn_human_translation
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Does the striatal indirect-pathway (iMSN) hypoactivity that causes dyskinetic attacks
    in PNKD mice actually occur in human PNKD?
  status: OPEN
  attaches_to:
  - "pathophysiology#Striatal Indirect-Pathway Medium Spiny Neuron Hypoactivity"
  rationale: >-
    The iMSN mechanism is unusually strong causal evidence — optically identified
    single-unit recordings during spontaneous attacks, chemogenetic sufficiency, and an
    identified endocannabinoid synaptic substrate — but all of it is mouse. It also runs
    against the classical model in which dyskinesia arises from direct-pathway
    hyperactivity, so it is not simply a confirmation of expectation. There is no human
    biomarker, imaging correlate or post-mortem finding that indexes iMSN firing in PNKD
    patients, and no human tissue or iPSC-derived striatal system has tested it. Until
    that gap is closed the node should be read as a well-supported model-organism
    mechanism whose translational validity is untested, not as established human
    pathophysiology.
  proposed_experiments:
  - experiment_id: pnkd_cb1_pharmacology_trial
    name: Endocannabinoid-system pharmacology in human PNKD
    description: >-
      Test whether CB1-directed pharmacology modifies attack frequency in patients with
      genetically confirmed PNKD, as the mouse endocannabinoid mechanism predicts.
    decision_criterion: >-
      A reduction in attack frequency with CB1 antagonism would be the first human
      evidence that the mouse endocannabinoid-iMSN mechanism operates in patients.
  - experiment_id: pnkd_ipsc_striatal_model
    name: Patient-derived iPSC striatal system carrying PNKD p.Ala7Val or p.Ala9Val
    description: >-
      Build iPSC-derived striatal organoid or corticostriatal co-culture systems from
      PNKD patients and assay endocannabinoid-dependent suppression of glutamatergic
      input onto D2 or indirect-pathway neurons.
  - experiment_id: pnkd_attack_locked_imaging
    name: Attack-locked functional imaging in PNKD patients
    description: >-
      Use task-based or attack-locked functional imaging in PNKD patients to seek an
      indirect-pathway signature during provoked attacks.
  evidence:
  - reference: PMID:35165171
    reference_title: "Striatal Indirect Pathway Dysfunction Underlies Motor Deficits in a Mouse Model of Paroxysmal Dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data show that striatal iMSN dysfunction contributes to the etiology of
      dyskinesia in PNKD, and suggest that indirect pathway hypoactivity may be a key
      mechanism for the generation of involuntary movements in other disorders.
    explanation: >-
      The mouse claim whose human validity is the open question. The authors themselves
      frame the generalisation as a suggestion.
- discussion_id: trigger_genotype_mapping_breakdown
  kind: OPEN_QUESTION
  prompt: >-
    How far can the trigger-based classification (PKD, PNKD, PED) still be trusted as a
    guide to genotype and therefore to treatment?
  status: OPEN
  attaches_to:
  - "pathophysiology#Trigger-Dependent Breach of the Motor Network Attack Threshold"
  rationale: >-
    The trigger-to-gene-to-treatment mapping is the practical value of this entry, and it
    is under strain. SLC2A1 variants have been found in patients phenotyped as PKD and as
    PNKD, not only PED; PRRT2 variants appear in hemiplegic migraine and episodic ataxia;
    ADCY5 alone can produce kinesigenic, exertional, non-kinesigenic and nocturnal attacks.
    Whether the correct response is to keep trigger-based syndromes as a first-pass
    heuristic that gates a broad panel, or to move to genotype-first testing in all cases,
    is unresolved and has direct cost-effectiveness consequences.
  evidence:
  - reference: PMID:26598494
    reference_title: "The clinical and genetic heterogeneity of paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SLC2A1 mutations were associated with variable phenotypes including paroxysmal
      kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, episodic ataxia and
      myotonia
    explanation: >-
      Direct demonstration that one gene crosses all three trigger-defined syndromes,
      undermining a strict one-syndrome-one-gene mapping.
  - reference: PMID:30242089
    reference_title: "Unravelling of the paroxysmal dyskinesias."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classically, PxD have been categorised according to their triggers and duration of
      the attacks, but increasing evidence suggests that there is a certain degree of
      clinical and genetic overlap and challenges the concept that one phenotype is
      attributable to one single aetiology.
    explanation: >-
      States the challenge to trigger-based nosology explicitly.
- discussion_id: diagnostic_delay
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the actual magnitude of diagnostic delay in paroxysmal dyskinesia, and how much
    of it is attributable to misdiagnosis as epilepsy, tics, or a functional disorder?
  status: OPEN
  attaches_to:
  - "pathophysiology#Trigger-Dependent Breach of the Motor Network Attack Threshold"
  rationale: >-
    Diagnostic delay in this group is repeatedly described qualitatively — PKD is often
    misdiagnosed clinically as epilepsy, individual patients carry Tourette or functional
    labels for years, and GLUT1 deficiency may be missed entirely despite being
    diet-responsive — but no cohort study quantifies the interval from first attack to
    correct diagnosis, its distribution across PKD, PNKD and PED, or the proportion of
    that interval attributable to each incorrect label. The gap matters because the delay
    is the principal preventable harm in an otherwise treatable and non-progressive group
    of disorders, and because a quantified delay is what would justify including
    paroxysmal dyskinesia in movement-disorder and epilepsy diagnostic pathways.
  proposed_experiments:
  - experiment_id: pxd_diagnostic_delay_cohort
    name: Multi-centre retrospective diagnostic-delay cohort
    description: >-
      Measure time from first attack to molecular or clinical diagnosis, stratified by
      subtype and by whether the patient first presented to epilepsy, movement-disorder,
      paediatric or psychiatric services, and record every incorrect label applied in the
      interval.
  - experiment_id: glut1_delayed_keto_outcome
    name: Outcome consequences of delayed ketogenic therapy in GLUT1-related PED
    description: >-
      Quantify the subset of GLUT1-related PED in which ketogenic therapy was started more
      than five years after symptom onset, and test whether delay correlates with residual
      cognitive or motor outcome.
  evidence:
  - reference: PMID:22101681
    reference_title: "Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal movement
      disorder and is often misdiagnosed clinically as epilepsy.
    explanation: >-
      Establishes that misdiagnosis is common, which is precisely the qualitative statement
      that has never been quantified.
animal_models:
- species: Mus musculus
  genotype: PNKD transgenic (mutant PNKD/MR-1)
  description: >-
    Transgenic mouse expressing the mutant PNKD/MR-1 protein. Attacks resembling human
    PNKD are provoked by caffeine and alcohol — the same triggers as in patients — which
    makes it an unusually faithful trigger-level model and the system in which the
    indirect-pathway mechanism was established.
  genes:
  - preferred_term: PNKD
    term:
      id: hgnc:9153
      label: PNKD
  evidence:
  - reference: PMID:35165171
    reference_title: "Striatal Indirect Pathway Dysfunction Underlies Motor Deficits in a Mouse Model of Paroxysmal Dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In this model, as in the human disorder PNKD, animals experience dyskinetic attacks
      in response to caffeine or alcohol.
    explanation: >-
      Documents trigger-level face validity of the PNKD mouse.
- species: Mus musculus
  genotype: Kcnma1 D434G knock-in (BK-D434G)
  description: >-
    Knock-in mouse carrying the human KCNMA1 p.Asp434Gly gain-of-function allele. It
    reproduces both arms of the human PNKD3 phenotype (absence epilepsy and dyskinesia),
    shows cortical pyramidal and Purkinje cell hyperexcitability, and responds to the BK
    blocker paxilline, providing pharmacological confirmation of the direction of effect.
  genes:
  - preferred_term: KCNMA1
    term:
      id: hgnc:6284
      label: KCNMA1
  evidence:
  - reference: PMID:35286197
    reference_title: "Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The BK-D434G mice manifest the clinical features of absence epilepsy and exhibit
      severe motor deficits and dyskinesia-like behaviors.
    explanation: >-
      Establishes construct and face validity of the KCNMA1 gain-of-function model.

📚

References & Deep Research

References

5

PMID:20301400

Familial Paroxysmal Nonkinesigenic Dyskinesia.

No top-level findings curated for this source.

PMID:20301603

Glucose Transporter Type 1 Deficiency Syndrome.

No top-level findings curated for this source.

PMID:30242089

Unravelling of the paroxysmal dyskinesias.

No top-level findings curated for this source.

PMID:26598494

The clinical and genetic heterogeneity of paroxysmal dyskinesias.

No top-level findings curated for this source.

PMID:38091244

Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 37 citations 2026-08-01T07:39:50.064356

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Paroxysmal Dyskinesia
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Paroxysmal Dyskinesia covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Paroxysmal Dyskinesia: comprehensive disease-characteristics report

Scope note. Paroxysmal dyskinesia (PD/PxD) is an umbrella phenotype rather than one molecular disease. The classic primary forms are paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED); older classifications also include paroxysmal hypnogenic dyskinesia (PHD). Accordingly, identifiers, inheritance, mechanisms, and treatment should be recorded at both umbrella and gene-defined subtype levels.

1. Disease information

PDs are rare hyperkinetic disorders characterized by recurrent, abrupt attacks of dystonia, chorea, athetosis, ballism, or combinations thereof, generally with preserved consciousness and a normal interictal examination. Classification is primarily by trigger: sudden voluntary movement/startle in PKD; alcohol, caffeine, stress, fatigue, or no clear trigger in PNKD; sustained exercise in PED; and sleep-related attacks in PHD. A recent systematic review states that PDs are “rare, episodic movement disorders characterized by sudden and involuntary hyperkinetic motor events.” (harvey2021paroxysmalmovementdisorders pages 1-2, pisano2025paroxysmaldyskinesiasin pages 1-2, xu2024paroxysmalkinesigenicdyskinesia pages 1-3)

Suggested identifiers and terminology

MONDO: use the MONDO umbrella concept for paroxysmal dyskinesia if available in the implementation’s current MONDO release, but retain separate descendant records for PKD, PNKD, and GLUT1-related PED. A stable umbrella MONDO identifier was not verified in the retrieved literature.
OMIM: subtype-level records are preferable; examples include PRRT2-associated PKD/PKD with infantile convulsions, PNKD-associated PNKD, KCNMA1-associated PNKD3, and SLC2A1/GLUT1 deficiency. OMIM gene IDs directly supported in retrieved text include PNKD, MIM 609023, and SLC2A1, MIM 138140. (harvey2021paroxysmalmovementdisorders pages 2-3, harvey2021paroxysmalmovementdisorders pages 3-4)
MeSH: Dyskinesias (D020820), with Chorea (D002819) and Movement Disorders as related concepts. (NCT06701851 chunk 1)
ICD: no single highly specific ICD-10 disease code covers all inherited PDs; coding commonly falls under G24.8, other dystonia, or another movement-disorder code plus the molecular syndrome. ICD-11 should likewise use the most specific dystonia/movement-disorder entity available and append genetic etiology.
Synonyms: paroxysmal dyskinesias; episodic dyskinesia; paroxysmal movement disorder; PKD/paroxysmal kinesigenic choreoathetosis; PNKD/paroxysmal dystonic choreoathetosis; PED/paroxysmal exertion-induced dyskinesia.
Source granularity: the evidence is predominantly aggregated disease-level literature, family studies, case series, systematic reviews, and registries—not routinely extracted individual EHR data.

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factors

Primary PD is predominantly genetic. Core causes are PRRT2 and TMEM151A for PKD, PNKD for classic PNKD, KCNMA1 for PNKD3, and SLC2A1 for PED/GLUT1 deficiency. Additional established or reported causes include ADCY5, GNAO1, SCN8A, KCNA1, CACNA1A, ATP1A3, RHOBTB2, TBC1D24, PDE2A, DEPDC5, FGF14, GCH1, PARK2, ECHS1, PDHA1/PDHX/DLAT, GLDC, BCKD-complex genes, SLC20A2, and PIGN. These latter disorders often include epilepsy, developmental impairment, persistent movement disorder, metabolic disease, or structural abnormalities rather than isolated PD. (pisano2025paroxysmaldyskinesiasin pages 8-11, harvey2021paroxysmalmovementdisorders pages 2-3, harvey2021paroxysmalmovementdisorders pages 3-4)

Secondary PD can follow demyelination, stroke, trauma, infection, autoimmune disease, metabolic disturbance, structural brain lesions, or medication/toxin exposure. Adult onset, inconsistent triggers, changing phenomenology, or abnormal interictal findings should therefore prompt evaluation for secondary or functional disorders. (gusmao2019paroxysmalmovementdisorders pages 31-34)

Risk factors

Family history/causal genotype: strongest risk factor for primary disease.
Sex: PKD has a reported male:female ratio of approximately 2–4:1. Why male expression is greater remains unresolved. (xu2024paroxysmalkinesigenicdyskinesia pages 9-10, xu2024paroxysmalkinesigenicdyskinesia pages 1-3)
Age: onset is usually childhood or adolescence, although infancy and adult onset occur.
Provoking exposures: sudden movement/startle in PKD; caffeine, alcohol, emotional stress, sleep deprivation, and fatigue in PNKD; exercise and sometimes fasting in SLC2A1-related PED; fever or illness in selected channelopathies/metabolic disorders. These are attack triggers, not generally causes of the inherited disease. (harvey2021paroxysmalmovementdisorders pages 2-3, harvey2021paroxysmalmovementdisorders pages 3-4)

Protective factors

No validated germline “protective variants” are established. Apparent environmental protection is mainly avoidance of individual triggers, adequate sleep, regular meals/avoidance of fasting in GLUT1 deficiency, and adherence to genotype-directed treatment. Evidence for exercise, smoking, alcohol, or nutritional factors as modifiers of disease acquisition is absent; alcohol and caffeine can instead provoke PNKD.

Gene–environment interaction

PD provides a strong trigger-threshold model: a pathogenic variant creates latent neuronal-network instability, while movement, stress, stimulants, alcohol, sleep loss, exercise, or fasting acutely pushes the network beyond the attack threshold. Incomplete penetrance—approximately 74.5–77.6% for PRRT2, 53.8% for TMEM151A, and approximately 95% for recurrent PNKD variants—implies contributions from background genotype, development, epigenetics, and exposures, although specific human modifier genes have not been validated. (xu2024paroxysmalkinesigenicdyskinesia pages 3-5, harvey2021paroxysmalmovementdisorders pages 3-4, harvey2021paroxysmalmovementdisorders pages 11-12)

3. Phenotypes

Phenotype	Characteristics and frequency	Suggested HPO terms
Paroxysmal dystonia/chorea	Core episodic manifestation; consciousness normally preserved. In PRRT2-PKD, attacks comprised dystonia 17.6%, chorea 15.2%, and both 67.1% in summarized cohorts. (harvey2021paroxysmalmovementdisorders pages 1-2, harvey2021paroxysmalmovementdisorders pages 2-3)	Paroxysmal dystonia; Chorea HP:0002072; Athetosis HP:0002305; Ballism
PKD attacks	Triggered by sudden voluntary movement or startle; usually <1 minute, often daily; onset mean 9.9 years, range 1–40; frequently declines in adulthood. Sensory aura may occur. (xu2024paroxysmalkinesigenicdyskinesia pages 1-3, harvey2021paroxysmalmovementdisorders pages 2-3)	Kinesigenic dyskinesia; Childhood onset HP:0011463; Episodic course
PNKD attacks	Stress, caffeine, alcohol, tea, fatigue, or emotion; usually 10 minutes–1 hour, occasionally up to 12 hours; often only a few attacks/year; mean onset about 5 years, range 6 months–35 years. (harvey2021paroxysmalmovementdisorders pages 3-4)	Non-kinesigenic dyskinesia; Dystonia HP:0001332
PED	Exercise/fatigue-provoked, often leg-predominant dystonia/choreoathetosis; SLC2A1 cases may have epilepsy, intellectual disability, spasticity, microcephaly, or ataxia. (harvey2021paroxysmalmovementdisorders pages 3-4, suls2008paroxysmalexerciseinduceddyskinesia pages 1-2)	Exercise-induced dystonia; Gait disturbance HP:0001288; Spasticity HP:0001257
Epilepsy	Infantile seizures occur in approximately 30% of PRRT2-associated PKD; absence epilepsy is prominent in KCNMA1-D434G and SLC2A1 disease. In one D434G family, 9/16 had absence epilepsy, 12/16 PNKD, and 5/16 both. (harvey2021paroxysmalmovementdisorders pages 2-3, dong2022neuronalmechanismof pages 1-2)	Seizure HP:0001250; Absence seizure HP:0002121; Infantile-onset seizure
Neurodevelopmental manifestations	Usually absent in isolated heterozygous PRRT2/PNKD disease, but intellectual disability, developmental delay, hypotonia, or persistent dyskinesia occur with biallelic PRRT2, 16p11.2 deletion, GNAO1, ADCY5, SCN8A, RHOBTB2, PIGN, and metabolic etiologies. (xu2024paroxysmalkinesigenicdyskinesia pages 3-5, harvey2021paroxysmalmovementdisorders pages 3-4)	Global developmental delay HP:0001263; Intellectual disability HP:0001249; Hypotonia HP:0001252
Interictal state	Often neurologically normal in classic primary PD; abnormal interictal ataxia, myokymia, spasticity, or persistent chorea suggests a pleiotropic gene or secondary disease. (harvey2021paroxysmalmovementdisorders pages 1-2, gusmao2019paroxysmalmovementdisorders pages 31-34)	Normal interictal examination; Ataxia HP:0001251; Myokymia HP:0002411

In a 2025 pediatric systematic review of 112 studies/605 patients, PKD represented 343/604 (56.8%), PNKD 142/604 (23.5%), and PED 119/604 (19.7%); among 476 with reported sex, 63.4% were male. Mean onset was 5.99 years, median 5 years, range 10 days–17 years. These figures describe the published pediatric literature, not population prevalence, and may be affected by referral/publication bias. (pisano2025paroxysmaldyskinesiasin pages 4-6)

Quality of life. Attacks can impair walking, school/work attendance, driving, sports, and social participation, and falls can cause injury. Anticipatory anxiety and trigger avoidance may be substantial even when examination is normal. Standardized EQ-5D/SF-36 data specific to classic PD are sparse; the recent review notes clinically important nonmotor and quality-of-life effects but does not provide a pooled instrument score. (pisano2025paroxysmaldyskinesiasin pages 11-12, harvey2021paroxysmalmovementdisorders pages 11-12)

4. Genetic and molecular information

Clinical entity / trigger	Principal gene(s) and inheritance	Typical attack / onset features	Mechanism	Practical treatment
PKD; sudden voluntary movement or startle	PRRT2 (usually AD, incomplete penetrance ~74.5%–77.6%; recurrent c.649dupC common, up to ~80% of PRRT2 mutation carriers), TMEM151A (AD, lower penetrance ~53.8%)	Brief recurrent dystonia/choreoathetosis; attacks usually <1 min; onset typically childhood/early adolescence; male:female about 2–4:1; PKD prevalence estimated ~1:150,000. PRRT2-PKD tends to have earlier onset, longer duration, choreoathetosis, bilateral involvement; TMEM151A cases tend to be purer dystonia with shorter attacks and more sporadic presentation.	PRRT2 loss-of-function/haploinsufficiency disrupts presynaptic signaling and neuronal excitability: altered Nav1.2/Nav1.6 regulation, impaired Na+/K+ ATPase activity, and abnormal synaptic vesicle docking/SNARE-associated release; PKD is viewed as both channelopathy and synaptopathy. TMEM151A data support loss-of-function/haploinsufficiency, but protein function remains less defined. Cerebellar and basal ganglia-thalamo-cortical circuits are implicated.	Carbamazepine or oxcarbazepine are first-line; often highly effective, especially in PRRT2-related PKD, sometimes at low dose. TMEM151A-linked disease also improves, though complete remission may be less consistent. Trigger avoidance (sleep deprivation, stress, stimulants if relevant); genetic counseling. (xu2024paroxysmalkinesigenicdyskinesia pages 9-10, xu2024paroxysmalkinesigenicdyskinesia pages 3-5, xu2024paroxysmalkinesigenicdyskinesia pages 5-6, xu2024paroxysmalkinesigenicdyskinesia pages 1-3, harvey2021paroxysmalmovementdisorders pages 2-3, NCT04023656 chunk 1)
PNKD; no clear kinesigenic trigger, commonly stress/alcohol/caffeine/strong emotion	PNKD (AD, near-complete penetrance ~95%; recurrent p.Ala7Val and p.Ala9Val), KCNMA1 (AD; PNKD3)	PNKD attacks are longer than PKD, typically 10 min to 1 h, but may last up to 12 h; onset from childhood to early adolescence (mean about 5 years, range 6 months–35 years); attacks may be infrequent, only a few per year. KCNMA1-associated disease may include paroxysmal dyskinesia with or without epilepsy and “drop-attack”/immobility-like episodes.	PNKD protein is synaptic and linked to regulation of neurotransmitter release/cellular redox-stress pathways. In mouse PNKD models, dyskinesia is associated with striatal indirect pathway (iMSN) hypoactivity and aberrant endocannabinoid-mediated suppression of glutamatergic input. KCNMA1 variants alter BK potassium channel function: GOF alleles (e.g., N999S, D434G) increase neuronal firing and lower seizure threshold; cortical pyramidal and cerebellar Purkinje cell hyperexcitability are implicated.	Avoid/limit alcohol, caffeine, emotional stress where relevant. Classic PNKD often responds poorly to medication but may improve with age. For KCNMA1-related disease, case-guided symptomatic therapy may include dextroamphetamine for immobility/drop-attack phenotype; mechanistic studies suggest BK inhibition as a future precision approach, but this is not established clinical standard. (gusmao2019paroxysmalmovementdisorders pages 1-6, harvey2021paroxysmalmovementdisorders pages 3-4, nelson2022striatalindirectpathway pages 1-2, park2022bkchannelproperties pages 1-2, dong2022neuronalmechanismof pages 1-2)
PED; prolonged exercise/fatigue, sometimes fasting	SLC2A1 (usually AD; rare AR reported), metabolic mimics including ECHS1 (AR), PDHA1/PDHX/DLAT (X-linked/AR pyruvate dehydrogenase complex disorders), BCKD complex genes (AR), GLDC (AR)	Often leg-predominant chorea/dystonia after exertion; may coexist with epilepsy. In SLC2A1-related PED, median CSF:blood glucose ratio reported 0.52 (normal >0.60); GLUT1 phenotype spectrum includes PED, PKD/PNKD, epilepsy/absence epilepsy, intellectual/developmental issues, and spasticity.	SLC2A1/GLUT1 deficiency reduces glucose transport across the blood-brain barrier, causing brain energy failure; imaging implicated corticostriate glucose metabolism abnormalities in PED. Metabolic mimics reflect impaired mitochondrial/pyruvate or amino acid metabolism.	Ketogenic diet is the key disease-modifying therapy for SLC2A1-related PED; early diagnosis matters. In the original SLC2A1 PED/epilepsy series, 3 patients were successfully treated with ketogenic diet. Consider targeted metabolic therapy in mimics (e.g., thiamine in pyruvate dehydrogenase deficiency; dietary manipulation in MSUD-related disease) and avoidance of provoking exertion/fasting. (harvey2021paroxysmalmovementdisorders pages 3-4, harvey2021paroxysmalmovementdisorders pages 7-8, suls2008paroxysmalexerciseinduceddyskinesia pages 1-2)
Pleiotropic paroxysmal dyskinesias; mixed triggers including sleep, exertion, stress, spontaneous episodes	ADCY5 (AD), GNAO1 (AD), SCN8A (AD)	Often broader neurodevelopmental/epileptic phenotypes rather than isolated dyskinesia. ADCY5 can cause PKD, PED, PNKD, nocturnal paroxysmal movements, facial/orofacial dyskinesia, hypotonia, developmental delay. GNAO1 commonly presents with severe hyperkinetic episodes plus developmental and epileptic encephalopathy. SCN8A may cause infantile seizures with later PKD/PKD-like episodes.	ADCY5 affects striatal cAMP signaling; GNAO1 perturbs G-protein signaling with network hyperkinetic instability; SCN8A alters Nav1.6 sodium channel excitability. These genes exemplify the overlap between movement-disorder, epilepsy, and developmental phenotypes.	ADCY5: caffeine may reduce symptoms; clonazepam, acetazolamide, and selected severe cases DBS are used in practice. GNAO1: severe hyperkinetic crises may lead to consideration of DBS. SCN8A: carbamazepine/oxcarbazepine may help when sodium-channel hyperexcitability is suspected. Broad NGS-based diagnosis is especially useful because treatment is genotype-informed rather than purely phenomenologic. (pisano2025paroxysmaldyskinesiasin pages 11-12, pisano2025paroxysmaldyskinesiasin pages 8-11, harvey2021paroxysmalmovementdisorders pages 3-4, harvey2021paroxysmalmovementdisorders pages 11-12)

Table: This table summarizes the major inherited paroxysmal dyskinesia entities by trigger pattern, principal genes, mechanism, and practical treatment implications. It is designed as a compact genotype-guided reference for differentiating classic PKD/PNKD/PED from pleiotropic dyskinesia syndromes.

Major genes and variants

PRRT2 (16p11.2): usually heterozygous autosomal-dominant loss of function/haploinsufficiency. More than 100 variants have been catalogued; frameshift/nonsense alleles predominate. NM_145239.3:c.649dupC is the recurrent hotspot, reported as up to 80% of PRRT2 mutation carriers in the 2024 review. Truncating proteins undergo proteasomal degradation; pathogenic missense alleles cluster toward the C-terminus and can mislocalize protein from membrane to cytoplasm. Rare biallelic variants produce more severe PKD, prolonged ataxia, epilepsy, and intellectual disability. A 16p11.2 deletion encompassing PRRT2 is an important structural cause. (xu2024paroxysmalkinesigenicdyskinesia pages 3-5, xu2024paroxysmalkinesigenicdyskinesia pages 1-3)
TMEM151A (11q13.2): more than 50 truncating, missense, and in-frame deletion variants reported. Patient transcript analysis for c.606_607insA showed approximately half-normal mRNA; available evidence supports loss of function/haploinsufficiency. Penetrance is estimated at 53.8%. (xu2024paroxysmalkinesigenicdyskinesia pages 3-5)
PNKD (2q35; MIM 609023): classic recurrent missense variants p.Ala7Val and p.Ala9Val, autosomal dominant with approximately 95% penetrance. Pathogenic PNKD variants account for about 70% of classic familial PNKD in the cited review. (harvey2021paroxysmalmovementdisorders pages 3-4)
SLC2A1 (1p34.2; MIM 138140): predominantly heterozygous/de novo or autosomal dominant loss-of-function variants; rare recessive disease occurs. Missense, nonsense, frameshift, splice, and deletion variants reduce GLUT1-mediated blood–brain-barrier glucose transport. (harvey2021paroxysmalmovementdisorders pages 3-4, suls2008paroxysmalexerciseinduceddyskinesia pages 1-2)
KCNMA1 (10q22.3): generally heterozygous/de novo or dominant channelopathy. p.Asp434Gly and p.Asn999Ser are gain-of-function BK-channel variants; p.His444Gln is loss of function in experimental systems. Variant effect—not merely gene name—is necessary for mechanistic and therapeutic interpretation. (park2022bkchannelproperties pages 1-2, dong2022neuronalmechanismof pages 1-2)

These are constitutional/germline disorders; somatic origin is not typical, although low-level mosaicism can be missed without deep sequencing. Population allele frequencies should be retrieved variant-by-variant from the current gnomAD release; pathogenic dominant alleles are expected to be absent or extremely rare. The retrieved literature does not provide reliable gnomAD frequencies for individual alleles, and none should be inferred.

Modifiers, epigenetics, and chromosomal abnormalities

Specific modifier genes and reproducible disease-associated methylation or chromatin signatures are not established. Reduced penetrance and intrafamilial variability support modifiers, but this remains an open research area. Copy-number analysis is important for 16p11.2 deletion/duplication, especially in PRRT2-negative sporadic PKD with developmental features. The 2025 pediatric review found 16p11.2 abnormalities in ten patients. (pisano2025paroxysmaldyskinesiasin pages 6-8, harvey2021paroxysmalmovementdisorders pages 11-12)

5. Environmental, lifestyle, and infectious information

There is no evidence that pollution, radiation, occupational exposure, smoking, or an infectious agent is a general cause of Mendelian PD. Alcohol and caffeine are reproducible PNKD precipitants; fatigue, stress, excitement, sleep deprivation, startle, exercise, fasting, fever, and meals can be subtype-specific triggers. Drugs, toxins, metabolic derangement, encephalitis, or structural lesions can cause secondary dyskinesia. Infection is therefore relevant primarily as an acquired neurologic trigger/differential, not as a transmissible cause. (gusmao2019paroxysmalmovementdisorders pages 31-34, harvey2021paroxysmalmovementdisorders pages 3-4)

6. Mechanism and pathophysiology

Upstream-to-downstream causal chains

PRRT2-PKD—synaptopathy/channelopathy: truncating or mislocalized PRRT2 → reduced presynaptic PRRT2 → impaired regulation of NaV1.2/NaV1.6, Na+/K+-ATPase, P/Q-type calcium channels, and SNARE-associated proteins SNAP25, VAMP2, STX1A, and synaptotagmins → reduced action-potential threshold, abnormal vesicle docking/release, and network instability → trigger-induced spreading depolarization/circuit discharge → brief dystonia/choreoathetosis. Human PRRT2-null iPSC neurons showed increased sodium-current density and reduced action-potential threshold. (xu2024paroxysmalkinesigenicdyskinesia pages 5-6)
PNKD-PNKD—striatal synaptic dysfunction: altered PNKD protein stability/cleavage and stress-response/redox function → abnormal presynaptic transmission → excessive endocannabinoid suppression of glutamatergic input to indirect-pathway medium spiny neurons (iMSNs) → reduced iMSN firing and basal-ganglia indirect-pathway output → alcohol/caffeine/stress-provoked dyskinesia. The iMSN/endocannabinoid chain is compelling mouse evidence but is not yet a validated human biomarker. (nelson2022striatalindirectpathway pages 1-2)
SLC2A1-PED—transportopathy: reduced endothelial GLUT1 → impaired glucose entry across the blood–brain barrier → low CSF glucose and deficient cerebral energy availability, accentuated by exertion/fasting → corticostriatal energetic failure → leg-predominant PED and, in broader phenotypes, epilepsy/developmental impairment. A human family study reported median CSF:blood glucose ratio 0.52, versus normal >0.60, and reduced mutant-transporter glucose uptake in Xenopus oocytes. (suls2008paroxysmalexerciseinduceddyskinesia pages 1-2)
KCNMA1-PNKD3—channelopathy: BK-channel GOF (D434G/N999S) → enhanced BK activity, altered action-potential repolarization and increased firing in selected neuronal populations → cortical/Purkinje-cell hyperexcitability, lower seizure threshold, and dyskinesia. D434G was autosomal dominant; in mice, BK inhibition suppressed hyperexcitability and motor/seizure phenotypes. (park2022bkchannelproperties pages 1-2, dong2022neuronalmechanismof pages 1-2)

Suggested GO terms: chemical synaptic transmission GO:0007268; synaptic vesicle exocytosis GO:0016079; regulation of membrane potential GO:0042391; action potential GO:0001508; sodium-ion transport GO:0006814; potassium-ion transport GO:0006813; glucose transmembrane transport GO:1904659; endocannabinoid signaling; long-term synaptic depression.

Suggested cell terms: neuron CL:0000540; glutamatergic neuron CL:0000679; medium spiny neuron CL:0000549; Purkinje cell CL:0000121; cerebellar granule cell; cerebral-cortex pyramidal neuron; brain microvascular endothelial cell.

Omics and advanced technologies

Human disease-specific bulk/single-cell transcriptomic, proteomic, lipidomic, spatial-transcriptomic, and epigenomic signatures are not sufficiently replicated for diagnostic use. Current mechanistic evidence is driven mainly by genetics, heterologous electrophysiology, patient-derived neurons, rodent neurophysiology, chemogenetics, and imaging. Experts explicitly call for functional and multi-omics studies at scale. (xu2024paroxysmalkinesigenicdyskinesia pages 5-6, harvey2021paroxysmalmovementdisorders pages 11-12)

7. Anatomical structures affected

PD is a functional central nervous-system network disorder rather than a destructive muscle disease. Principal circuits include cerebellum, striatum/basal ganglia, thalamus, motor/premotor cortex, and their reciprocal connections. PRRT2 work emphasizes the cerebellar granule-cell→Purkinje-cell→deep-nuclear pathway and spreading depolarization, while imaging also implicates basal-ganglia–thalamo-cortical and cerebello-thalamic networks. PNKD mouse evidence localizes a critical deficit to striatal iMSNs; SLC2A1 adds the brain microvascular endothelium/BBB and corticostriatal metabolic pathway. (xu2024paroxysmalkinesigenicdyskinesia pages 9-10, xu2024paroxysmalkinesigenicdyskinesia pages 5-6, nelson2022striatalindirectpathway pages 1-2)

Suggested anatomy terms: brain UBERON:0000955; cerebral cortex UBERON:0000956; cerebellum UBERON:0002037; striatum UBERON:0002435; thalamus UBERON:0001897; basal ganglion; blood–brain barrier. Subcellular compartments: presynaptic active zone GO:0048786, synaptic vesicle GO:0008021, axon initial segment GO:0043194, plasma membrane GO:0005886, voltage-gated channel complex. Attacks may be unilateral, bilateral, or generalized; PRRT2-positive PKD is comparatively associated with bilateral involvement. (xu2024paroxysmalkinesigenicdyskinesia pages 3-5)

8. Temporal development

Classic PD usually begins acutely with individual attacks against an otherwise normal background, but the inherited predisposition is chronic. PKD commonly starts in later childhood/early adolescence, peaks during adolescence, and often becomes less frequent in the third decade. PNKD generally begins in childhood and also frequently improves with age. SLC2A1, KCNMA1, PIGN, and pleiotropic developmental disorders can begin in infancy and persist. There are no formal early/intermediate/end stages; the appropriate course annotation is episodic, nonprogressive or improving, unless the molecular syndrome includes neurodevelopmental or neurodegenerative disease. (harvey2021paroxysmalmovementdisorders pages 1-2, gusmao2019paroxysmalmovementdisorders pages 1-6, NCT04023656 chunk 1)

The key intervention window is early molecular diagnosis: immediate sodium-channel-blocker therapy can restore function in PKD, while early ketogenic treatment in GLUT1 deficiency may prevent avoidable, potentially irreversible neurologic impairment.

9. Inheritance and population

Epidemiology: PKD prevalence is estimated at approximately 1:150,000. Reliable population-wide incidence/prevalence estimates for umbrella PD, PNKD, and PED are unavailable. (xu2024paroxysmalkinesigenicdyskinesia pages 1-3, NCT04023656 chunk 1)
Inheritance: predominantly autosomal dominant for PRRT2, TMEM151A, PNKD, KCNMA1, SLC2A1, ADCY5, GNAO1, SCN8A, KCNA1, and CACNA1A; autosomal recessive or X-linked inheritance occurs in metabolic and selected synaptic disorders. (harvey2021paroxysmalmovementdisorders pages 2-3, harvey2021paroxysmalmovementdisorders pages 3-4)
Penetrance/expressivity: incomplete and age dependent for PRRT2 and TMEM151A; high but not absolute for classic PNKD. Expressivity is markedly variable, including infantile seizures, migraine, episodic ataxia, or isolated dyskinesia within one PRRT2 family. (xu2024paroxysmalkinesigenicdyskinesia pages 3-5, xu2024paroxysmalkinesigenicdyskinesia pages 1-3)
Anticipation: not established for classic PD.
Mosaicism/germline mosaicism: possible in apparently de novo disease but not quantified.
Founder effects: recurrent PRRT2 c.649dupC reflects a mutable homopolymer hotspot rather than one proven worldwide founder. Population-specific founder alleles may exist but were not established by the retrieved evidence.
Carrier frequency: no reliable general estimate; obtain from current population databases for recessive genes and counsel using variant-specific frequencies.
Consanguinity: relevant to biallelic PRRT2, TBC1D24, PDE2A, ECHS1, BCKD-complex, GLDC, PIGN, and other recessive causes.
Population: disease occurs worldwide. Published pediatric data show male predominance, but no ancestry is known to be universally protected or at high risk.

10. Diagnostics

Clinical diagnosis

Document attack phenomenology, awareness, trigger, duration, frequency, distribution, aura, family history, interictal examination, and treatment response; smartphone video is highly valuable. Classic PKD criteria include a recognized kinesigenic trigger, short attacks, preserved consciousness, no pain, normal examination between attacks, exclusion of secondary disease, and often response to carbamazepine. The foundational diagnostic-criteria paper is Bruno et al., 28 December 2004, PMID 15623687. (NCT04023656 chunk 1)

Investigations

EEG/video-EEG: usually normal during dyskinesia; indicated where epilepsy, altered awareness, or sleep attacks are suspected. It is especially important for differentiating sleep-related dyskinesia from sleep-related hypermotor epilepsy. (pisano2025paroxysmaldyskinesiasin pages 6-8, suls2008paroxysmalexerciseinduceddyskinesia pages 1-2)
MRI brain: typically normal in primary disease; obtain for adult/atypical onset, focal deficit, progressive course, or suspected secondary cause.
EMG: not routine, but myotonic discharges support myotonia congenita rather than PKD. (xu2024paroxysmalkinesigenicdyskinesia pages 3-5)
Metabolic tests: fasting serum glucose with paired CSF glucose and lactate when GLUT1 deficiency is suspected; lactate, amino/organic acids, acylcarnitines, and targeted enzyme/cofactor studies for metabolic PED/PNKD.
Biomarkers: hypoglycorrhachia/low CSF:blood glucose ratio is the most established biochemical marker for SLC2A1 disease. There is no validated circulating biomarker for PRRT2-, TMEM151A-, or PNKD-related disease.

Genetic testing algorithm

Use a multigene paroxysmal movement-disorder/epilepsy panel including at minimum PRRT2, TMEM151A, PNKD, SLC2A1, KCNMA1, ADCY5, GNAO1, SCN8A, KCNA1, CACNA1A, ATP1A3, RHOBTB2, TBC1D24, PDE2A, DEPDC5, FGF14, GCH1, and relevant metabolic genes.
Ensure deletion/duplication analysis, particularly 16p11.2/PRRT2 and SLC2A1.
If phenotype is classic familial PKD, PRRT2 sequencing including c.649dupC is a reasonable rapid first test; test TMEM151A in PRRT2-negative cases.
Use trio WES/WGS for complex, developmental, or panel-negative disease. WGS offers better CNV, deep-intronic, repeat, and noncoding coverage. Consider high-depth sequencing/another tissue for mosaicism.
Interpret variants under ACMG/AMP criteria with segregation and functional evidence. Reduced penetrance means an unaffected carrier does not automatically refute pathogenicity.

NGS diagnostic yields vary from 11–51% across cohorts; in a literature-enriched 2025 pediatric systematic review, 505/605 (83.5%) had a genetic diagnosis involving 38 genes. The difference illustrates major ascertainment effects. (pisano2025paroxysmaldyskinesiasin pages 6-8, harvey2021paroxysmalmovementdisorders pages 1-2)

Differential diagnosis

Epileptic seizures—including frontal/sleep-related hypermotor epilepsy—functional movement disorder, tics/stereotypies, episodic ataxia, migraine aura/hemiplegic migraine, myotonia, dopa-responsive dystonia, hyperekplexia, panic attacks, syncope, transient ischemia, multiple sclerosis, stroke, structural basal-ganglia lesions, autoimmune encephalitis, drug-induced dyskinesia, and metabolic crises should be considered. Preserved awareness, trigger consistency, normal ictal EEG, and absence of postictal confusion favor PD but are not individually definitive. (gusmao2019paroxysmalmovementdisorders pages 31-34)

Screening: no population newborn screen exists. Cascade testing is appropriate after a pathogenic familial variant is identified; prenatal and preimplantation testing are technically possible following genetic counseling.

11. Outcome and prognosis

Classic PKD and PNKD do not usually shorten life expectancy, and disease-specific mortality statistics are unavailable. PKD prognosis is generally favorable: attacks respond to treatment and commonly decline between ages 20–30. PNKD often improves with age but may remain medication resistant. GLUT1 deficiency prognosis depends on prompt metabolic treatment and associated developmental/epileptic burden. Severe GNAO1, PIGN, biallelic PRRT2, or developmental channelopathy phenotypes derive morbidity from encephalopathy, epilepsy, status dystonicus, falls, and persistent disability rather than episodic attacks alone. (gusmao2019paroxysmalmovementdisorders pages 1-6, NCT04023656 chunk 1)

Prognostic factors include genotype, biallelic versus monoallelic state, developmental impairment, epilepsy, structural/CNV findings, and treatment response. No validated molecular prognostic biomarker exists. A Korean prospective registry, NCT04023656, targets 100 adults and follows remission, ≥50% improvement, worsening, and medication use for up to ten years. (NCT04023656 chunk 1)

12. Treatment

Practical genotype-directed strategy

PRRT2/TMEM151A PKD: low-dose carbamazepine or oxcarbazepine is first line; lamotrigine, phenytoin, or another antiseizure agent may be alternatives when intolerant. Sodium-channel inhibition is mechanistically consistent with PRRT2-dependent NaV1.2/NaV1.6 dysregulation. Monitor sedation, dizziness, rash, hyponatremia, hepatic/hematologic toxicity, interactions, and ancestry-appropriate HLA risk before carbamazepine. (xu2024paroxysmalkinesigenicdyskinesia pages 5-6, xu2024paroxysmalkinesigenicdyskinesia pages 1-3)
Classic PNKD: avoid caffeine/alcohol and individualized triggers. Clonazepam, diazepam, levetiracetam, valproate, or oxcarbazepine have anecdotal benefit, but response is less reliable than in PKD. (gusmao2019paroxysmalmovementdisorders pages 1-6, harvey2021paroxysmalmovementdisorders pages 2-3)
SLC2A1/GLUT1 deficiency: ketogenic dietary therapy is disease directed; modified Atkins/other ketogenic formulations may be individualized by a metabolic/ketogenic team. Three patients in the landmark SLC2A1 PED/epilepsy study were successfully treated. (suls2008paroxysmalexerciseinduceddyskinesia pages 1-2)
ADCY5: caffeine can paradoxically reduce dyskinesia through adenosine A2A signaling; clonazepam or acetazolamide may help. Severe refractory disease may be considered for globus pallidus deep-brain stimulation (DBS).
GNAO1/severe hyperkinetic crises: intensive supportive management and, in selected refractory cases, DBS.
KCNMA1: dextroamphetamine has helped selected N999S-associated immobility/drop attacks, but evidence is limited. BK-channel inhibition improved D434G mouse phenotypes and remains experimental—not standard human treatment. (park2022bkchannelproperties pages 1-2, dong2022neuronalmechanismof pages 1-2)
Metabolic mimics: treat the defect—e.g., thiamine-responsive pyruvate-dehydrogenase deficiency or dietary management for intermittent maple-syrup-urine disease—rather than treating phenomenology alone. (harvey2021paroxysmalmovementdisorders pages 13-14, harvey2021paroxysmalmovementdisorders pages 3-4)

In the 2025 pediatric review, 97/112 studies reported treatment; 67 used carbamazepine/oxcarbazepine, and 40 studies reported complete resolution, particularly in PRRT2-positive cases. These are study-level—not patient-level—response proportions and should not be interpreted as an unbiased trial rate. (pisano2025paroxysmaldyskinesiasin pages 8-11)

Advanced therapy: no approved gene, RNA, or cell therapy exists. Physical/occupational therapy, fall prevention, school/work accommodations, and psychological support address disability; botulinum toxin is rarely relevant unless persistent focal dystonia exists.

Suggested NCIT intervention concepts: Carbamazepine; Oxcarbazepine; Clonazepam; Ketogenic Diet; Deep Brain Stimulation; Physical Therapy; Occupational Therapy; Genetic Counseling. Suggested CHEBI entities include carbamazepine CHEBI:3387, caffeine CHEBI:27732, ethanol CHEBI:16236, glucose CHEBI:17234, and ketone bodies.

Current studies

NCT06701851 (TRIGGER), first posted 22 November 2024, is a recruiting French basic-science fMRI/EEG study of controllable PRRT2-related attacks, examining cerebellar, basal-ganglia, cortical, and striato-cerebellar activity; planned enrollment is at least one highly selected participant, so it is mechanistic rather than therapeutic. NCT04023656 is the Korean ten-year prognosis registry described above. No robust phase II/III disease-modifying drug trial was identified. (NCT06701851 chunk 1, NCT04023656 chunk 1)

13. Prevention

Primary prevention of a de novo or inherited pathogenic variant is not available. Reproductive options include cascade testing, partner testing for recessive disease, prenatal diagnosis, and preimplantation genetic testing after nondirective counseling. Secondary prevention consists of early recognition—especially of treatable SLC2A1 disease—and early genotype-directed therapy. Tertiary prevention includes trigger avoidance, medication/diet adherence, seizure control, fall precautions, and emergency plans for severe dyskinetic crises. Vaccination, antimicrobial prophylaxis, and public-health environmental interventions are not disease-specific preventive measures.

14. Other species and natural disease

Naturally occurring PD is well documented in dogs (Canis lupus familiaris; NCBI Taxonomy 9615) and reported in cats (Felis catus; Taxonomy 9685). The 2024 canine review recognizes kinesigenic, non-kinesigenic, and exertion-related forms and recommends history plus video documentation; dogs normally remain conscious and have no postictal phase. (mandigers2024canineparoxysmaldyskinesia—a pages 1-2)

A particularly informative natural model is autosomal-recessive PNKD-like disease in Soft-Coated Wheaten Terriers caused by homozygous PIGN c.398C>T, predicted p.Thr133Ile. All 25 affected dogs were homozygous, versus 0/1,185 dogs without known PD; attacks lasted minutes to >4 hours and could occur >10/day. The variant reduced cell-surface CD59 in PIGN-null cells, connecting defective GPI-anchor biosynthesis to dyskinesia. This is analogous mechanistically—but not phenotypically identical—to human PIGN developmental epileptic-dyskinetic disease. (kolicheski2017ahomozygouspign pages 1-2)

Other canine entities include BCAN-associated episodic falling and breed-associated syndromes in Border Terriers, Maltese dogs, Markiesjes, Labrador Retrievers, and Jack Russell Terriers; inheritance is not solved in all. There is no zoonotic transmission.

15. Model organisms and experimental systems

PRRT2 knockout/knockdown mice and patient iPSC neurons: reproduce increased intrinsic excitability, altered axon-initial-segment/Nav function, abnormal synaptic vesicle handling, and cerebellar network instability. They are strong mechanistic models but do not capture all human trigger specificity or incomplete penetrance. (xu2024paroxysmalkinesigenicdyskinesia pages 5-6)
PNKD transgenic mice: caffeine/alcohol provoke attacks resembling human PNKD. Optical recording showed reduced striatal iMSN firing; chemogenetic iMSN inhibition triggered dyskinesia, and aberrant endocannabinoid-dependent suppression of glutamatergic input was implicated. This is direct cell-type causal evidence in mice. (nelson2022striatalindirectpathway pages 1-2)
Kcnma1 knock-in mice: N999S and D434G GOF models show increased BK current/firing and reduced seizure threshold; N999S mice exhibit stress-induced immobility rescued by acute dextroamphetamine. D434G mice show cortical pyramidal and Purkinje-cell hyperexcitability; paxilline improved seizures and locomotor deficits. Translation is limited because paxilline is not an established safe human therapy. (park2022bkchannelproperties pages 1-2, dong2022neuronalmechanismof pages 1-2)
SLC2A1 systems: Xenopus-oocyte transporter assays establish reduced glucose uptake; mouse models and metabolic studies test cerebral energy failure and ketogenic rescue. (suls2008paroxysmalexerciseinduceddyskinesia pages 1-2)
Natural canine PIGN disease: offers a large-animal, spontaneous recessive model of GPI-anchor-associated PNKD, although canine progression can be more severe than classic human PNKD. (kolicheski2017ahomozygouspign pages 1-2)

Useful resources are MGI/IMSR/MMRRC for mouse alleles, OMIA for inherited animal disease, and breed-specific DNA-test registries. Zebrafish, Drosophila, organoid, and CRISPR-screen findings were not sufficiently represented in the retrieved evidence to support disease-specific conclusions.

Evidence appraisal and recent developments

The strongest recent advance is the 2024 synthesis of PRRT2 and TMEM151A PKD mechanisms, integrating ion-channel, transporter, synaptic-vesicle, cerebellar, and systems-circuit evidence. The emerging consensus is that gene-defined PDs are not one “basal-ganglia disease”: they are convergent synaptopathies, channelopathies, and transportopathies acting across cerebellar–striatal–cortical networks. (xu2024paroxysmalkinesigenicdyskinesia pages 9-10, xu2024paroxysmalkinesigenicdyskinesia pages 5-6)

The principal limitations are small cohorts, referral bias, limited controlled treatment trials, sparse standardized quality-of-life measurement, and little replicated human multi-omics. Much treatment evidence remains observational. Nonetheless, molecular diagnosis already has immediate real-world utility: PRRT2/TMEM151A predicts sodium-channel-blocker responsiveness, SLC2A1 identifies a treatable cerebral-energy disorder, and pleiotropic genes trigger surveillance for epilepsy and developmental complications. (pisano2025paroxysmaldyskinesiasin pages 8-11, harvey2021paroxysmalmovementdisorders pages 11-12)

Key primary-literature PMIDs explicitly available in retrieved records: Bruno diagnostic criteria—PMID 15623687; Mao genotype–phenotype cohort—PMID 24661410; Li PRRT2/drug response—PMID 23535490; Gardiner clinical/genetic heterogeneity—PMID 26598494; Méneret European PRRT2 cohort—PMID 22744660. Full DOI/URL examples include Xu et al., published online 13 December 2023/2024 issue, https://doi.org/10.1007/s12264-023-01157-z; Nelson et al., 30 March 2022, https://doi.org/10.1523/JNEUROSCI.1614-20.2022; Park et al., 12 July 2022, https://doi.org/10.7554/eLife.77953; Suls et al., 26 June 2008, https://doi.org/10.1093/brain/awn113; and Mandigers et al., 18 July 2024, https://doi.org/10.3389/fvets.2024.1441332. (xu2024paroxysmalkinesigenicdyskinesia pages 1-3, nelson2022striatalindirectpathway pages 1-2, mandigers2024canineparoxysmaldyskinesia—a pages 1-2, park2022bkchannelproperties pages 1-2, NCT04023656 chunk 1)

References

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(pisano2025paroxysmaldyskinesiasin pages 1-2): Giulia Pisanò, Martina Gnazzo, Giulia Sigona, Carlo Alberto Cesaroni, Agnese Pantani, Anna Cavalli, Susanna Rizzi, Daniele Frattini, and Carlo Fusco. Paroxysmal dyskinesias in paediatric age: a systematic review. Journal of Clinical Medicine, 14:5925, Aug 2025. URL: https://doi.org/10.3390/jcm14175925, doi:10.3390/jcm14175925. This article has 6 citations.
(xu2024paroxysmalkinesigenicdyskinesia pages 1-3): Jiao-Jiao Xu, Hong-Fu Li, and Zhi-Ying Wu. Paroxysmal kinesigenic dyskinesia: genetics and pathophysiological mechanisms. Neuroscience Bulletin, 40:952-962, Dec 2024. URL: https://doi.org/10.1007/s12264-023-01157-z, doi:10.1007/s12264-023-01157-z. This article has 28 citations and is from a peer-reviewed journal.
(harvey2021paroxysmalmovementdisorders pages 2-3): Susan Harvey, Mary D. King, and Kathleen M. Gorman. Paroxysmal movement disorders. Jun 2021. URL: https://doi.org/10.3389/fneur.2021.659064, doi:10.3389/fneur.2021.659064. This article has 47 citations and is from a peer-reviewed journal.
(harvey2021paroxysmalmovementdisorders pages 3-4): Susan Harvey, Mary D. King, and Kathleen M. Gorman. Paroxysmal movement disorders. Jun 2021. URL: https://doi.org/10.3389/fneur.2021.659064, doi:10.3389/fneur.2021.659064. This article has 47 citations and is from a peer-reviewed journal.
(NCT06701851 chunk 1): Neural Correlates of Movement Disorders Associated With PRRT2 Related Paroxysmal Kinesigenic Dyskinesia - an Ancillary Study of AMEDYST Research. Institut National de la Santé Et de la Recherche Médicale, France. 2025. ClinicalTrials.gov Identifier: NCT06701851
(pisano2025paroxysmaldyskinesiasin pages 8-11): Giulia Pisanò, Martina Gnazzo, Giulia Sigona, Carlo Alberto Cesaroni, Agnese Pantani, Anna Cavalli, Susanna Rizzi, Daniele Frattini, and Carlo Fusco. Paroxysmal dyskinesias in paediatric age: a systematic review. Journal of Clinical Medicine, 14:5925, Aug 2025. URL: https://doi.org/10.3390/jcm14175925, doi:10.3390/jcm14175925. This article has 6 citations.
(gusmao2019paroxysmalmovementdisorders pages 31-34): Claudio M. De Gusmao and Laura Silveira-Moriyama. Paroxysmal movement disorders – practical update on diagnosis and management. Expert Review of Neurotherapeutics, 19:807-822, Aug 2019. URL: https://doi.org/10.1080/14737175.2019.1648211, doi:10.1080/14737175.2019.1648211. This article has 39 citations and is from a peer-reviewed journal.
(xu2024paroxysmalkinesigenicdyskinesia pages 9-10): Jiao-Jiao Xu, Hong-Fu Li, and Zhi-Ying Wu. Paroxysmal kinesigenic dyskinesia: genetics and pathophysiological mechanisms. Neuroscience Bulletin, 40:952-962, Dec 2024. URL: https://doi.org/10.1007/s12264-023-01157-z, doi:10.1007/s12264-023-01157-z. This article has 28 citations and is from a peer-reviewed journal.
(xu2024paroxysmalkinesigenicdyskinesia pages 3-5): Jiao-Jiao Xu, Hong-Fu Li, and Zhi-Ying Wu. Paroxysmal kinesigenic dyskinesia: genetics and pathophysiological mechanisms. Neuroscience Bulletin, 40:952-962, Dec 2024. URL: https://doi.org/10.1007/s12264-023-01157-z, doi:10.1007/s12264-023-01157-z. This article has 28 citations and is from a peer-reviewed journal.
(harvey2021paroxysmalmovementdisorders pages 11-12): Susan Harvey, Mary D. King, and Kathleen M. Gorman. Paroxysmal movement disorders. Jun 2021. URL: https://doi.org/10.3389/fneur.2021.659064, doi:10.3389/fneur.2021.659064. This article has 47 citations and is from a peer-reviewed journal.
(suls2008paroxysmalexerciseinduceddyskinesia pages 1-2): A. Suls, P. Dedeken, K. Goffin, H. Van Esch, P. Dupont, D. Cassiman, J. Kempfle, T. V. Wuttke, Y. Weber, H. Lerche, Z. Afawi, W. Vandenberghe, A. D. Korczyn, S. F. Berkovic, D. Ekstein, S. Kivity, P. Ryvlin, L. R. F. Claes, L. Deprez, S. Maljevic, A. Vargas, T. Van Dyck, D. Goossens, J. Del-Favero, K. Van Laere, P. De Jonghe, and W. Van Paesschen. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in slc2a1, encoding the glucose transporter glut1. Brain, 131:1831-1844, Jun 2008. URL: https://doi.org/10.1093/brain/awn113, doi:10.1093/brain/awn113. This article has 419 citations and is from a highest quality peer-reviewed journal.
(dong2022neuronalmechanismof pages 1-2): Ping Dong, Yang Zhang, Arsen S. Hunanyan, Mohamad A. Mikati, Jianmin Cui, and Huanghe Yang. Neuronal mechanism of a bk channelopathy in absence epilepsy and dyskinesia. Proceedings of the National Academy of Sciences of the United States of America, Mar 2022. URL: https://doi.org/10.1073/pnas.2200140119, doi:10.1073/pnas.2200140119. This article has 35 citations and is from a highest quality peer-reviewed journal.
(pisano2025paroxysmaldyskinesiasin pages 4-6): Giulia Pisanò, Martina Gnazzo, Giulia Sigona, Carlo Alberto Cesaroni, Agnese Pantani, Anna Cavalli, Susanna Rizzi, Daniele Frattini, and Carlo Fusco. Paroxysmal dyskinesias in paediatric age: a systematic review. Journal of Clinical Medicine, 14:5925, Aug 2025. URL: https://doi.org/10.3390/jcm14175925, doi:10.3390/jcm14175925. This article has 6 citations.
(pisano2025paroxysmaldyskinesiasin pages 11-12): Giulia Pisanò, Martina Gnazzo, Giulia Sigona, Carlo Alberto Cesaroni, Agnese Pantani, Anna Cavalli, Susanna Rizzi, Daniele Frattini, and Carlo Fusco. Paroxysmal dyskinesias in paediatric age: a systematic review. Journal of Clinical Medicine, 14:5925, Aug 2025. URL: https://doi.org/10.3390/jcm14175925, doi:10.3390/jcm14175925. This article has 6 citations.
(xu2024paroxysmalkinesigenicdyskinesia pages 5-6): Jiao-Jiao Xu, Hong-Fu Li, and Zhi-Ying Wu. Paroxysmal kinesigenic dyskinesia: genetics and pathophysiological mechanisms. Neuroscience Bulletin, 40:952-962, Dec 2024. URL: https://doi.org/10.1007/s12264-023-01157-z, doi:10.1007/s12264-023-01157-z. This article has 28 citations and is from a peer-reviewed journal.
(NCT04023656 chunk 1): Han-Joon Kim. Prognosis of Paroxysmal Kinesigenic Choreoathetosis in Korea. Seoul National University Hospital. 2016. ClinicalTrials.gov Identifier: NCT04023656
(gusmao2019paroxysmalmovementdisorders pages 1-6): Claudio M. De Gusmao and Laura Silveira-Moriyama. Paroxysmal movement disorders – practical update on diagnosis and management. Expert Review of Neurotherapeutics, 19:807-822, Aug 2019. URL: https://doi.org/10.1080/14737175.2019.1648211, doi:10.1080/14737175.2019.1648211. This article has 39 citations and is from a peer-reviewed journal.
(nelson2022striatalindirectpathway pages 1-2): Alexandra B. Nelson, Allison E. Girasole, Hsien-Yang Lee, Louis J. Ptáček, and Anatol C. Kreitzer. Striatal indirect pathway dysfunction underlies motor deficits in a mouse model of paroxysmal dyskinesia. The Journal of Neuroscience, 42:2835-2848, Feb 2022. URL: https://doi.org/10.1523/jneurosci.1614-20.2022, doi:10.1523/jneurosci.1614-20.2022. This article has 17 citations.
(park2022bkchannelproperties pages 1-2): Su Mi Park, Cooper E Roache, Philip H Iffland, Hans J Moldenhauer, Katia K Matychak, Amber E Plante, Abby G Lieberman, Peter B Crino, and Andrea Meredith. Bk channel properties correlate with neurobehavioral severity in three kcnma1-linked channelopathy mouse models. Jul 2022. URL: https://doi.org/10.7554/elife.77953, doi:10.7554/elife.77953. This article has 37 citations and is from a domain leading peer-reviewed journal.
(harvey2021paroxysmalmovementdisorders pages 7-8): Susan Harvey, Mary D. King, and Kathleen M. Gorman. Paroxysmal movement disorders. Jun 2021. URL: https://doi.org/10.3389/fneur.2021.659064, doi:10.3389/fneur.2021.659064. This article has 47 citations and is from a peer-reviewed journal.
(pisano2025paroxysmaldyskinesiasin pages 6-8): Giulia Pisanò, Martina Gnazzo, Giulia Sigona, Carlo Alberto Cesaroni, Agnese Pantani, Anna Cavalli, Susanna Rizzi, Daniele Frattini, and Carlo Fusco. Paroxysmal dyskinesias in paediatric age: a systematic review. Journal of Clinical Medicine, 14:5925, Aug 2025. URL: https://doi.org/10.3390/jcm14175925, doi:10.3390/jcm14175925. This article has 6 citations.
(harvey2021paroxysmalmovementdisorders pages 13-14): Susan Harvey, Mary D. King, and Kathleen M. Gorman. Paroxysmal movement disorders. Jun 2021. URL: https://doi.org/10.3389/fneur.2021.659064, doi:10.3389/fneur.2021.659064. This article has 47 citations and is from a peer-reviewed journal.
(mandigers2024canineparoxysmaldyskinesia—a pages 1-2): Paul J. J. Mandigers, Koen M. Santifort, Mark Lowrie, and Laurent Garosi. Canine paroxysmal dyskinesia—a review. Frontiers in Veterinary Science, Jul 2024. URL: https://doi.org/10.3389/fvets.2024.1441332, doi:10.3389/fvets.2024.1441332. This article has 11 citations and is from a peer-reviewed journal.
(kolicheski2017ahomozygouspign pages 1-2): Ana L. Kolicheski, Gary S. Johnson, Tendai Mhlanga-Mutangadura, Jeremy F. Taylor, Robert D. Schnabel, Taroh Kinoshita, Yoshiko Murakami, and Dennis P. O’Brien. A homozygous pign missense mutation in soft-coated wheaten terriers with a canine paroxysmal dyskinesia. Neurogenetics, 18:39-47, Nov 2017. URL: https://doi.org/10.1007/s10048-016-0502-4, doi:10.1007/s10048-016-0502-4. This article has 41 citations and is from a peer-reviewed journal.

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

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Paroxysmal Dyskinesia: comprehensive disease-characteristics report

1. Disease information

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factors

Risk factors

Protective factors

Gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

Major genes and variants

Modifiers, epigenetics, and chromosomal abnormalities

5. Environmental, lifestyle, and infectious information

6. Mechanism and pathophysiology

Upstream-to-downstream causal chains

Omics and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical diagnosis

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11. Outcome and prognosis

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