PACS2-Related Developmental and Epileptic Encephalopathy

Mendelian MONDO:0054845 Pathograph 12 Show in embeddings browser Epilepsy Neurological Disease

PACS2-related developmental and epileptic encephalopathy (DEE66) is an autosomal dominant disorder caused by a heterozygous, almost always de novo, missense variant in PACS2 - overwhelmingly the recurrent c.625G>A, p.(Glu209Lys) change. PACS2 encodes a multifunctional sorting protein that traffics cargo between the endoplasmic reticulum, Golgi, mitochondria, lysosomes and plasma membrane. The clinical picture is neonatal- or early-infantile-onset epilepsy that is hard to control in the first year but often improves in early childhood, global developmental delay, hypotonia, facial dysmorphism, and cerebellar dysgenesis on MRI. The disorder is unusual among the developmental and epileptic encephalopathies for this partly remitting seizure course, and the small adult literature hints at a second, later phase of progressive decline.

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1
Inheritance
9
Pathophys.
20
Phenotypes
3
Gaps
12
Pathograph
1
Genes
3
Medical Actions
1
Models
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Heterozygous, arising de novo in the great majority of reported individuals.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals."
Establishes the heterozygous de novo mechanism in the delineating cohort.
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Discussions and Knowledge Gaps

3
The entire molecular mechanism of DEE66 - altered proteostasis, 14-3-3-epsilon binding, apoptotic susceptibility - was measured in colorectal carcinoma and 293T cells. Does any of it hold in a neuron, a cerebellum, or a developing brain?
HUMAN MODEL MISMATCH OPEN mismatch_heterologous_cell_line_versus_neural_disease
Attached to
pathophysiology#Increased Susceptibility to Stress-Induced Apoptosis pathophysiology#Altered PACS2 Proteostasis pathophysiology#Cerebellar Dysgenesis
This is the sharpest limitation in the entry, and it is structural rather than incidental. Every mechanistic measurement supporting the apoptosis arm comes from transfected transformed cell lines, and the apoptosis readout additionally requires an applied stressor rather than reporting spontaneous death. The disease phenotype, meanwhile, is a cerebellar malformation and a neonatal cortical epilepsy - neither of which is a cell-autonomous stress-death phenotype, and neither of which has been reproduced in any published in vivo model. A mouse carrying the variant has been reported to exist but no peer-reviewed phenotypic characterisation is available, and patient-derived iPSC neurons are in progress without published data. So the causal edge from apoptotic susceptibility to cerebellar dysgenesis is typed as having unknown intermediates for a reason: it is the field's working hypothesis, not a demonstrated route. The alternative possibility, that the developmental malformation arises from disturbed cargo trafficking during cerebellar morphogenesis with apoptosis playing little part, is equally consistent with everything currently published, and the same systematic review names candidate intermediates for it - neuronal migration, neurogenesis, cerebellum development and dendritic arborization - none of which requires cell death.
Proposed experiments
Isogenic E209K cerebellar organoids with apoptosis and trafficking readouts
exp_isogenic_ipsc_cerebellar_organoid_e209k
Differentiate patient-derived and CRISPR-corrected isogenic iPSC lines into cerebellar organoids and measure, side by side, baseline and stressed apoptosis in Purkinje and granule lineages, foliation and vermis morphology, and cargo trafficking through the PACS2 furin-binding region. If dysgenesis appears without a baseline apoptosis difference, the trafficking route is implicated and the apoptosis arm is an artefact of the heterologous system.
Show evidence (3 references)
PMID:36188273 SUPPORT In Vitro
"we found that PACS-2 E209K increased susceptibility to staurosporine-induced apoptosis in HCT 116 cells"
Names both the effect and the cell line, which is precisely the mismatch: HCT116 is a colorectal carcinoma line, not neural tissue.
PMID:36188273 SUPPORT In Vitro
"Overall, our findings suggest PACS-2 E209K alters PACS-2 proteostasis and favors complex formation with 14-3-3ε, leading to increased cell death in the presence of environmental stressors."
The authors' own conclusion is conditional on environmental stressors, which is a weaker claim than the constitutive developmental death the cerebellar phenotype would require.
PMID:38540691 SUPPORT Human Clinical
"Glu209Lys mutation alters the regulatory domain, reflected by difficulties in PACS2 binding cargo proteins, which negatively impacts neuronal migration, neurogenesis, interneural communication, cerebellum development, and dendritic arborization"
Names the trafficking-centred alternative route to cerebellar dysgenesis, which is the competing account this mismatch cannot currently exclude.
Seizures in DEE66 are difficult to control in the first year and then frequently improve or remit in early childhood. What changes? And does the underlying mechanism remit with them, or does it persist and re-emerge?
KNOWLEDGE GAP OPEN gap_why_the_epilepsy_improves_with_age
Attached to
pathophysiology#Neonatal-Onset Epilepsy with Age-Dependent Improvement pathophysiology#Cortical Network Hyperexcitability
Age-dependent improvement sets DEE66 apart from most developmental and epileptic encephalopathies, where drug resistance persists, and it is a clinically consequential difference: it changes what families are told and how aggressively early polytherapy is pursued. Yet nothing explains it. The cerebellar dysgenesis is a fixed malformation and cannot remit, so whatever improves is not the structural lesion. No electrophysiological work in any PACS2 system has characterised cortical excitability at any age, so there is no measurement of the thing that is supposed to be changing. The question is sharpened by the small adult literature, which describes progressive decline rather than continued improvement - only four adults have been reported, so this is a signal rather than an established biphasic course, but if real it would mean the early remission masks an ongoing process rather than reflecting a resolved one.
Proposed experiments
Developmental time course of cortical excitability in an E209K model
exp_longitudinal_excitability_across_development
In a validated in vivo or organoid E209K model, record cortical network excitability at neonatal, juvenile and adult equivalent stages, and ask whether excitability normalises on the same schedule as the clinical seizures. A model whose excitability normalises would locate the remission in the cortex; one whose excitability persists unchanged while seizures stop would point instead to a compensatory change elsewhere and would support the concern that the improvement is symptomatic rather than mechanistic.
Show evidence (2 references)
PMID:29656858 SUPPORT Human Clinical
"Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
The observation itself - difficult control followed by improvement - which is what has no mechanistic account.
PMID:38540691 SUPPORT Human Clinical
"Only 4 cases have been reported in adults to date."
Quantifies how thin the adult evidence is, which is why the possible later progressive phase is raised as a question rather than curated as a disease stage.
PACS2's role at mitochondria-associated ER membranes is routinely invoked to explain DEE66. Has any study actually measured a MAM defect for the E209K variant?
KNOWLEDGE GAP OPEN gap_mam_role_asserted_but_not_measured_for_e209k
Attached to
pathophysiology#Impaired PACS2 Autoregulatory Domain Function pathophysiology#Increased Susceptibility to Stress-Induced Apoptosis
PACS2 is well established in the general cell-biology literature as a regulator of ER-mitochondria contact sites, and reviews of this disorder frequently carry that role forward as the mechanism. The gap is that the step from "PACS2 does this" to "the E209K variant breaks this" was not evidenced in any source verified for this entry. This entry therefore curates only what was measured - autoregulatory-domain impairment, slowed turnover, increased 14-3-3-epsilon association, increased stress-induced apoptosis - and deliberately does not carry a MAM node, because doing so would import a plausible mechanism as though it were a finding. That matters beyond bookkeeping: a MAM-centred model predicts calcium-handling and mitochondrial-energetics phenotypes and suggests quite different therapeutic targets from a trafficking-centred or proteostasis-centred model, and the three are currently not distinguished by evidence.
Proposed experiments
Direct measurement of ER-mitochondria contact in E209K neurons
exp_mam_integrity_in_e209k_neurons
In isogenic patient-derived neurons, quantify ER-mitochondria contact site number and width by electron microscopy or split-fluorophore reporter, together with ER-to-mitochondria calcium transfer and mitochondrial membrane potential. This would either substantiate the MAM model in the correct cell type or exclude it, and in either case it would tell curators whether the widely repeated MAM account belongs in the pathograph.
Show evidence (1 reference)
PMID:29656858 SUPPORT In Vitro
"Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function."
The most specific published functional consequence of the variant. Its own hedge - "may disturb cellular function" - marks how far short of a defined organelle phenotype the evidence currently stops.
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Pathophysiology

9
De Novo PACS2 p.Glu209Lys Missense Variant
A heterozygous de novo missense variant, in nearly all reported individuals the recurrent c.625G>A p.(Glu209Lys) change. This node records the lesion only. Note the disorder is defined by one recurrent substitution rather than by a spectrum of loss-of-function alleles, which is why the downstream arms are all consequences of a single specific protein change rather than of absent protein.
Downstream
Impaired PACS2 Autoregulatory Domain Function The substitution sits in the predicted autoregulatory domain and degrades its function.
Altered PACS2 Proteostasis The variant protein turns over more slowly than wild type.
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals."
The recurrent de novo variant in the founding cohort.
Impaired PACS2 Autoregulatory Domain Function
The variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 cargo/furin-binding region and its client proteins. This is the trafficking-control arm, and it is separate from the proteostasis arm below because the two were established by different experiments.
intracellular protein transport GO:0006886 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated intracellular protein transport (GO:0006886). GO:0006886 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Show evidence (1 reference)
PMID:29656858 SUPPORT In Vitro
"Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function."
The functional measurement for this arm. Note the source's own hedge - "may disturb cellular function" - which is why no specific downstream cargo defect is asserted here.
Altered PACS2 Proteostasis
The E209K protein has a slower turnover rate and longer half-life than wild type. Curated separately from the autoregulatory arm because it is a stability change rather than an interaction-control change, and because it is what the increased 14-3-3-epsilon association was attributed to.
Experimental models
HCT116 cells expressing PACS-2 E209K CELL LINE Provides the turnover measurement showing the variant protein is longer-lived than wild type.
Downstream
Increased 14-3-3-epsilon Association The stabilised variant protein forms more complex with 14-3-3-epsilon.
Show evidence (1 reference)
PMID:36188273 SUPPORT In Vitro
"we observed that the PACS-2 E209K protein exhibited a slower turnover rate relative to PACS-2 wild type (WT) upon cycloheximide treatment in 293T cells"
The turnover measurement, made by cycloheximide chase in 293T cells.
Increased 14-3-3-epsilon Association
The variant protein shows increased association with 14-3-3-epsilon, a regulatory protein in neurodevelopment. This is the specific altered interaction that the proteostasis change produces, and the one the apoptosis phenotype is attributed to.
Downstream
Increased Susceptibility to Stress-Induced Apoptosis The authors attribute the increased cell death to this complex formation.
Show evidence (1 reference)
PMID:36188273 SUPPORT In Vitro
"a regulatory protein in neurodevelopment known as 14-3-3ε was identified as having an increased association with PACS-2 E209K"
The interaction measurement behind this node.
Increased Susceptibility to Stress-Induced Apoptosis
Cells expressing E209K die more readily than wild-type-expressing cells when challenged with staurosporine. The conditional framing matters and is preserved here: this is increased susceptibility under an applied stressor, not constitutive cell death. The cell type in which it was measured is a serious limitation, recorded in the discussions.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
HCT116 cells expressing PACS-2 E209K CELL LINE Demonstrates that the variant increases apoptotic susceptibility under an applied stressor, and links that to increased 14-3-3-epsilon complex formation.
Downstream
Cerebellar Dysgenesis Proposed as the route to the cerebellar phenotype, but the link is untested in neural tissue - see the discussion on the heterologous cell system.
Show evidence (2 references)
PMID:36188273 SUPPORT In Vitro
"we found that PACS-2 E209K increased susceptibility to staurosporine-induced apoptosis in HCT 116 cells"
The apoptosis measurement, together with the cell line it was made in.
PMID:36188273 SUPPORT In Vitro
"Overall, our findings suggest PACS-2 E209K alters PACS-2 proteostasis and favors complex formation with 14-3-3ε, leading to increased cell death in the presence of environmental stressors."
The authors' summary chain, and the phrase "in the presence of environmental stressors" is the conditionality this node preserves.
Cerebellar Dysgenesis
Foliar distortion of the cerebellum with vermis hypoplasia and posterior fossa anomalies. This is the imaging finding that most distinguishes DEE66 from other developmental and epileptic encephalopathies, and it is a malformation rather than a degenerative change.
Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology. granule cell CL:0000120 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granule cell (CL:0000120). CL:0000120 is a cell type from the Cell Ontology.
Show evidence (2 references)
PMID:29656858 SUPPORT Human Clinical
"Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe."
Establishes dysgenesis as the characteristic pattern and its severity range, contrasted against the paralogous PACS1 disorder.
PMID:38540691 SUPPORT Human Clinical
"Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement."
The imaging findings across the systematic review cohort.
Cortical Network Hyperexcitability
Cortical networks become seizure-prone in the neonatal period. This node is inferred from the clinical seizure phenotype: no electrophysiological characterisation of excitability has been published in any PACS2 model or in patient-derived neurons, which is a stated gap rather than an oversight.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Neonatal-Onset Epilepsy with Age-Dependent Improvement A hyperexcitable neonatal cortex generates the presenting seizures.
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
Supports that a seizure-generating cortical state exists in the neonatal period. Typed PARTIAL because it evidences the seizures, not the excitability mechanism this node names.
Neonatal-Onset Epilepsy with Age-Dependent Improvement
Mixed focal and generalised seizures begin in the neonatal period and are difficult to control through the first year, but many patients improve in early childhood. The age-dependent improvement is curated as part of this node rather than as a separate outcome, because it is a property of the seizure disorder itself and distinguishes DEE66 from most developmental and epileptic encephalopathies.
Downstream
Global Developmental Delay Early seizure burden plausibly compounds the developmental phenotype that the malformation arm also produces; the published data do not separate them.
Show evidence (2 references)
PMID:29656858 SUPPORT Human Clinical
"Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
Gives both the onset and the characteristic later improvement.
PMID:29656858 SUPPORT Human Clinical
"Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control."
Contrasts the seizure course against the paralogous PACS1 disorder, which is what makes the neonatal onset a discriminating feature.
Global Developmental Delay
Delayed motor and speech milestones with intellectual disability of variable degree. Two upstream routes converge here - the cerebellar and cortical malformation arm, and the neonatal seizure burden - and no published analysis separates their contributions.
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism."
Names global developmental delay as a core feature of the syndrome.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PACS2-Related Developmental and Epileptic Encephalopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

20
Eye 2
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait."
Nystagmus is named in the symptom list. No band is asserted, because the quote groups it with other symptoms without giving its own count.
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"The most commonly reported facial anomalies and dysmorphisms included hypertelorism, broad nasal roots, thin upper lips, highly arched eyebrows, long eyelashes, wide-spaced teeth, and down-turned lip corners."
Hypertelorism is named first among the common facial features. No frequency band is asserted, because the source ranks the features without giving counts.
Genitourinary 1
Cryptorchidism OCCASIONAL HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"Other symptoms and organ involvement included limb distal malformations and changes (12 cases), ocular abnormalities (strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma) (11 cases), hematological disturbances (5 cases), cryptorchidism (5 cases), cardiac (atrial and ventricular)..."
5 of 30 is 17% of the whole cohort, in the 5-29% OCCASIONAL band. Note the denominator is all patients rather than males only, so the true rate among males is higher; the band is taken conservatively against the reported denominator.
Head and Neck 1
Abnormal facial shape FREQUENT HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"Facial dysmorphism and other organs' involvement were also frequently reported."
States facial dysmorphism as frequently reported across the systematic review cohort.
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait."
Hypotonia is listed among the most common symptoms.
Nervous System 7
Seizures VERY_FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250), qualified as neonatal onset. HP:0001250 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism."
Epilepsy is named first among the defining features of the cohort.
Focal-onset seizure HP:0007359 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal-onset seizure (HP:0007359). HP:0007359 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
Focal seizures are named as part of the mixed pattern. No frequency band is asserted, because the quote establishes the pattern rather than a count.
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait."
Delayed global development is listed among the most common symptoms in the 30-patient systematic review.
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait."
Limited intellectual capacity is among the most common reported symptoms.
Autism HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism."
The phrase "with or without autism" is why this phenotype carries no frequency band - the source explicitly marks it as variable.
Cerebellar vermis hypoplasia HP:0001320 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar vermis hypoplasia (HP:0001320). HP:0001320 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement."
Vermis hypoplasia is named in the imaging findings.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement."
Lateral ventricle enlargement is named in the same imaging series.
Other 8
Broad-based gait HP:0002136 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad-based gait (HP:0002136). HP:0002136 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait."
Wide-based gait is named in the symptom list, consistent with the cerebellar involvement this entry models.
Cerebellar dysplasia FREQUENT HP:0007033 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar dysplasia (HP:0007033). HP:0007033 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe."
Establishes dysgenesis as the characteristic cerebellar pattern.
Thin upper lip vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"The most commonly reported facial anomalies and dysmorphisms included hypertelorism, broad nasal roots, thin upper lips, highly arched eyebrows, long eyelashes, wide-spaced teeth, and down-turned lip corners."
Thin upper lips are named in the same list.
Enlarged cisterna magna FREQUENT HP:0002280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enlarged cisterna magna (HP:0002280). HP:0002280 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"Abnormal neuroimaging findings were observed including dysgenesis of the cerebellar folia (15 cases), mega cisterna magna (13 cases), inferior vermis hypoplasia (8 cases)"
13 of 30 is 43%, in the 30-79% FREQUENT band, and second only to foliar dysgenesis in the same enumeration.
Ocular abnormalities FREQUENT Abnormality of the eye HP:0000478 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the eye (HP:0000478). HP:0000478 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"Other symptoms and organ involvement included limb distal malformations and changes (12 cases), ocular abnormalities (strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma) (11 cases), hematological disturbances (5 cases), cryptorchidism (5 cases), cardiac (atrial and ventricular)..."
11 of 30 is 37%, in the FREQUENT band. The count is given for the group, which is why the umbrella term is used rather than splitting into six phenotypes with no individual counts behind them.
Distal limb malformation FREQUENT Abnormality of limbs HP:0040064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of limbs (HP:0040064). HP:0040064 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"Other symptoms and organ involvement included limb distal malformations and changes (12 cases), ocular abnormalities (strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma) (11 cases), hematological disturbances (5 cases), cryptorchidism (5 cases), cardiac (atrial and ventricular)..."
12 of 30 is 40%, in the FREQUENT band.
Septal defect OCCASIONAL Abnormal cardiac septum morphology HP:0001671 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cardiac septum morphology (HP:0001671). HP:0001671 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"Other symptoms and organ involvement included limb distal malformations and changes (12 cases), ocular abnormalities (strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma) (11 cases), hematological disturbances (5 cases), cryptorchidism (5 cases), cardiac (atrial and ventricular)..."
4 of 30 is 13%, in the OCCASIONAL band. The umbrella septum term is used because the source counts atrial and ventricular defects together.
Hematological abnormality OCCASIONAL Abnormality of blood and blood-forming tissues HP:0001871 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of blood and blood-forming tissues (HP:0001871). HP:0001871 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"Other symptoms and organ involvement included limb distal malformations and changes (12 cases), ocular abnormalities (strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma) (11 cases), hematological disturbances (5 cases), cryptorchidism (5 cases), cardiac (atrial and ventricular)..."
5 of 30 is 17%, in the OCCASIONAL band.
🧬

Genetic Associations

1
PACS2 (A heterozygous de novo missense variant in PACS2, in nearly all reported individuals the recurrent c.625G>A p.(Glu209Lys) change, causes DEE66.)
Gene: PACS2 hgnc:23794 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PACS2 (hgnc:23794). hgnc:23794 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:29656858 SUPPORT Human Clinical
"PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation."
Gives the protein's function and its relationship to PACS1.
PMID:29656858 SUPPORT Human Clinical
"Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase."
Describes the furin-binding region whose regulation the pathogenic variant impairs.
PMID:38540691 SUPPORT Human Clinical
"Glu209Lys and one case of the heterogenous missense variant PACS2 pGlu211Lys"
Records the second recurrent allele and, importantly, that it rests on a single case - which is why the curated mechanism stays scoped to E209K.
+ 2 more references
💊

Medical Actions

3
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: valproic acid CHEBI:39867 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses valproic acid (CHEBI:39867). CHEBI:39867 is a therapeutic agent from Chemical Entities of Biological Interest. levetiracetam CHEBI:6437 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levetiracetam (CHEBI:6437). CHEBI:6437 is a therapeutic agent from Chemical Entities of Biological Interest. phenobarbital CHEBI:8069 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses phenobarbital (CHEBI:8069). CHEBI:8069 is a therapeutic agent from Chemical Entities of Biological Interest. carbamazepine CHEBI:3387 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carbamazepine (CHEBI:3387). CHEBI:3387 is a therapeutic agent from Chemical Entities of Biological Interest.
Seizures require multiple medication trials in the first year and are difficult to control, but frequently become easier to control or remit with age. This entry does not rank individual agents, because the cited sources describe the course rather than comparing drugs head to head.
Mechanism Target:
INHIBITS Neonatal-Onset Epilepsy with Age-Dependent Improvement — Symptomatic seizure suppression. The link is to the seizure node only - no antiseizure medication addresses the trafficking or proteostasis arms.
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
Typed PARTIAL deliberately: the source establishes that seizures are controlled with difficulty and later improve, but does not attribute the improvement to medication rather than to the natural course.
Show evidence (2 references)
PMID:29656858 SUPPORT Human Clinical
"Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control."
Establishes the difficulty of control that motivates multi-agent management.
PMID:38540691 SUPPORT Human Clinical
"were treated with valproate or levetiracetam (~50%), phenobarbital (~33%), and carbamazepine (~25%), and seizure frequency appeared to decrease with age"
Gives the agents actually used and their approximate response rates, which is what the therapeutic_agent bindings above record. Note these are proportions treated with each agent rather than a controlled efficacy comparison.
Pyridoxal Phosphate
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pyridoxal 5'-phosphate CHEBI:18405 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyridoxal 5'-phosphate (CHEBI:18405). CHEBI:18405 is a therapeutic agent from Chemical Entities of Biological Interest.
Intravenous pyridoxal phosphate produced an initial seizure response in reported cases, and seizures recurred when treatment was switched to oral vitamin B6. That pairing is the clinically actionable part: it suggests responsiveness specific to the active cofactor rather than to pyridoxine, and it is worth a trial early in a neonatal-onset encephalopathy where the alternative is prolonged multi-agent empiricism. The evidence is a small number of reported cases, not a trial.
Mechanism Target:
INHIBITS Neonatal-Onset Epilepsy with Age-Dependent Improvement — Symptomatic seizure response. No mechanism links pyridoxal phosphate to the PACS2 trafficking defect, so the link is to the seizure node only and this entry makes no claim that the response is disease-specific.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"initially responded to intravenous pyridoxal phosphate"
The reported seizure response.
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"However, seizure recurrence occurred when the treatment was shifted to oral vitamin B6"
Typed PARTIAL because it qualifies rather than supports the treatment: the response did not persist on oral pyridoxine, which is what distinguishes a pyridoxal-phosphate-specific effect from general vitamin B6 responsiveness and is also the reason the benefit cannot be called durable.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Offered given the near-universal de novo occurrence and autosomal dominant inheritance once established, with recurrence risk limited to gonadal mosaicism.
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.)."
States genetic counselling as one of the direct consequences of establishing the molecular diagnosis in this disease group.
🔬

Diagnosis

3
Molecular Genetic Testing for a PACS2 Variant
Diagnosis rests on identifying the heterozygous PACS2 variant, in nearly all cases the recurrent c.625G>A p.(Glu209Lys). Exome or genome sequencing, or a developmental and epileptic encephalopathy gene panel including PACS2, is the route. Because the allele is absent from population databases and classified pathogenic in ClinVar, a single heterozygous finding is diagnostic in the right clinical context rather than requiring functional confirmation.
Whole Exome Sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:29656858 SUPPORT Human Clinical
"Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals."
Exome sequencing is how the entity was defined and remains the diagnostic route.
PMID:38540691 SUPPORT Human Clinical
"According to ClinVar, it is pathogenic/likely pathogenic"
The classification that makes a single heterozygous finding actionable.
Brain MRI
MRI supports the diagnosis rather than establishing it. Cerebellar foliar dysgenesis with mega cisterna magna and vermis hypoplasia is the characteristic pattern, but imaging is normal in a fifth of patients, so a normal scan does not exclude the diagnosis.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38540691 SUPPORT Human Clinical
"Abnormal neuroimaging findings were observed including dysgenesis of the cerebellar folia (15 cases), mega cisterna magna (13 cases), inferior vermis hypoplasia (8 cases)"
The imaging pattern, and its counts out of 30 show why it is supportive rather than diagnostic.
Electroencephalography
EEG characterises the seizure disorder and is part of the neonatal work-up that typically precedes genetic testing.
Electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29656858 SUPPORT Human Clinical
"Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
Typed PARTIAL: the source characterises the seizure types EEG would classify, without describing EEG findings specific to this disorder.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Around 100 individuals described worldwide as of 2024, with 30 assembled in the largest systematic review. No population rate has been estimated, so the count is recorded as literature cases rather than converted to a rate.
Show evidence (2 references)
PMID:38540691 SUPPORT Human Clinical
"A total of 11 articles and 29 patients were included in this review, to which we added our own experience for a total of 30 patients."
Gives the systematic review's denominator, which is the firmest published count.
PMID:38540691 SUPPORT Human Clinical
"Only 4 cases have been reported in adults to date."
Shows how thin ascertainment is beyond childhood, which bears on any prevalence reading of the case count.
🧫

Experimental Models

1
HCT116 cells expressing PACS-2 E209K CELL_LINE
Human colorectal carcinoma cells transfected with wild-type or E209K PACS-2. This is currently the only published system in which the variant's molecular consequences have been measured, which is both why it carries most of this entry's mechanism and why its limitations are recorded prominently.
Pathograph links
Increased Susceptibility to Stress-Induced Apoptosis measures fidelity: low Demonstrates that the variant increases apoptotic susceptibility under an applied stressor, and links that to increased 14-3-3-epsilon complex formation.
Limitations: A colorectal carcinoma line is not a neuron, a cerebellum, or a developing brain, and the readout requires an exogenous stressor - staurosporine - rather than reporting constitutive death. The system is also transfection-based rather than expressing the variant from its endogenous locus at physiological level, so stoichiometry with 14-3-3-epsilon and other partners is not that of a patient cell. The relationship is typed MEASURES rather than RECAPITULATES for that reason: it establishes a property of the mutant protein, not a disease model.
Readouts
Staurosporine-induced apoptosis in E209K versus wild-type cells
Direction: INCREASED
Interpretation: E209K-expressing cells die more readily than wild-type-expressing cells under staurosporine challenge.
Show evidence (1 reference)
PMID:36188273 SUPPORT In Vitro
"we found that PACS-2 E209K increased susceptibility to staurosporine-induced apoptosis in HCT 116 cells"
The apoptosis measurement behind this readout.
Show evidence (1 reference)
PMID:36188273 SUPPORT In Vitro
"As the PACS-2 E209K missense mutation has become a marker for neurodevelopmental disorders, we sought to characterize its biochemical properties."
States the study's purpose as biochemical characterisation of the variant, which is the level at which this system is informative.
Altered PACS2 Proteostasis measures fidelity: low Provides the turnover measurement showing the variant protein is longer-lived than wild type.
Limitations: Turnover was measured by cycloheximide chase in 293T cells, another non-neuronal transformed line, so the half-life difference is a property of the protein in that context and may not hold in a post-mitotic neuron with different chaperone and degradation capacity.
Readouts
PACS-2 protein turnover on cycloheximide chase
Direction: DECREASED
Interpretation: Turnover rate falls - equivalently, half-life rises - for E209K relative to wild type.
Show evidence (1 reference)
PMID:36188273 SUPPORT In Vitro
"The longer half-life of PACS-2 E209K suggests a disruption in its proteostasis, with the potential for altered protein-protein interactions."
The half-life result behind this readout.
{ }

Source YAML

click to show 
name: PACS2-Related Developmental and Epileptic Encephalopathy
creation_date: "2026-08-19T19:10:00Z"
category: Mendelian
synonyms:
- Developmental and epileptic encephalopathy 66
- DEE66
- EIEE66
- PACS2 syndrome
description: >-
  PACS2-related developmental and epileptic encephalopathy (DEE66) is an autosomal
  dominant disorder caused by a heterozygous, almost always de novo, missense variant
  in PACS2 - overwhelmingly the recurrent c.625G>A, p.(Glu209Lys) change. PACS2
  encodes a multifunctional sorting protein that traffics cargo between the
  endoplasmic reticulum, Golgi, mitochondria, lysosomes and plasma membrane. The
  clinical picture is neonatal- or early-infantile-onset epilepsy that is hard to
  control in the first year but often improves in early childhood, global
  developmental delay, hypotonia, facial dysmorphism, and cerebellar dysgenesis on
  MRI. The disorder is unusual among the developmental and epileptic encephalopathies
  for this partly remitting seizure course, and the small adult literature hints at a
  second, later phase of progressive decline.
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 66
  term:
    id: MONDO:0054845
    label: developmental and epileptic encephalopathy, 66
parents:
- Epilepsy
- Neurological Disease
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous, arising de novo in the great majority of reported individuals.
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals."
    explanation: >-
      Establishes the heterozygous de novo mechanism in the delineating cohort.

pathophysiology:
- name: De Novo PACS2 p.Glu209Lys Missense Variant
  biological_scale: MOLECULAR
  description: >-
    A heterozygous de novo missense variant, in nearly all reported individuals the
    recurrent c.625G>A p.(Glu209Lys) change. This node records the lesion only. Note
    the disorder is defined by one recurrent substitution rather than by a spectrum of
    loss-of-function alleles, which is why the downstream arms are all consequences of
    a single specific protein change rather than of absent protein.
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals."
    explanation: >-
      The recurrent de novo variant in the founding cohort.
  downstream:
  - target: Impaired PACS2 Autoregulatory Domain Function
    causal_link_type: DIRECT
    description: >-
      The substitution sits in the predicted autoregulatory domain and degrades its
      function.
  - target: Altered PACS2 Proteostasis
    causal_link_type: DIRECT
    description: >-
      The variant protein turns over more slowly than wild type.

- name: Impaired PACS2 Autoregulatory Domain Function
  biological_scale: MOLECULAR
  description: >-
    The variant reduces the ability of the predicted autoregulatory domain to modulate
    the interaction between the PACS2 cargo/furin-binding region and its client
    proteins. This is the trafficking-control arm, and it is separate from the
    proteostasis arm below because the two were established by different experiments.
  biological_processes:
  - preferred_term: intracellular protein transport
    term:
      id: GO:0006886
      label: intracellular protein transport
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function."
    explanation: >-
      The functional measurement for this arm. Note the source's own hedge - "may
      disturb cellular function" - which is why no specific downstream cargo defect is
      asserted here.

- name: Altered PACS2 Proteostasis
  biological_scale: MOLECULAR
  description: >-
    The E209K protein has a slower turnover rate and longer half-life than wild type.
    Curated separately from the autoregulatory arm because it is a stability change
    rather than an interaction-control change, and because it is what the increased
    14-3-3-epsilon association was attributed to.
  evidence:
  - reference: PMID:36188273
    reference_title: "The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we observed that the PACS-2 E209K protein exhibited a slower turnover rate relative to PACS-2 wild type (WT) upon cycloheximide treatment in 293T cells"
    explanation: >-
      The turnover measurement, made by cycloheximide chase in 293T cells.
  downstream:
  - target: Increased 14-3-3-epsilon Association
    causal_link_type: DIRECT
    description: >-
      The stabilised variant protein forms more complex with 14-3-3-epsilon.

- name: Increased 14-3-3-epsilon Association
  biological_scale: MOLECULAR
  description: >-
    The variant protein shows increased association with 14-3-3-epsilon, a regulatory
    protein in neurodevelopment. This is the specific altered interaction that the
    proteostasis change produces, and the one the apoptosis phenotype is attributed
    to.
  evidence:
  - reference: PMID:36188273
    reference_title: "The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a regulatory protein in neurodevelopment known as 14-3-3ε was identified as having an increased association with PACS-2 E209K"
    explanation: >-
      The interaction measurement behind this node.
  downstream:
  - target: Increased Susceptibility to Stress-Induced Apoptosis
    causal_link_type: DIRECT
    description: >-
      The authors attribute the increased cell death to this complex formation.

- name: Increased Susceptibility to Stress-Induced Apoptosis
  biological_scale: CELLULAR
  description: >-
    Cells expressing E209K die more readily than wild-type-expressing cells when
    challenged with staurosporine. The conditional framing matters and is preserved
    here: this is increased susceptibility under an applied stressor, not constitutive
    cell death. The cell type in which it was measured is a serious limitation,
    recorded in the discussions.
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:36188273
    reference_title: "The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we found that PACS-2 E209K increased susceptibility to staurosporine-induced apoptosis in HCT 116 cells"
    explanation: >-
      The apoptosis measurement, together with the cell line it was made in.
  - reference: PMID:36188273
    reference_title: "The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overall, our findings suggest PACS-2 E209K alters PACS-2 proteostasis and favors complex formation with 14-3-3ε, leading to increased cell death in the presence of environmental stressors."
    explanation: >-
      The authors' summary chain, and the phrase "in the presence of environmental
      stressors" is the conditionality this node preserves.
  downstream:
  - target: Cerebellar Dysgenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed as the route to the cerebellar phenotype, but the link is untested in
      neural tissue - see the discussion on the heterologous cell system.

- name: Cerebellar Dysgenesis
  biological_scale: TISSUE
  description: >-
    Foliar distortion of the cerebellum with vermis hypoplasia and posterior fossa
    anomalies. This is the imaging finding that most distinguishes DEE66 from other
    developmental and epileptic encephalopathies, and it is a malformation rather than
    a degenerative change.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: granule cell
    term:
      id: CL:0000120
      label: granule cell
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe."
    explanation: >-
      Establishes dysgenesis as the characteristic pattern and its severity range,
      contrasted against the paralogous PACS1 disorder.
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement."
    explanation: >-
      The imaging findings across the systematic review cohort.

- name: Cortical Network Hyperexcitability
  biological_scale: TISSUE
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
  description: >-
    Cortical networks become seizure-prone in the neonatal period. This node is
    inferred from the clinical seizure phenotype: no electrophysiological
    characterisation of excitability has been published in any PACS2 model or in
    patient-derived neurons, which is a stated gap rather than an oversight.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
    explanation: >-
      Supports that a seizure-generating cortical state exists in the neonatal period.
      Typed PARTIAL because it evidences the seizures, not the excitability mechanism
      this node names.
  downstream:
  - target: Neonatal-Onset Epilepsy with Age-Dependent Improvement
    causal_link_type: DIRECT
    description: >-
      A hyperexcitable neonatal cortex generates the presenting seizures.

- name: Neonatal-Onset Epilepsy with Age-Dependent Improvement
  biological_scale: ORGANISM
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Recurrent Unprovoked Seizures"
  description: >-
    Mixed focal and generalised seizures begin in the neonatal period and are
    difficult to control through the first year, but many patients improve in early
    childhood. The age-dependent improvement is curated as part of this node rather
    than as a separate outcome, because it is a property of the seizure disorder
    itself and distinguishes DEE66 from most developmental and epileptic
    encephalopathies.
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
    explanation: >-
      Gives both the onset and the characteristic later improvement.
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control."
    explanation: >-
      Contrasts the seizure course against the paralogous PACS1 disorder, which is
      what makes the neonatal onset a discriminating feature.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Early seizure burden plausibly compounds the developmental phenotype that the
      malformation arm also produces; the published data do not separate them.

- name: Global Developmental Delay
  biological_scale: ORGANISM
  description: >-
    Delayed motor and speech milestones with intellectual disability of variable
    degree. Two upstream routes converge here - the cerebellar and cortical
    malformation arm, and the neonatal seizure burden - and no published analysis
    separates their contributions.
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism."
    explanation: >-
      Names global developmental delay as a core feature of the syndrome.

phenotypes:
- category: Neurological
  name: Seizures
  frequency: VERY_FREQUENT
  description: >-
    Mixed focal and generalised seizures with neonatal or early infantile onset.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism."
    explanation: >-
      Epilepsy is named first among the defining features of the cohort.

- category: Neurological
  name: Focal-onset seizure
  description: >-
    Focal seizures occur alongside generalised seizures in the same individuals.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
    explanation: >-
      Focal seizures are named as part of the mixed pattern. No frequency band is
      asserted, because the quote establishes the pattern rather than a count.

- category: Neurological
  name: Global developmental delay
  frequency: VERY_FREQUENT
  description: Delayed motor and speech milestones.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait."
    explanation: >-
      Delayed global development is listed among the most common symptoms in the
      30-patient systematic review.

- category: Neurological
  name: Intellectual disability
  frequency: VERY_FREQUENT
  description: Intellectual capacity is limited, ranging from mild to severe.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait."
    explanation: >-
      Limited intellectual capacity is among the most common reported symptoms.

- category: Neurological
  name: Hypotonia
  frequency: FREQUENT
  description: Hypotonia is a common finding.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait."
    explanation: >-
      Hypotonia is listed among the most common symptoms.

- category: Neurological
  name: Nystagmus
  description: Nystagmus is reported among the common neurological signs.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait."
    explanation: >-
      Nystagmus is named in the symptom list. No band is asserted, because the quote
      groups it with other symptoms without giving its own count.

- category: Neurological
  name: Broad-based gait
  description: A wide-based gait is reported among the motor findings.
  phenotype_term:
    preferred_term: Broad-based gait
    term:
      id: HP:0002136
      label: Broad-based gait
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait."
    explanation: >-
      Wide-based gait is named in the symptom list, consistent with the cerebellar
      involvement this entry models.

- category: Behavioral
  name: Autism
  description: >-
    Autistic features occur in a subset; the delineating cohort describes the
    developmental phenotype as occurring with or without autism.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism."
    explanation: >-
      The phrase "with or without autism" is why this phenotype carries no frequency
      band - the source explicitly marks it as variable.

- category: Neuroimaging
  name: Cerebellar dysplasia
  frequency: FREQUENT
  description: >-
    Foliar distortion of the cerebellum, the most characteristic imaging finding.
  phenotype_term:
    preferred_term: Cerebellar dysplasia
    term:
      id: HP:0007033
      label: Cerebellar dysplasia
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe."
    explanation: >-
      Establishes dysgenesis as the characteristic cerebellar pattern.

- category: Neuroimaging
  name: Cerebellar vermis hypoplasia
  description: Vermis hypoplasia is reported among the posterior fossa findings.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement."
    explanation: >-
      Vermis hypoplasia is named in the imaging findings.

- category: Neuroimaging
  name: Ventriculomegaly
  description: Enlargement of the lateral ventricles is reported on MRI.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement."
    explanation: >-
      Lateral ventricle enlargement is named in the same imaging series.

- category: Craniofacial
  name: Abnormal facial shape
  frequency: FREQUENT
  description: >-
    Facial dysmorphism is a defining feature named in the delineating paper's title.
    It is variable and often subtle rather than a single recognisable gestalt, which
    is why it is curated as the umbrella term with two of the commonest specific
    features below rather than as a named facial phenotype.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Facial dysmorphism and other organs' involvement were also frequently reported."
    explanation: >-
      States facial dysmorphism as frequently reported across the systematic review
      cohort.

- category: Craniofacial
  name: Hypertelorism
  description: >-
    Hypertelorism heads the list of commonly reported facial anomalies.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most commonly reported facial anomalies and dysmorphisms included hypertelorism, broad nasal roots, thin upper lips, highly arched eyebrows, long eyelashes, wide-spaced teeth, and down-turned lip corners."
    explanation: >-
      Hypertelorism is named first among the common facial features. No frequency band
      is asserted, because the source ranks the features without giving counts.

- category: Craniofacial
  name: Thin upper lip vermilion
  description: A thin upper lip is among the commonly reported facial features.
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most commonly reported facial anomalies and dysmorphisms included hypertelorism, broad nasal roots, thin upper lips, highly arched eyebrows, long eyelashes, wide-spaced teeth, and down-turned lip corners."
    explanation: >-
      Thin upper lips are named in the same list.

- category: Neuroimaging
  name: Enlarged cisterna magna
  frequency: FREQUENT
  description: >-
    Mega cisterna magna is the second most frequent neuroimaging finding, after
    cerebellar foliar dysgenesis.
  phenotype_term:
    preferred_term: Enlarged cisterna magna
    term:
      id: HP:0002280
      label: Enlarged cisterna magna
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal neuroimaging findings were observed including dysgenesis of the cerebellar folia (15 cases), mega cisterna magna (13 cases), inferior vermis hypoplasia (8 cases)"
    explanation: >-
      13 of 30 is 43%, in the 30-79% FREQUENT band, and second only to foliar
      dysgenesis in the same enumeration.

- category: Ophthalmological
  name: Ocular abnormalities
  frequency: FREQUENT
  description: >-
    Strabismus, nystagmus, hypermetropia, astigmatism, myopia and coloboma are
    reported together as a group; the source counts the group rather than each
    finding, so they are curated as one entry with the umbrella term.
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other symptoms and organ involvement included limb distal malformations and changes (12 cases), ocular abnormalities (strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma) (11 cases), hematological disturbances (5 cases), cryptorchidism (5 cases), cardiac (atrial and ventricular) septal defects (4 cases), hydronephrosis (2 cases)"
    explanation: >-
      11 of 30 is 37%, in the FREQUENT band. The count is given for the group, which
      is why the umbrella term is used rather than splitting into six phenotypes with
      no individual counts behind them.

- category: Musculoskeletal
  name: Distal limb malformation
  frequency: FREQUENT
  description: >-
    Distal limb malformations are the most frequent extraneurological finding.
  phenotype_term:
    preferred_term: Abnormality of limbs
    term:
      id: HP:0040064
      label: Abnormality of limbs
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other symptoms and organ involvement included limb distal malformations and changes (12 cases), ocular abnormalities (strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma) (11 cases), hematological disturbances (5 cases), cryptorchidism (5 cases), cardiac (atrial and ventricular) septal defects (4 cases), hydronephrosis (2 cases)"
    explanation: >-
      12 of 30 is 40%, in the FREQUENT band.

- category: Genitourinary
  name: Cryptorchidism
  frequency: OCCASIONAL
  description: Cryptorchidism is reported in a minority of affected males.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other symptoms and organ involvement included limb distal malformations and changes (12 cases), ocular abnormalities (strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma) (11 cases), hematological disturbances (5 cases), cryptorchidism (5 cases), cardiac (atrial and ventricular) septal defects (4 cases), hydronephrosis (2 cases)"
    explanation: >-
      5 of 30 is 17% of the whole cohort, in the 5-29% OCCASIONAL band. Note the
      denominator is all patients rather than males only, so the true rate among males
      is higher; the band is taken conservatively against the reported denominator.

- category: Cardiovascular
  name: Septal defect
  frequency: OCCASIONAL
  description: Atrial and ventricular septal defects are reported.
  phenotype_term:
    preferred_term: Abnormal cardiac septum morphology
    term:
      id: HP:0001671
      label: Abnormal cardiac septum morphology
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other symptoms and organ involvement included limb distal malformations and changes (12 cases), ocular abnormalities (strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma) (11 cases), hematological disturbances (5 cases), cryptorchidism (5 cases), cardiac (atrial and ventricular) septal defects (4 cases), hydronephrosis (2 cases)"
    explanation: >-
      4 of 30 is 13%, in the OCCASIONAL band. The umbrella septum term is used because
      the source counts atrial and ventricular defects together.

- category: Hematologic
  name: Hematological abnormality
  frequency: OCCASIONAL
  description: >-
    Hematological disturbances, described elsewhere in the same source as anemia and
    neutropenia, occur in a minority.
  phenotype_term:
    preferred_term: Abnormality of blood and blood-forming tissues
    term:
      id: HP:0001871
      label: Abnormality of blood and blood-forming tissues
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other symptoms and organ involvement included limb distal malformations and changes (12 cases), ocular abnormalities (strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma) (11 cases), hematological disturbances (5 cases), cryptorchidism (5 cases), cardiac (atrial and ventricular) septal defects (4 cases), hydronephrosis (2 cases)"
    explanation: >-
      5 of 30 is 17%, in the OCCASIONAL band.

genetic:
- name: PACS2
  gene_term:
    preferred_term: PACS2
    term:
      id: hgnc:23794
      label: PACS2
  relationship_type: CAUSATIVE
  association: >-
    A heterozygous de novo missense variant in PACS2, in nearly all reported
    individuals the recurrent c.625G>A p.(Glu209Lys) change, causes DEE66.
  notes: >-
    PACS2 encodes a multifunctional sorting protein that traffics cargo between the
    endoplasmic reticulum, Golgi, mitochondria, lysosomes and plasma membrane, working
    through an N-terminal furin-binding region that engages cargo together with
    adaptor proteins. Unlike most developmental and epileptic encephalopathy genes,
    the disorder is defined by one recurrent substitution rather than a spectrum of
    loss-of-function alleles, so the mechanism curated here is the consequence of a
    specific protein change and not of absent protein. Deliberate scope note: PACS2's
    role at mitochondria-associated ER membranes is well described in the general cell
    biology literature and is frequently invoked for this disorder, but no source
    verified for this entry measures a MAM-integrity defect for the E209K variant
    itself. The entry therefore curates what was measured - autoregulatory-domain
    impairment, slowed turnover, increased 14-3-3-epsilon association and increased
    stress-induced apoptosis - and does not assert a MAM defect. PACS1, the paralog,
    causes Schuurs-Hoeijmakers syndrome through its own recurrent variant, and the two
    disorders were explicitly compared when DEE66 was delineated. A second recurrent
    allele, p.(Glu211Lys), is reported in a single case and sits two residues from the
    main hotspot in the same regulatory region; the mechanism curated here is derived
    from E209K and this entry does not assume the two behave identically. The c.625G>A
    allele is absent from population databases and classified pathogenic or likely
    pathogenic in ClinVar, which is what makes a single heterozygous finding
    diagnostic in the right clinical context.
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation."
    explanation: >-
      Gives the protein's function and its relationship to PACS1.
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase."
    explanation: >-
      Describes the furin-binding region whose regulation the pathogenic variant
      impairs.
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glu209Lys and one case of the heterogenous missense variant PACS2 pGlu211Lys"
    explanation: >-
      Records the second recurrent allele and, importantly, that it rests on a single
      case - which is why the curated mechanism stays scoped to E209K.
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is not found in population databases, such as the Genome Aggregation Database (gnomAD)"
    explanation: >-
      Population-database absence, one half of the variant-interpretation evidence.
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "According to ClinVar, it is pathogenic/likely pathogenic"
    explanation: >-
      The clinical classification, the other half.

experimental_models:
- name: HCT116 cells expressing PACS-2 E209K
  experimental_model_type: CELL_LINE
  description: >-
    Human colorectal carcinoma cells transfected with wild-type or E209K PACS-2. This
    is currently the only published system in which the variant's molecular
    consequences have been measured, which is both why it carries most of this entry's
    mechanism and why its limitations are recorded prominently.
  modeled_mechanisms:
  - target: Increased Susceptibility to Stress-Induced Apoptosis
    relationship: MEASURES
    fidelity: LOW
    description: >-
      Demonstrates that the variant increases apoptotic susceptibility under an
      applied stressor, and links that to increased 14-3-3-epsilon complex formation.
    limitations: >-
      A colorectal carcinoma line is not a neuron, a cerebellum, or a developing
      brain, and the readout requires an exogenous stressor - staurosporine - rather
      than reporting constitutive death. The system is also transfection-based rather
      than expressing the variant from its endogenous locus at physiological level, so
      stoichiometry with 14-3-3-epsilon and other partners is not that of a patient
      cell. The relationship is typed MEASURES rather than RECAPITULATES for that
      reason: it establishes a property of the mutant protein, not a disease model.
    readouts:
    - name: Staurosporine-induced apoptosis in E209K versus wild-type cells
      target: Increased Susceptibility to Stress-Induced Apoptosis
      direction: INCREASED
      interpretation: >-
        E209K-expressing cells die more readily than wild-type-expressing cells under
        staurosporine challenge.
      evidence:
      - reference: PMID:36188273
        reference_title: "The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "we found that PACS-2 E209K increased susceptibility to staurosporine-induced apoptosis in HCT 116 cells"
        explanation: The apoptosis measurement behind this readout.
    evidence:
    - reference: PMID:36188273
      reference_title: "The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "As the PACS-2 E209K missense mutation has become a marker for neurodevelopmental disorders, we sought to characterize its biochemical properties."
      explanation: >-
        States the study's purpose as biochemical characterisation of the variant,
        which is the level at which this system is informative.
  - target: Altered PACS2 Proteostasis
    relationship: MEASURES
    fidelity: LOW
    description: >-
      Provides the turnover measurement showing the variant protein is longer-lived
      than wild type.
    limitations: >-
      Turnover was measured by cycloheximide chase in 293T cells, another
      non-neuronal transformed line, so the half-life difference is a property of the
      protein in that context and may not hold in a post-mitotic neuron with different
      chaperone and degradation capacity.
    readouts:
    - name: PACS-2 protein turnover on cycloheximide chase
      target: Altered PACS2 Proteostasis
      direction: DECREASED
      interpretation: >-
        Turnover rate falls - equivalently, half-life rises - for E209K relative to
        wild type.
      evidence:
      - reference: PMID:36188273
        reference_title: "The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The longer half-life of PACS-2 E209K suggests a disruption in its proteostasis, with the potential for altered protein-protein interactions."
        explanation: The half-life result behind this readout.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Around 100 individuals described worldwide as of 2024, with 30 assembled in the
    largest systematic review. No population rate has been estimated, so the count is
    recorded as literature cases rather than converted to a rate.
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 11 articles and 29 patients were included in this review, to which we added our own experience for a total of 30 patients."
    explanation: >-
      Gives the systematic review's denominator, which is the firmest published count.
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 4 cases have been reported in adults to date."
    explanation: >-
      Shows how thin ascertainment is beyond childhood, which bears on any prevalence
      reading of the case count.

diagnosis:
- name: Molecular Genetic Testing for a PACS2 Variant
  description: >-
    Diagnosis rests on identifying the heterozygous PACS2 variant, in nearly all cases
    the recurrent c.625G>A p.(Glu209Lys). Exome or genome sequencing, or a
    developmental and epileptic encephalopathy gene panel including PACS2, is the
    route. Because the allele is absent from population databases and classified
    pathogenic in ClinVar, a single heterozygous finding is diagnostic in the right
    clinical context rather than requiring functional confirmation.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals."
    explanation: >-
      Exome sequencing is how the entity was defined and remains the diagnostic route.
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "According to ClinVar, it is pathogenic/likely pathogenic"
    explanation: >-
      The classification that makes a single heterozygous finding actionable.

- name: Brain MRI
  description: >-
    MRI supports the diagnosis rather than establishing it. Cerebellar foliar
    dysgenesis with mega cisterna magna and vermis hypoplasia is the characteristic
    pattern, but imaging is normal in a fifth of patients, so a normal scan does not
    exclude the diagnosis.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal neuroimaging findings were observed including dysgenesis of the cerebellar folia (15 cases), mega cisterna magna (13 cases), inferior vermis hypoplasia (8 cases)"
    explanation: >-
      The imaging pattern, and its counts out of 30 show why it is supportive rather
      than diagnostic.

- name: Electroencephalography
  description: >-
    EEG characterises the seizure disorder and is part of the neonatal work-up that
    typically precedes genetic testing.
  diagnosis_term:
    preferred_term: Electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
    explanation: >-
      Typed PARTIAL: the source characterises the seizure types EEG would classify,
      without describing EEG findings specific to this disorder.

treatments:
- name: Antiseizure Medication
  description: >-
    Seizures require multiple medication trials in the first year and are difficult to
    control, but frequently become easier to control or remit with age. This entry
    does not rank individual agents, because the cited sources describe the course
    rather than comparing drugs head to head.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: phenobarbital
      term:
        id: CHEBI:8069
        label: phenobarbital
    - preferred_term: carbamazepine
      term:
        id: CHEBI:3387
        label: carbamazepine
  target_mechanisms:
  - target: Neonatal-Onset Epilepsy with Age-Dependent Improvement
    treatment_effect: INHIBITS
    description: >-
      Symptomatic seizure suppression. The link is to the seizure node only - no
      antiseizure medication addresses the trafficking or proteostasis arms.
    evidence:
    - reference: PMID:29656858
      reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
      explanation: >-
        Typed PARTIAL deliberately: the source establishes that seizures are
        controlled with difficulty and later improve, but does not attribute the
        improvement to medication rather than to the natural course.
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control."
    explanation: >-
      Establishes the difficulty of control that motivates multi-agent management.
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were treated with valproate or levetiracetam (~50%), phenobarbital (~33%), and carbamazepine (~25%), and seizure frequency appeared to decrease with age"
    explanation: >-
      Gives the agents actually used and their approximate response rates, which is
      what the therapeutic_agent bindings above record. Note these are proportions
      treated with each agent rather than a controlled efficacy comparison.

- name: Pyridoxal Phosphate
  description: >-
    Intravenous pyridoxal phosphate produced an initial seizure response in reported
    cases, and seizures recurred when treatment was switched to oral vitamin B6. That
    pairing is the clinically actionable part: it suggests responsiveness specific to
    the active cofactor rather than to pyridoxine, and it is worth a trial early in a
    neonatal-onset encephalopathy where the alternative is prolonged multi-agent
    empiricism. The evidence is a small number of reported cases, not a trial.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridoxal 5'-phosphate
      term:
        id: CHEBI:18405
        label: pyridoxal 5'-phosphate
  target_mechanisms:
  - target: Neonatal-Onset Epilepsy with Age-Dependent Improvement
    treatment_effect: INHIBITS
    description: >-
      Symptomatic seizure response. No mechanism links pyridoxal phosphate to the
      PACS2 trafficking defect, so the link is to the seizure node only and this
      entry makes no claim that the response is disease-specific.
    evidence:
    - reference: PMID:38540691
      reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "initially responded to intravenous pyridoxal phosphate"
      explanation: >-
        The reported seizure response.
  evidence:
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, seizure recurrence occurred when the treatment was shifted to oral vitamin B6"
    explanation: >-
      Typed PARTIAL because it qualifies rather than supports the treatment: the
      response did not persist on oral pyridoxine, which is what distinguishes a
      pyridoxal-phosphate-specific effect from general vitamin B6 responsiveness and
      is also the reason the benefit cannot be called durable.

- name: Genetic Counseling
  description: >-
    Offered given the near-universal de novo occurrence and autosomal dominant
    inheritance once established, with recurrence risk limited to gonadal mosaicism.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.)."
    explanation: >-
      States genetic counselling as one of the direct consequences of establishing the
      molecular diagnosis in this disease group.

discussions:
- discussion_id: mismatch_heterologous_cell_line_versus_neural_disease
  prompt: >-
    The entire molecular mechanism of DEE66 - altered proteostasis, 14-3-3-epsilon
    binding, apoptotic susceptibility - was measured in colorectal carcinoma and 293T
    cells. Does any of it hold in a neuron, a cerebellum, or a developing brain?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Increased Susceptibility to Stress-Induced Apoptosis
  - pathophysiology#Altered PACS2 Proteostasis
  - pathophysiology#Cerebellar Dysgenesis
  rationale: >-
    This is the sharpest limitation in the entry, and it is structural rather than
    incidental. Every mechanistic measurement supporting the apoptosis arm comes from
    transfected transformed cell lines, and the apoptosis readout additionally
    requires an applied stressor rather than reporting spontaneous death. The disease
    phenotype, meanwhile, is a cerebellar malformation and a neonatal cortical
    epilepsy - neither of which is a cell-autonomous stress-death phenotype, and
    neither of which has been reproduced in any published in vivo model. A mouse
    carrying the variant has been reported to exist but no peer-reviewed phenotypic
    characterisation is available, and patient-derived iPSC neurons are in progress
    without published data. So the causal edge from apoptotic susceptibility to
    cerebellar dysgenesis is typed as having unknown intermediates for a reason: it is
    the field's working hypothesis, not a demonstrated route. The alternative
    possibility, that the developmental malformation arises from disturbed cargo
    trafficking during cerebellar morphogenesis with apoptosis playing little part, is
    equally consistent with everything currently published, and the same systematic
    review names candidate intermediates for it - neuronal migration, neurogenesis,
    cerebellum development and dendritic arborization - none of which requires cell
    death.
  evidence:
  - reference: PMID:36188273
    reference_title: "The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we found that PACS-2 E209K increased susceptibility to staurosporine-induced apoptosis in HCT 116 cells"
    explanation: >-
      Names both the effect and the cell line, which is precisely the mismatch: HCT116
      is a colorectal carcinoma line, not neural tissue.
  - reference: PMID:36188273
    reference_title: "The Phosphofurin Acidic Cluster Sorting Protein 2 (PACS-2) E209K Mutation Responsible for PACS-2 Syndrome Increases Susceptibility to Apoptosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overall, our findings suggest PACS-2 E209K alters PACS-2 proteostasis and favors complex formation with 14-3-3ε, leading to increased cell death in the presence of environmental stressors."
    explanation: >-
      The authors' own conclusion is conditional on environmental stressors, which is
      a weaker claim than the constitutive developmental death the cerebellar
      phenotype would require.
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glu209Lys mutation alters the regulatory domain, reflected by difficulties in PACS2 binding cargo proteins, which negatively impacts neuronal migration, neurogenesis, interneural communication, cerebellum development, and dendritic arborization"
    explanation: >-
      Names the trafficking-centred alternative route to cerebellar dysgenesis, which
      is the competing account this mismatch cannot currently exclude.
  proposed_experiments:
  - experiment_id: exp_isogenic_ipsc_cerebellar_organoid_e209k
    name: Isogenic E209K cerebellar organoids with apoptosis and trafficking readouts
    description: >-
      Differentiate patient-derived and CRISPR-corrected isogenic iPSC lines into
      cerebellar organoids and measure, side by side, baseline and stressed apoptosis
      in Purkinje and granule lineages, foliation and vermis morphology, and cargo
      trafficking through the PACS2 furin-binding region. If dysgenesis appears
      without a baseline apoptosis difference, the trafficking route is implicated and
      the apoptosis arm is an artefact of the heterologous system.

- discussion_id: gap_why_the_epilepsy_improves_with_age
  prompt: >-
    Seizures in DEE66 are difficult to control in the first year and then frequently
    improve or remit in early childhood. What changes? And does the underlying
    mechanism remit with them, or does it persist and re-emerge?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Neonatal-Onset Epilepsy with Age-Dependent Improvement
  - pathophysiology#Cortical Network Hyperexcitability
  rationale: >-
    Age-dependent improvement sets DEE66 apart from most developmental and epileptic
    encephalopathies, where drug resistance persists, and it is a clinically
    consequential difference: it changes what families are told and how aggressively
    early polytherapy is pursued. Yet nothing explains it. The cerebellar dysgenesis
    is a fixed malformation and cannot remit, so whatever improves is not the
    structural lesion. No electrophysiological work in any PACS2 system has
    characterised cortical excitability at any age, so there is no measurement of the
    thing that is supposed to be changing. The question is sharpened by the small
    adult literature, which describes progressive decline rather than continued
    improvement - only four adults have been reported, so this is a signal rather than
    an established biphasic course, but if real it would mean the early remission
    masks an ongoing process rather than reflecting a resolved one.
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood."
    explanation: >-
      The observation itself - difficult control followed by improvement - which is
      what has no mechanistic account.
  - reference: PMID:38540691
    reference_title: "Characteristics of Developmental and Epileptic Encephalopathy Associated with PACS2 p.Glu209Lys Pathogenic Variant-Our Experience and Systematic Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 4 cases have been reported in adults to date."
    explanation: >-
      Quantifies how thin the adult evidence is, which is why the possible later
      progressive phase is raised as a question rather than curated as a disease
      stage.
  proposed_experiments:
  - experiment_id: exp_longitudinal_excitability_across_development
    name: Developmental time course of cortical excitability in an E209K model
    description: >-
      In a validated in vivo or organoid E209K model, record cortical network
      excitability at neonatal, juvenile and adult equivalent stages, and ask whether
      excitability normalises on the same schedule as the clinical seizures. A model
      whose excitability normalises would locate the remission in the cortex; one
      whose excitability persists unchanged while seizures stop would point instead to
      a compensatory change elsewhere and would support the concern that the
      improvement is symptomatic rather than mechanistic.

- discussion_id: gap_mam_role_asserted_but_not_measured_for_e209k
  prompt: >-
    PACS2's role at mitochondria-associated ER membranes is routinely invoked to
    explain DEE66. Has any study actually measured a MAM defect for the E209K variant?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired PACS2 Autoregulatory Domain Function
  - pathophysiology#Increased Susceptibility to Stress-Induced Apoptosis
  rationale: >-
    PACS2 is well established in the general cell-biology literature as a regulator of
    ER-mitochondria contact sites, and reviews of this disorder frequently carry that
    role forward as the mechanism. The gap is that the step from "PACS2 does this" to
    "the E209K variant breaks this" was not evidenced in any source verified for this
    entry. This entry therefore curates only what was measured - autoregulatory-domain
    impairment, slowed turnover, increased 14-3-3-epsilon association, increased
    stress-induced apoptosis - and deliberately does not carry a MAM node, because
    doing so would import a plausible mechanism as though it were a finding. That
    matters beyond bookkeeping: a MAM-centred model predicts calcium-handling and
    mitochondrial-energetics phenotypes and suggests quite different therapeutic
    targets from a trafficking-centred or proteostasis-centred model, and the three
    are currently not distinguished by evidence.
  evidence:
  - reference: PMID:29656858
    reference_title: "A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function."
    explanation: >-
      The most specific published functional consequence of the variant. Its own hedge
      - "may disturb cellular function" - marks how far short of a defined organelle
      phenotype the evidence currently stops.
  proposed_experiments:
  - experiment_id: exp_mam_integrity_in_e209k_neurons
    name: Direct measurement of ER-mitochondria contact in E209K neurons
    description: >-
      In isogenic patient-derived neurons, quantify ER-mitochondria contact site
      number and width by electron microscopy or split-fluorophore reporter, together
      with ER-to-mitochondria calcium transfer and mitochondrial membrane potential.
      This would either substantiate the MAM model in the correct cell type or exclude
      it, and in either case it would tell curators whether the widely repeated MAM
      account belongs in the pathograph.
📚

References & Deep Research

Deep Research

1
Claude Code ▸
PACS2-Related Developmental and Epileptic Encephalopathy (DEE66): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 22 citations 2026-08-19T20:12:56.614982

PACS2-Related Developmental and Epileptic Encephalopathy (DEE66): Comprehensive Research Report

1. Disease Information

Overview. PACS2-Related Developmental and Epileptic Encephalopathy — officially catalogued as Developmental and Epileptic Encephalopathy 66 (DEE66), and previously termed Early Infantile Epileptic Encephalopathy 66 (EIEE66) — is an autosomal dominant neurodevelopmental disorder caused by a heterozygous, almost always de novo, missense variant in PACS2 (phosphofurin acidic cluster sorting protein 2), located at chromosome 14q32.33. It is characterized by neonatal- or early-infantile-onset epilepsy, global developmental delay/intellectual disability, hypotonia, characteristic facial dysmorphism, and cerebellar dysgenesis on brain MRI, often accompanied by extraneurologic features (ophthalmologic, cardiac, limb, hematologic) (OMIM #618067; Olson et al. 2018, PMID:29656858).

Key identifiers: - OMIM: #618067 (DEE66, phenotype); 610423 (PACS2, gene) - Gene: PACS2, HGNC:23794, chromosome 14q32.33 - NIH GTR condition: C4748070 ("Developmental and epileptic encephalopathy, 66") - Disease Ontology:* DOID:0080446 - Likely MONDO term for this entity corresponds to DEE66 (curators should verify exact MONDO CURIE via OMIM/Mondo cross-reference at curation time — not independently confirmed in this research pass)

Synonyms: Early Infantile Epileptic Encephalopathy 66 (EIEE66); PACS2 syndrome; DEE66; PACS2-related neurodevelopmental disorder.

Evidence basis: Nearly all published knowledge derives from aggregated case series and systematic reviews of individually reported and cohort patients (not large-cohort EHR/registry data) — the disease was first delineated in 2018 in 14 unrelated patients (PMID:29656858) and subsequent literature has grown the total to roughly ~50–100 reported individuals worldwide as of 2022–2024 (PACS2 Research Foundation; Genetics in Medicine Open 2024).

2. Etiology

Disease causal factor: A single, essentially monogenic mechanism — heterozygous missense variation in PACS2, almost always the recurrent c.625G>A, p.(Glu209Lys) [E209K] variant, arising de novo in the vast majority of cases (PMID:29656858; PMC10968252 — 30/30 reviewed patients carried this variant).

Genetic risk factors: - The E209K substitution affects a highly conserved glutamic acid residue within a domain of PACS2 involved in phosphorylation-dependent regulatory interactions (Ser207/208/213 cluster) ([Mammalian Genome 2024, doi:10.1007/s00335-024-10098-5]). - A second, rarer recurrent variant, E211K, has also been reported and studied mechanistically alongside E209K, both impairing mitochondria-associated membrane (MAM) integrity via disturbance of PACS2 phosphorylation at the Ser207/208/213 cluster. - Additional distinct missense variants have been reported in isolated cases with atypical/milder or expanded phenotypes (e.g., malformations of cortical development, migrating focal seizures of infancy), suggesting some allelic heterogeneity beyond the two hotspot residues (Checri et al. 2024, Epileptic Disorders, doi:10.1002/epd2.20184; ScienceDirect migrating focal seizures paper). - No inherited/parental transmission has been documented in the majority of families — parents are typically wild-type at the variant position, confirming de novo origin (e.g., the Saudi family study, PMC10963950). - PACS2's paralog PACS1 causes the related Schuurs-Hoeijmakers syndrome (PACS1 neurodevelopmental disorder, recurrent p.Arg203Trp), with substantial phenotypic overlap (developmental delay 100%, dysmorphism 100%, seizures 63% in PACS1) — evidence of a shared pathway mechanism (Karger Molecular Syndromology 2024, PACS2/PACS1/VACTERL overlap).

Environmental risk factors: None established; this is a purely genetic, non-environmentally-triggered disorder based on current literature.

Protective factors: None reported in the literature (genetic or environmental). No modifier alleles have been characterized.

Gene-environment interactions: Not applicable / not studied — no evidence of environmental modulation of phenotype severity.

3. Phenotypes

Seizures / epilepsy (universal, ~100%)

  • Onset: Neonatal to early infantile; in the largest systematic review (n=30), onset ranged from day 1 of life to 10 months, with 76.7% (23/30) presenting within the first 2 weeks of life (PMC10968252).
  • Seizure semiology: Focal motor seizures, tonic seizures (often affecting upper limbs), autonomic manifestations (apnea, cyanosis), abnormal eye movements/eye rolling, myoclonic seizures, and generalized tonic-clonic seizures (often febrile-triggered); focal-onset with secondary generalization predominates in the neonatal period (PMC10137075).
  • Course: Seizures are typically difficult to control in infancy/early childhood, requiring multiple anti-seizure medication trials, but frequently become easier to control — or resolve — with advancing age; 29% of patients ≥5 years old discontinued anti-seizure medication in one cohort.
  • HPO suggestions: HP:0032796 (Seizure — DEE), HP:0032810 (focal-onset seizure), HP:0002123 (generalized tonic-clonic seizure), HP:0002121 (generalized non-motor seizure), HP:0011097 (epileptic spasm as needed), HP:0007359 (focal-onset seizure), HP:0011182 (electroencephalographic abnormality), HP:0002133 (status epilepticus if applicable).

Global developmental delay / intellectual disability (~80%, universal in most series)

  • Delayed motor and speech milestones (delayed global development 80% [24/30]; speech delay 63% [19/30]).
  • Intellectual disability ranges mild to severe; progressive cognitive decline reported in adult cases.
  • HPO: HP:0001263 (Global developmental delay), HP:0001249 (Intellectual disability), HP:0000750 (Delayed speech and language development).

Hypotonia (~57%, 17/30)

  • HPO: HP:0001252 (Hypotonia).

Behavioral abnormalities (~50%, 15/30) including autism spectrum features

  • ASD reported in ~18% (4/22 with data) in one cohort.
  • HPO: HP:0000708 (Behavioral abnormality), HP:0000717 (Autism).

Movement/neurological signs

  • Nystagmus (13%, 4/30), wide-based gait (13%), pyramidal syndrome (13%).
  • HPO: HP:0000639 (Nystagmus), HP:0002136 (Broad-based gait), HP:0007256 (Progressive spasticity/pyramidal signs).

Facial dysmorphism (common but variable/subtle)

  • Hypertelorism, broad/wide nasal root, thin upper lip, highly arched eyebrows, long eyelashes, wide-spaced teeth, down-turned corners of the mouth, down-slanting palpebral fissures.
  • HPO: HP:0000316 (Hypertelorism), HP:0000414 (Broad nasal tip/root — HP:0000455), HP:0000219 (Thin upper lip vermilion), HP:0004585 (Highly arched eyebrow), HP:0000582 (Downslanted palpebral fissures), HP:0000160 (Narrow mouth or wide mouth per variant description).

Ophthalmologic features (~37%, 11/30)

  • Strabismus, nystagmus, hypermetropia, astigmatism, myopia, coloboma.
  • HPO: HP:0000486 (Strabismus), HP:0000540 (Hypermetropia), HP:0000544 (Coloboma).

Cardiac (septal defects; also tetralogy of Fallot reported in one case expanding the phenotype)

  • Atrial/ventricular septal defects: 4/30 cases (~13%); complex congenital heart disease (tetralogy of Fallot) reported in a novel case with VACTERL-like overlap.
  • HPO: HP:0001631 (ASD), HP:0001629 (VSD), HP:0001636 (Tetralogy of Fallot).

Other systemic features

  • Cryptorchidism (5 cases), distal limb malformations (12 cases), hematologic disturbances (5 cases), hydronephrosis (2 cases); anal atresia and vertebral anomalies reported in one expanded VACTERL-overlap case.
  • HPO: HP:0000028 (Cryptorchidism), HP:0002830 (Limb undergrowth/distal anomaly per specific finding), HP:0004320 (Ectopic anus/anal atresia — HP:0002023), HP:0000924 (Abnormality of the skeletal system for vertebral anomalies).

Brain imaging (MRI) findings

  • Cerebellar foliar dysgenesis (50%, 15/30) — the most characteristic neuroimaging finding.
  • Mega cisterna magna (43%, 13/30).
  • Inferior vermis hypoplasia (27%, 8/30).
  • Reduced white matter (20%, 6/30).
  • Lateral ventricle enlargement (13%).
  • Hypothalamic fusion anomalies (10%).
  • Negative/normal neuroimaging in ~20% (6/30).
  • Progressive findings in adults: severe cerebral/cerebellar atrophy, demyelinating lesions.
  • HPO: HP:0007033 (Cerebellar dysplasia/dysgenesis), HP:0002324 (Cerebellar vermis hypoplasia), HP:0002534 (Cisterna magna malformation — mega cisterna magna HP:0006955), HP:0002500 (delayed CNS myelination/HP:0002500 or reduced white matter HP:0002119), HP:0002119 (Ventriculomegaly).

Quality of life impact: Not systematically studied via validated instruments (EQ-5D/SF-36) in the literature reviewed; qualitative reports describe substantial burden from refractory neonatal/infantile seizures, limited verbal communication, poor social functioning, and — in adults — progressive neurological decline including new-onset facial hemispasm, ataxia, and tetraparesis in the oldest reported cases (PMC10968252).

4. Genetic/Molecular Information

Causal gene: PACS2 (HGNC:23794; OMIM *610423), chromosome 14q32.33.

Recurrent pathogenic variant: - c.625G>A, p.Glu209Lys (E209K) — the dominant, recurrent, de novo variant found in the overwhelming majority (~30/30 in the largest systematic review) of published DEE66 patients (PMID:29656858; PMC10968252). - c.631G>A, p.Glu211Lys (E211K) — a second, rarer recurrent hotspot variant, mechanistically studied alongside E209K. - Additional rare missense variants reported in association with somewhat expanded/atypical phenotypes (cortical malformation, migrating focal seizures of infancy, complex congenital heart disease/VACTERL overlap).

Variant classification: Pathogenic/likely pathogenic per ACMG criteria for the recurrent hotspot variants (de novo, absent from population databases, functionally validated). Curators should confirm current ClinVar star-rating and classification directly.

Variant type/class: Missense, heterozygous, gain-of-function/dominant-negative-like mechanism (see below) rather than simple loss-of-function.

Population frequency: The E209K and E211K variants are not present in gnomAD population databases (consistent with a highly penetrant de novo dominant disorder); specific PACS2 gene-level constraint metrics (pLI/LOEUF) were not confirmed in this research pass and should be pulled directly from the gnomAD browser at curation time.

Origin: Predominantly germline de novo; no confirmed cases of parental mosaicism or inherited transmission were found in this search, though the possibility of parental gonadal mosaicism has not been excluded in the literature.

Functional consequence — molecular mechanism: - PACS2 is a multifunctional sorting protein and a key regulator of mitochondria-associated membranes (MAMs) — physical tethering sites between the endoplasmic reticulum (ER) and mitochondria — controlling ER–mitochondria calcium signaling, lipid synthesis, mitophagy, ER homeostasis, and apoptosis (PACS-2: A key regulator of MAMs, PMID:32673704; PMC6627983). - The E209K (and E211K) mutations disturb PACS2 phosphorylation at the Ser207/208/213 cluster, impairing MAM integrity (Mammalian Genome 2024, doi:10.1007/s00335-024-10098-5). - Functional studies (HCT116 cell model) show E209K PACS-2 has slower protein turnover relative to wild-type upon cycloheximide treatment, and increased association with 14-3-3ε by co-immunoprecipitation. Upon apoptotic stress (staurosporine), E209K-expressing cells show markedly increased apoptosis (~80% apoptotic cells vs. ~41% for wild-type PACS-2), whereas wild-type PACS-2 is protective against stress-induced cell death (PMC9520720). The authors state: "increased levels of apoptosis agree with DEE66 patient phenotypes involving epilepsy and cerebellar dysgenesis." - This suggests a gain-of-function/altered-function mechanism (aberrant 14-3-3 client recruitment promoting apoptosis) rather than simple haploinsufficiency — consistent with the recurrent, hotspot nature of the variant and absence of reported loss-of-function (truncating) alleles causing the same phenotype. - Downstream cellular consequences implicated: disrupted MAM formation, impaired ER–mitochondria Ca²⁺ flux, inhibited mitophagy, impaired energy metabolism, and increased apoptotic susceptibility in neurons/cerebellar cells, plausibly explaining the progressive cerebellar dysgenesis/atrophy phenotype. - Suggested GO terms: GO:0032865 (regulation of mitochondrial outer membrane permeabilization), GO:0032469 (endoplasmic reticulum calcium ion homeostasis), GO:0044233 (ER-mitochondrion membrane contact site organization), GO:0006915 (apoptotic process), GO:0000422 (mitophagy).

Epigenetics/chromosomal abnormalities: No epigenetic mechanism or chromosomal-scale abnormality has been implicated; disease is driven by point missense variants.

5. Environmental Information

No environmental factors, lifestyle exposures, or infectious triggers have been implicated as causal or modifying for PACS2-related DEE66 in the literature reviewed. Febrile illness has been noted as a trigger for individual generalized tonic-clonic seizure episodes in some patients (a symptomatic exacerbant, not a disease cause) (PMC10137075).

6. Mechanism / Pathophysiology

Causal chain (proposed): 1. Trigger: De novo heterozygous PACS2 missense variant (predominantly E209K) alters a conserved residue near the Ser207/208/213 phosphorylation cluster. 2. Molecular consequence: Altered PACS2 phosphorylation/turnover kinetics and increased binding to 14-3-3ε, altering the normal pool of PACS2 client protein interactions. 3. MAM/organelle consequence: Impaired mitochondria-associated membrane (ER-mitochondria contact site) integrity; disrupted ER-mitochondria Ca²⁺ transfer; disrupted mitophagy and mitochondrial energy metabolism. 4. Cellular consequence: Increased susceptibility to apoptosis under cellular stress, particularly relevant to cerebellar granule/Purkinje neuron populations and cortical neurons during critical developmental windows. 5. Tissue/organ consequence: Cerebellar foliar dysgenesis, vermis hypoplasia, progressive cerebral/cerebellar atrophy (especially notable in the few reported adult cases), and cortical network dysfunction predisposing to neonatal-onset epilepsy. 6. Clinical manifestation: Neonatal/infantile-onset, often refractory, focal-onset epilepsy; global developmental delay/ID; hypotonia; behavioral/autistic features; and variable dysmorphic/extraneurologic features.

Upstream vs. downstream: The PACS2 phosphorylation/14-3-3 interaction defect is the most upstream molecular lesion identified; MAM/Ca²⁺-handling disruption and apoptotic susceptibility are intermediate; cerebellar dysgenesis/atrophy and cortical hyperexcitability are downstream tissue-level consequences producing the clinical phenotype.

Cell types implicated: Cerebellar Purkinje and granule neurons (dysgenesis/atrophy phenotype), cortical neurons (epileptogenesis), and more broadly any cell type dependent on ER-mitochondria MAM signaling (vascular smooth muscle cells and cardiomyocytes have also been separately studied for PACS2's MAM role, relevant to the cardiac phenotype overlap with PACS1/VACTERL).

Molecular pathway/GO terms: Suggested — GO:0044233 (ER-mitochondrion membrane contact site organization), GO:0051560 (mitochondrial calcium ion homeostasis), GO:0000422 (mitophagy), GO:0006915 (apoptotic process), GO:0035556 (intracellular signal transduction, for 14-3-3-mediated signaling).

Cell Ontology suggestions: CL:0000121 (Purkinje cell), CL:0000120 (granule cell), CL:0000540 (neuron), CL:0002319 (neural cell, generic).

Advanced/omics data: No large-scale transcriptomic, proteomic, or single-cell datasets specific to PACS2 patient tissue were identified in this search; iPSC-neuron models are in active development (see Model Organisms, section 15) but published multi-omic datasets from these models were not found as of this research date.

7. Anatomical Structures Affected

Organ level: - Primary: Central nervous system — cerebrum (cortex), cerebellum (vermis and foliae). - Secondary/associated: Cardiovascular system (septal defects, tetralogy of Fallot), ophthalmologic structures (globe/refraction, strabismus), genitourinary (cryptorchidism, hydronephrosis), gastrointestinal (anal atresia in expanded phenotype), hematologic system, and craniofacial skeleton (dysmorphic features). - Body systems: Nervous, cardiovascular, ophthalmologic, musculoskeletal, genitourinary.

UBERON suggestions: UBERON:0002037 (cerebellum), UBERON:0002038 (cerebellar vermis), UBERON:0000955 (brain), UBERON:0001017 (central nervous system), UBERON:0007100 (primary circulatory organ/heart region for septal defects), UBERON:0000970 (eye).

Tissue/cell level: Cerebellar cortex (Purkinje/granule cell layers), cerebral cortical neurons; craniofacial soft tissue (dysmorphism).

Subcellular level: Mitochondria-associated ER membranes (MAMs), mitochondrial outer membrane, endoplasmic reticulum. GO Cellular Component: GO:0044233 (ER-mitochondrion membrane contact site), GO:0005741 (mitochondrial outer membrane), GO:0005783 (endoplasmic reticulum).

Localization: Bilateral/symmetric cerebellar involvement typically; no reported lateralization pattern.

8. Temporal Development

  • Onset: Congenital/neonatal-to-infantile for the core neurological phenotype; seizure onset from day 1 of life to 10 months, with the large majority (76.7%) within the first two weeks of life. Rare later-onset (childhood) presentations reported for milder allelic variants.
  • Onset pattern: Typically acute/abrupt seizure onset in the neonatal period.
  • Progression: Epilepsy often initially difficult to control (multiple ASM trials/combinations needed in infancy/childhood), frequently improving or resolving with age (many patients seizure-free or medication-free by later childhood/adolescence). In contrast, the cognitive/neurodegenerative trajectory in the very limited adult cohort (only 4 adults reported as of the 2024 systematic review) shows progressive cerebral/cerebellar atrophy, new-onset movement abnormalities (facial hemispasm, ataxia), and cognitive regression — suggesting a biphasic course (early epileptic encephalopathy, later progressive neurodegeneration).
  • Disease course pattern: Chronic, lifelong; not classically relapsing-remitting but with an early severe epileptic phase that may partially remit, followed by potential later-life progressive decline.
  • Critical periods: Neonatal/early infantile period represents the critical window of epileptogenic vulnerability; timely genetic diagnosis in this window is emphasized in the literature as important for guiding management (e.g., trial of pyridoxal phosphate) and counseling.

9. Inheritance and Population

Epidemiology: True population prevalence/incidence is unknown (ultra-rare disease). Approximately ~50 cases were known by December 2022, growing to roughly ~100 individuals described worldwide by 2024 (PACS2 Research Foundation; PMC10968252).

Inheritance pattern: Autosomal dominant, with the overwhelming majority of cases arising de novo. No confirmed familial recurrence via germline transmission was found in this search; recurrence risk beyond the general de novo/gonadal mosaicism risk (~1%) has not been formally established in the literature.

Penetrance: Appears to be high/complete for the core epilepsy/developmental phenotype among E209K carriers reported to date, though one case of a "developmentally typical" patient with the classic c.625G>A variant and a milder phenotype (responsive to carbamazepine) has been reported, raising the possibility of variable expressivity (mosaicism was considered but excluded by deep sequencing coverage in that case).

Expressivity: Variable — phenotype severity ranges from classic severe DEE66 with refractory neonatal seizures and marked cerebellar dysgenesis to milder presentations with typical development.

Genetic anticipation: Not applicable (not a repeat-expansion disorder).

Germline mosaicism: Not formally documented but biologically plausible given the pattern of exclusively de novo occurrence; not excluded as an explanation for rare phenotypic variability.

Founder effects: None reported; cases have been described across diverse populations (including a Saudi family), consistent with recurrent de novo mutation at a mutational hotspot rather than a founder allele.

Consanguinity: Not implicated as a risk factor (autosomal dominant de novo mechanism).

Sex ratio: Roughly equal in the largest reviewed cohort (16 male, 14 female, n=30) — no strong sex bias reported.

Geographic distribution: Global; cases reported from North America, Europe, Middle East (Saudi Arabia), and elsewhere with no evident geographic clustering.

10. Diagnostics

Genetic testing (primary diagnostic modality): - Whole exome sequencing (WES) or whole genome sequencing (WGS), typically trio-based (proband + parents), is the standard diagnostic approach given the phenotype's genetic heterogeneity overlap with other early-infantile DEEs; this is how essentially all reported cases have been ascertained. - Epilepsy/DEE gene panels including PACS2 are also used clinically (e.g., listed on Genomics England PanelApp "Early onset or syndromic epilepsy" panel). - Single-gene Sanger confirmation of the recurrent E209K hotspot can be pursued when clinical suspicion is high (classic facial/cerebellar/seizure phenotype). - Genetic diagnosis timing in the reviewed cohort ranged widely (4 months to 37 years of age), reflecting historically low disease awareness, especially in adults.

Neuroimaging: Brain MRI is a key diagnostic-supportive test — cerebellar foliar dysgenesis, mega cisterna magna, and vermis hypoplasia are characteristic (though absent in ~20% of cases, so a normal MRI does not exclude the diagnosis).

EEG: Variable findings — focal/multifocal interictal discharges (often centrotemporal/frontal), burst suppression, or hypsarrhythmia in some neonatal presentations; some normalize over time.

Differential diagnosis: Other genetic DEEs presenting in the neonatal/early infantile period (e.g., KCNQ2-, SCN2A-, STXBP1-, CDKL5-related DEEs), pyridoxine-dependent epilepsy (given some PACS2 patients show transient pyridoxal-phosphate responsiveness), other cerebellar dysgenesis syndromes, and — given phenotypic overlap — PACS1-related neurodevelopmental disorder (Schuurs-Hoeijmakers syndrome).

Screening: No population or newborn screening program exists (ultra-rare, not detected by standard newborn metabolic screening); diagnosis relies entirely on clinical suspicion triggering genetic testing.

Standardized diagnostic criteria: No formal consensus diagnostic criteria; diagnosis is molecular (identification of a pathogenic PACS2 variant) in the appropriate clinical context per ILAE epilepsy classification framework for developmental and epileptic encephalopathies.

11. Outcome / Prognosis

Survival/mortality: No systematic mortality data identified in this search; the disorder is not classically described as life-limiting in early reports, though severity varies widely.

Seizure outcome: Often improves with age — many patients achieve better seizure control or seizure freedom in later childhood, with ~29% of patients ≥5 years old able to discontinue anti-seizure medication in one series.

Developmental/cognitive outcome: Ranges from low-average intelligence to severe developmental impairment; most patients have some degree of intellectual disability, speech delay, and behavioral disturbance (including autism spectrum features in ~18%).

Adult/long-term course: Limited data (only 4 adult cases reported by 2024) suggest a concerning pattern of progressive neurodegeneration in adulthood — accelerating cerebral/cerebellar atrophy, demyelinating changes, cognitive regression, and new motor symptoms (facial hemispasm, ataxia, tetraparesis) — highlighting a need for longitudinal natural history studies as the cohort ages.

Prognostic factors: Specific genotype-phenotype correlations beyond "E209K = classic/most common phenotype" are not well established; the rarer E211K and other missense variants may correlate with atypical presentations (milder or with additional features like cortical malformation or complex congenital heart disease), but sample sizes are too small for robust conclusions.

12. Treatment

Anti-seizure pharmacotherapy (symptomatic, not disease-modifying): - Valproic acid and levetiracetam — reported effective in roughly half of patients. - Phenobarbital — improvement in about one-third. - Carbamazepine/oxcarbazepine — effective in about one-quarter; notably one patient with typical development responded well to carbamazepine. - Vigabatrin — reported effective in some cases. - Pyridoxal phosphate (vitamin B6, active form) — showed promising, though sometimes transient, effectiveness in some cases; seizure recurrence occurred when switched to standard oral B6 (pyridoxine) in at least one report, suggesting a possible pyridoxal-phosphate-specific responsiveness worth trialing early.

NCIT suggestion: NCIT:C15986 (Pharmacotherapy) as the treatment_term, with therapeutic_agent bound to CHEBI terms for valproic acid (CHEBI:39867), levetiracetam (CHEBI:6437), carbamazepine (CHEBI:3387), vigabatrin (CHEBI:9944), phenobarbital (CHEBI:8069).

Supportive/rehabilitative care: Physical therapy, occupational therapy, speech therapy for hypotonia, motor delay, and speech delay; behavioral/developmental interventions for autism spectrum features. NCIT: NCIT:C15302 (Physical Therapy), NCIT:C159273 (Speech Therapy), NCIT:C121351 (Occupational Therapy).

Surgical/interventional: Cardiac surgical repair for structural congenital heart defects (septal defect closure, tetralogy of Fallot repair) in affected individuals. NCIT:C15329 (Surgical Procedure).

Experimental / emerging precision therapies (active development, not yet clinically available): - Antisense oligonucleotide (ASO) therapy: An allele-specific ASO strategy targeting the mutant E209K transcript while sparing wild-type PACS2 expression is in development in partnership with the n-Lorem Foundation (a nonprofit providing individualized ASO therapies for ultra-rare diseases), modeled on the analogous, more advanced PACS1 syndrome ASO program (see PACS1 mouse model RNA-targeted therapy work, PMC9901029; Nature Communications 2023). - Drug repurposing via high-throughput Cell Painting screening: The PACS2 Research Foundation, in partnership with Charles River Laboratories (Leiden), screened the Broad Institute's Drug Repurposing Hub (~6,808 compounds) against patient-derived fibroblasts using morphological (Cell Painting) profiling compared to an unaffected twin sibling's cells, identifying several candidate compounds that shifted the diseased-cell morphological signature toward the healthy phenotype; potency/dose-optimization screening is ongoing as of the most recent reporting (Charles River Eureka blog). - PROTAC (targeted protein degradation) approaches to selectively degrade mutant PACS2 protein are proposed as an emerging strategy, pending further mechanistic clarification (PACS2 Cure Roadmap, Perlara).

Genetic counseling: Recommended for all newly diagnosed families given the near-universal de novo occurrence, low but non-zero recurrence risk (germline mosaicism), and autosomal dominant inheritance pattern once established. NCIT:C15240 (Genetic Counseling).

Clinical trials: No PACS2-specific registered interventional clinical trials (NCT identifiers) were identified in this search; the disease remains in the preclinical/translational research stage for targeted therapies.

13. Prevention

No primary, secondary, or tertiary prevention strategies exist for this de novo genetic disorder — there are no known modifiable risk factors. The main "prevention" mechanism available is prenatal/preimplantation genetic diagnosis for families with a previously affected child (relevant given theoretical germline mosaicism recurrence risk), and genetic counseling for recurrence risk discussion. No immunization, screening program, or public health intervention is applicable. NCIT:C15240 (Genetic Counseling) remains the most relevant preventive/counseling intervention captured in ontology terms.

14. Other Species / Natural Disease

No naturally occurring PACS2-associated disease has been reported in non-human species (companion animals or wildlife) in the literature reviewed — this is a human-only reported condition to date, consistent with its very recent (2018) delineation and ultra-rare status. PACS2 is evolutionarily conserved (the E209 residue is conserved down to zebrafish, per the PACS2 Cure Roadmap document), supporting cross-species relevance for engineered models (see below) but no evidence of spontaneous veterinary cases.

15. Model Organisms

This is an area of very active, ongoing translational development, primarily driven by the PACS2 Research Foundation and academic/industry collaborators (Perlara PBC "cure roadmap"; Jackson Laboratory; Charles River Laboratories):

  • Yeast: Not a viable model — PACS2 has no ortholog in yeast.
  • Drosophila / C. elegans: Deprioritized — the critical glutamate at position 209 is not conserved in fly or worm PACS orthologs, limiting translational relevance.
  • Zebrafish: E209 is conserved in zebrafish PACS2, making a heterozygous E209K knock-in zebrafish model biologically feasible; proposed for future generation (deprioritized pending cellular-assay proof of concept as of the most recent roadmap update). No published zebrafish PACS2 model was identified as of this search.
  • Mouse: A Pacs2^E209K/+ mouse model reportedly exists (noted as "approved in Poland" per the PACS2 Research Foundation) but requires further phenotypic characterization; a humanized Pacs2 E209K/+ mouse model at The Jackson Laboratory has been proposed specifically to support preclinical ASO testing. No peer-reviewed publication describing detailed phenotype recapitulation in this mouse model was identified in this search — this represents a knowledge gap in the current literature (model exists per foundation reporting, but published characterization is not yet available).
  • Patient-derived iPSCs: Multiple iPSC lines have been generated from PACS2 patients (e.g., "Lena's" fibroblast-derived iPSCs) and are being differentiated into neurons in collaboration with academic labs (e.g., Dr. A. Guemez-Gamboa) to study E209K effects on neuronal mitochondrial function, protein interactions, and developmental phenotypes, alongside CRISPR-corrected isogenic controls. No published dataset from these iPSC-neuron models was identified as of this research pass.
  • Cell line models (non-neuronal): HCT116 human colorectal carcinoma cells transfected with PACS-2 WT vs. E209K have been used to directly demonstrate increased apoptotic susceptibility and altered 14-3-3ε binding (PMC9520720). Patient-derived dermal fibroblasts have been used for the Cell Painting drug-repurposing screen described above.

Model limitations: No model to date has published in vivo confirmation of the characteristic cerebellar dysgenesis or epilepsy phenotype seen in human patients — this is an important translational gap. Curators modeling this disease should flag a HUMAN_MODEL_MISMATCH-type caveat: current functional/mechanistic data (apoptosis susceptibility, MAM/14-3-3 interaction) derive from heterologous cell-line overexpression systems (HCT116) rather than neurons or an in vivo nervous system model, so translational validity of the apoptosis-centric mechanism to human cerebellar/cortical pathology in situ remains to be directly confirmed.

Summary of Key Ontology Term Suggestions

Domain Suggested terms
Disease OMIM:618067; DOID:0080446; (MONDO CURIE to be confirmed)
Gene HGNC:23794 (PACS2); OMIM:*610423
Phenotypes (HP) HP:0032796/HP:0032810 (seizures), HP:0001263 (global DD), HP:0001249 (ID), HP:0001252 (hypotonia), HP:0000717 (autism), HP:0007033 (cerebellar dysgenesis), HP:0002324 (vermis hypoplasia), HP:0006955 (mega cisterna magna), HP:0000582 (downslanted palpebral fissures), HP:0000316 (hypertelorism), HP:0001629/HP:0001631 (septal defects), HP:0000486 (strabismus)
GO (biological process) GO:0044233 (ER-mitochondrion MCS organization), GO:0051560 (mitochondrial Ca²⁺ homeostasis), GO:0000422 (mitophagy), GO:0006915 (apoptotic process)
CL (cell type) CL:0000121 (Purkinje cell), CL:0000120 (cerebellar granule cell), CL:0000540 (neuron)
UBERON UBERON:0002037 (cerebellum), UBERON:0002038 (cerebellar vermis), UBERON:0000955 (brain)
CHEBI (drugs) CHEBI:39867 (valproic acid), CHEBI:6437 (levetiracetam), CHEBI:3387 (carbamazepine), CHEBI:9944 (vigabatrin), CHEBI:8069 (phenobarbital)
NCIT (treatment) NCIT:C15986 (Pharmacotherapy), NCIT:C15302 (Physical Therapy), NCIT:C15240 (Genetic Counseling), NCIT:C15329 (Surgical Procedure)

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 12
Resolved 10
Unresolved (possible confabulation) 2
Unverifiable 0
References weighed for topical relevance 10
On topic 5
Off topic 2

Unresolved references

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

  • DOI:10.1002/epd2.20184](https://onlinelibrary.wiley.com/doi/abs/10.1002/epd2.20184 (1 mention) - Identifier did not resolve to a record
  • DOI:10.1159/000539473/911172/PACS2-PACS1-and-VACTERL-A-Clinical-Overlap (3 mentions) - Identifier did not resolve to a record

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:32673704 (4 mentions) - PACS-2: A key regulator of mitochondria-associated membranes (MAMs).
  • shared terms: disease
  • PMC:PMC6627983 (4 mentions) - The Multifunctional Sorting Protein PACS-2 Controls Mitophagosome Formation in Human Vascular Smooth Muscle Cells through Mitochondria-ER Contact Sites.
  • shared terms: cell, model

Weighed against this report's own most characteristic terms: phenotype, pacs2, seizure, disease, cerebellar, patient, developmental, variant, genetic, e209k, hpo, cell, dysgenesis, epilepsy, novo, model, development, disorder, neonatal, feature.