Developmental And Epileptic Encephalopathy 38

Mendelian MONDO:0014868 Pathograph 11 Show in embeddings browser Genetic Developmental and Epileptic Encephalopathy

DEE38 (EIEE38) is an autosomal recessive developmental and epileptic encephalopathy caused by biallelic loss-of-function variants in ARV1, a multi-pass endoplasmic-reticulum transmembrane protein. ARV1 was first characterized in yeast as a sterol/lipid homeostasis factor, but its disease-relevant human role is as a facilitating component of the GPI N-acetylglucosaminyltransferase (GPI-GnT) complex that initiates glycosylphosphatidylinositol (GPI) anchor biosynthesis; loss of ARV1 therefore reduces cell-surface expression of GPI-anchored proteins, placing DEE38 among the inherited GPI-deficiency disorders. Affected infants present in the first months of life with early-onset refractory seizures (including epilepsy of infancy with migrating focal seizures), profound global developmental delay with regression, axial hypotonia, cortical visual impairment, and progressive cerebral and cerebellar atrophy. A missense allelic subset shows a somewhat milder, ataxia-and-elevated-AFP presentation, and dilated cardiomyopathy has been reported in a minority. There is no disease-modifying therapy; the untreated course is frequently lethal in childhood, usually from aspiration and respiratory infection.

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1
Inheritance
4
Pathophys.
21
Phenotypes
2
Gaps
11
Pathograph
1
Genes
3
Medical Actions
2
Models
10
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
DEE38 is autosomal recessive: affected individuals carry biallelic ARV1 variants (homozygous in consanguineous families, or compound heterozygous). Reported alleles include missense (p.Gly189Arg), in-frame deletions (p.Lys59_Asn98del, p.Leu185del), splice variants (c.294+1G>A, c.674-2A>T) and truncating/frameshift variants (p.Ser122Glnfs*7, p.Trp163*, p.Phe144Argfs*5).
Autosomal recessive inheritance
Show evidence (2 references)
PMID:32165008 SUPPORT Human Clinical
"Here we describe seven patients from two unrelated families with biallelic splice mutations in ARV1."
Documents biallelic causation across two unrelated families, consistent with recessive inheritance.
PMID:34296759 SUPPORT Human Clinical
"We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants."
Independent confirmation of biallelic recessive causation and of allelic heterogeneity.
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Discussions and Knowledge Gaps

2
Is the neuronal injury in ARV1 deficiency driven mainly by the GPI-anchor biosynthesis defect, by disruption of ARV1's ancestral sterol/sphingolipid trafficking role, or by both acting together?
KNOWLEDGE GAP OPEN gap_gpi_versus_lipid_driver
Attached to
pathophysiology#Impaired GPI Anchor Biosynthesis pathophysiology#Neuronal Dysfunction and Epileptic Encephalopathy
Yeast Arv1 has documented roles in both GPI-anchor flow and sterol/sphingolipid homeostasis, and human ARV1 conserves both. The strongest direct human evidence points at the GPI-anchoring branch: patient cells show reduced surface GPI-anchored proteins, the 2025 reconstitution work places ARV1 in the GPI-GnT complex, and a patient allele impaired GPI-anchored Gas1 maturation without affecting sphingolipid synthesis. But whether residual lipid dyshomeostasis contributes independently to neuronal injury is not resolved, and the branch point is stated as open in the literature.
Proposed experiments
Dissecting GPI versus lipid contributions in ARV1-null neurons
exp_neuronal_gpi_vs_lipid_dissection
In ARV1-null human iPSC-derived neurons, separately restore GPI-anchoring (e.g. by re-expressing an ARV1 mutant competent for GPI-GnT support but not lipid handling, or vice versa) and measure rescue of neuronal excitability, survival and GPI-anchored protein levels, to attribute the neuronal phenotype to each function.
Show evidence (1 reference)
PMID:32462292 SUPPORT In Vitro
"complementation tests in yeast showed that the ARV1 p.Gly189Arg mutation leads to deficient maturation of Gas1, a GPI-anchored protein, but does not affect sphingolipid synthesis"
Evidence that at least one patient allele separates the GPI defect from the sphingolipid role, which is the crux of this open question.
By what route does reduced surface expression of GPI-anchored proteins produce neuronal hyperexcitability and seizures in the developing brain?
KNOWLEDGE GAP OPEN gap_excitation_inhibition_route
Attached to
pathophysiology#Reduced Cell-Surface GPI-Anchored Protein Expression pathophysiology#Neuronal Dysfunction and Epileptic Encephalopathy
The link from the measured cellular defect to seizures is drawn by analogy to other inherited GPI-deficiency disorders that share the clinical and imaging picture, and to a proposed role for ER stress from immature GPI-anchored proteins. No excitation-inhibition measurement exists in ARV1 deficiency, so the entry deliberately does not conform to the epilepsy_excitation_inhibition_imbalance module: doing so would assert a mechanism that has not been measured here.
Proposed experiments
Excitation-inhibition measurement in ARV1-deficient neural models
exp_arv1_neuronal_excitability
Use multi-electrode array or patch-clamp recordings in ARV1-null iPSC neuronal networks (and the neuronal Arv1 knockout mouse) to test whether a measurable excitation-inhibition imbalance underlies the seizures, and whether it tracks with loss of specific GPI-anchored synaptic/adhesion proteins.
Show evidence (1 reference)
PMID:34017911 SUPPORT Human Clinical
"this severe syndrome can be assigned to the group of inherited GPI deficiency disorders, with which it shares remarkably similar clinical and neuroimaging features"
The analogy-based reasoning that stands in for a demonstrated excitation-inhibition route, which is what this gap flags.
⚙

Pathophysiology

4
Biallelic ARV1 Loss of Function
ARV1 is a ubiquitously expressed ~271-residue multi-pass ER transmembrane protein with an N-terminal conserved ARV1 homology domain carrying a putative zinc-binding motif. Biallelic variants reduce or abolish functional ARV1: truncating and frameshift alleles trigger nonsense-mediated decay, splice variants reduce transcript and protein and delete conserved domains, and missense/in-frame-deletion alleles fail (or only partially rescue) the temperature-sensitive growth defect of arv1-null yeast. Neither the p.Lys59_Asn98del nor the previously reported p.Gly189Arg allele produced detectable protein in mammalian cells.
ARV1 hgnc:29561 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ARV1 (hgnc:29561). hgnc:29561 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired GPI Anchor Biosynthesis Loss of ARV1 removes a facilitating component of the GPI-GnT complex that initiates GPI-anchor assembly.
Show evidence (2 references)
PMID:27270415 SUPPORT In Vitro
"In contrast to wild type human ARV1, neither variant expressed detectable levels of protein in mammalian cells."
Directly demonstrates loss of ARV1 protein for the disease-associated variants, grounding the loss-of-function trigger.
PMID:35227294 SUPPORT Other
"The human ARV1 encodes a ubiquitously expressed 271-amino-acid protein containing the N-terminal ARV1 homology domain (AHD), which also includes a putative zinc-binding motif and the first of six predicted transmembrane domains"
Source for the protein architecture (length, AHD, zinc-binding motif, transmembrane topology) described in this node.
Impaired GPI Anchor Biosynthesis
The disease-relevant consequence of ARV1 loss is impaired initiation of GPI anchor biosynthesis. ARV1 associates with PIGQ within the GPI-GnT complex and promotes efficient recruitment of the phosphatidylinositol substrate; an ARV1 mutant unable to associate with PIGQ loses the ability to enhance GPI-GnT activity. In a complementation assay the human p.Gly189Arg allele caused deficient maturation of the GPI-anchored protein Gas1 without affecting sphingolipid synthesis, isolating the GPI-anchoring defect as the mechanistically decisive lesion. Whether ARV1's ancestral sterol/sphingolipid trafficking role contributes independently to neuronal injury is unresolved (see gap_gpi_versus_lipid_driver).
GPI anchor biosynthetic process GO:0006506 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased GPI anchor biosynthetic process (GO:0006506). GO:0006506 is a biological process from the Gene Ontology. ↓ DECREASED
phosphatidylinositol N-acetylglucosaminyltransferase activity GO:0017176 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phosphatidylinositol N-acetylglucosaminyltransferase activity (GO:0017176). GO:0017176 is a molecular function from the Gene Ontology. ↓ DECREASED
Experimental models
Yeast arv1-null complementation assay OTHER Yeast complementation grades how well each human ARV1 allele supports GPI-anchor synthesis, providing the functional read on allele severity.
Downstream
Reduced Cell-Surface GPI-Anchored Protein Expression Failure of GPI-anchor assembly reduces the amount of mature GPI available to anchor client proteins at the cell surface.
Show evidence (2 references)
PMID:40378954 SUPPORT In Vitro
"ARV1 associates with PIGQ, a GPI-GnT component, and ARV1 mutants defective in this association lose their ability to enhance GPI-GnT activity, showing that association with PIGQ is critical for ARV1's function."
Establishes the molecular mechanism by which ARV1 supports GPI-GnT activity and how its loss impairs the pathway.
PMID:32462292 SUPPORT In Vitro
"complementation tests in yeast showed that the ARV1 p.Gly189Arg mutation leads to deficient maturation of Gas1, a GPI-anchored protein, but does not affect sphingolipid synthesis"
Isolates the GPI-anchoring defect from the sphingolipid role for a patient allele, supporting GPI biosynthesis as the decisive lesion.
Reduced Cell-Surface GPI-Anchored Protein Expression
Patient neutrophils and fibroblasts show significantly reduced surface expression of multiple GPI-anchored proteins (CD16 with ~5% residual expression, CD66b, CD55/CD59, and reduced FLAER binding in neutrophils; CD59 and CD87/uPAR in fibroblasts). This cellular readout is what assigns ARV1 deficiency to the inherited GPI-deficiency disorders and is corrected by lentiviral re-expression of wild-type ARV1, establishing it as the reversible core molecular defect.
Neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology. Dermal fibroblast CL:0002620 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Dermal fibroblast, annotated with skin fibroblast (CL:0002620). CL:0002620 is a cell type from the Cell Ontology.
Downstream
Neuronal Dysfunction and Epileptic Encephalopathy Loss of GPI-anchored signaling and adhesion proteins on developing neuronal membranes is the proposed route to the encephalopathy, by analogy to other inherited GPI-deficiency disorders that share the clinical and neuroimaging picture. The intervening steps are not demonstrated in human neural tissue.
Show evidence (2 references)
PMID:32165008 SUPPORT In Vitro
"The splice variants resulted in decreased ARV1 expression and significant decreases in GPI-anchored protein on the membranes of neutrophils and fibroblasts, indicating that the loss of ARV1 results in impaired GPI-anchor synthesis."
Direct measurement of reduced surface GPI-anchored proteins in patient cells.
PMID:34296759 SUPPORT In Vitro
"Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype. A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively..."
Independent confirmation of the surface deficit and its correction by wild-type ARV1, establishing reversibility of the core defect.
Neuronal Dysfunction and Epileptic Encephalopathy
The clinical endpoint is an early-infantile developmental and epileptic encephalopathy with drug-refractory seizures, profound developmental delay with regression, and progressive cerebral and cerebellar atrophy. A neuronal conditional knockout of Arv1 in mice recapitulates the seizure phenotype and a severe adult survival defect, supporting a neuron-autonomous requirement for ARV1. This entry does not declare conformance to the epilepsy_excitation_inhibition_imbalance module: no excitation-inhibition measurement exists in ARV1 deficiency and asserting that mechanism would substitute a plausible route for an evidenced one (see gap_excitation_inhibition_route).
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.
Animal models
Neuronal Arv1 conditional knockout mouse Mouse recapitulates Neuron-specific loss of Arv1 reproduces the seizure phenotype and a severe survival defect, isolating a neuronal requirement for ARV1.
Show evidence (2 references)
PMID:27270415 SUPPORT Model Organism
"Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood."
Demonstrates that neuron-specific loss of Arv1 is sufficient for the seizure phenotype, supporting neuronal dysfunction as the disease endpoint.
PMID:32165008 SUPPORT Human Clinical
"The patients presented with early onset epilepsy, global developmental delays, profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy."
Characterizes the clinical endpoint syndrome across a multi-patient series.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Developmental And Epileptic Encephalopathy 38 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

21
Cardiovascular 1
Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35227294 SUPPORT Human Clinical
"The finding of dilated cardiomyopathy in the presented as well as in three previously reported patients from two different families indicates that dilated cardiomyopathy is a part of the ARV1-induced DEE38 phenotype. However, more data are needed to make this conclusion definitive."
Reports dilated cardiomyopathy in a subset and flags it as not yet definitively established, which the description preserves.
Digestive 1
Feeding difficulties VERY_FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32165008 SUPPORT Human Clinical
"our patients present with early onset seizures, central hypotonia, severe developmental delay, visual impairment and feeding difficulties, supporting the clinical diagnosis of IEE38"
Names feeding difficulties among the features present across the series, the basis for the VERY_FREQUENT band.
PMID:32165008 SUPPORT Human Clinical
"Poor feeding, choking episodes and probable aspiration pneumonia were managed with NG-feeding from age 17 months."
A worked example connecting the feeding difficulty to aspiration, the mortality mechanism recorded under progression.
Eye 3
Cortical visual impairment Cerebral visual impairment HP:0100704 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cortical visual impairment, annotated with Cerebral visual impairment (HP:0100704). HP:0100704 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32165008 SUPPORT Human Clinical
"profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy"
Reports cortical visual impairment in the patient series.
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:32165008 SUPPORT Human Clinical
"An ophthalmological examination confirmed visual inattention, nystagmus, roving eye movements and small optic discs on fundoscopy."
Documents nystagmus and roving eye movements on formal ophthalmological examination.
Retinal dystrophy HP:0000556 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal dystrophy (HP:0000556). HP:0000556 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35227294 SUPPORT Human Clinical
"one additional patient with the homozygous ARV1 p.K59_N98del splice variant who showed severe neurodevelopmental delay, an intractable infantile onset seizure, movement disorder, and retinal dystrophy and died at the age of 1 year"
Documents retinal dystrophy in a reported patient, sourced from the case-summary review of the original report.
Metabolism 2
Refractory epilepsy Refractory drug response HP:0020174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Refractory epilepsy, annotated with Refractory drug response (HP:0020174). HP:0020174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34017911 SUPPORT Human Clinical
"Intractable nonmotor seizures started in both at the eighth month of life, exhibiting the electroclinical characteristics of epilepsy of infancy with migrating focal seizures (EIMFS)."
Documents intractable (refractory) seizures in the ARV1 spectrum.
Elevated circulating alpha-fetoprotein concentration HP:0006254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating alpha-fetoprotein concentration (HP:0006254). HP:0006254 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37749428 SUPPORT Human Clinical
"ARV1 can also be associated with increased alpha-fetoprotein."
States the alpha-fetoprotein elevation associated with ARV1.
Musculoskeletal 3
Axial hypotonia VERY_FREQUENT HP:0008936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial hypotonia (HP:0008936). HP:0008936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34017911 SUPPORT Human Clinical
"both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity"
Reports severe axial hypotonia as an early feature.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral spasticity, annotated with Spasticity (HP:0001257), qualified as course progressive. HP:0001257 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:32165008 SUPPORT Human Clinical
"The neurodegenerative course (increasing seizures, central hypotonia, peripheral spasticity, ataxia and dystonia) appeared to be progressive in Family II"
Names peripheral spasticity as part of the progressive neurodegenerative course, which the clinical_course qualifier records.
Abnormal skeletal muscle morphology HP:0011805 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal skeletal muscle morphology (HP:0011805). HP:0011805 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35227294 SUPPORT Human Clinical
"the muscle histology of ARV1 patients, as well as of ARV1-knockout mice, indicated that at least skeletal muscle impairment is also a part of the ARV1-associated phenotype"
States the histological skeletal-muscle involvement in patients; the same sentence cites the concordant knockout-mouse histology.
Nervous System 11
Epileptic encephalopathy HP:0200134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34296759 SUPPORT Human Clinical
"Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features."
Establishes the early-onset refractory-seizure encephalopathy as the core presentation.
Migrating focal seizures HP:0032786 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Migrating focal seizure (HP:0032786). HP:0032786 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34017911 SUPPORT Human Clinical
"adds epilepsy with migrating focal seizures and myoclonic status to the spectrum of epilepsy phenotypes"
Explicitly adds migrating focal seizures to the ARV1 epilepsy spectrum.
Myoclonic status epilepticus HP:0002133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Status epilepticus (HP:0002133). HP:0002133 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34017911 SUPPORT Human Clinical
"continuous epileptiform EEG activity of extremely high amplitude appeared in association with myoclonic status, leading to severely impaired alertness and responsiveness"
Documents myoclonic status epilepticus in the ARV1 spectrum.
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:32165008 SUPPORT Human Clinical
"The patients presented with early onset epilepsy, global developmental delays, profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy."
Reports global developmental delay across the patient series.
Developmental regression HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376), qualified as course progressive. HP:0002376 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:34296759 SUPPORT Human Clinical
"early onset refractory seizures followed by regression and specific neuroimaging features"
States that regression follows the refractory seizures.
Intellectual disability 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:35227294 SUPPORT Human Clinical
"we present a novel homozygous in-frame ARV1-deletion (c.554_556delTAT, p.L185del) in a 21-year old Caucasian man with developmental delay, intellectual disability, seizures, walking and speech impairments"
Documents intellectual disability in a long-surviving affected adult.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059), qualified as course progressive. HP:0002059 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:34017911 SUPPORT Human Clinical
"Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination."
Documents progressive atrophic changes on serial imaging.
Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272), qualified as course progressive. HP:0001272 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:34017911 SUPPORT Human Clinical
"Postmortem neuropathologic examination of the brain, performed in one, revealed atrophic brain changes, mainly involving the cerebellum."
Neuropathologic confirmation of cerebellar-predominant atrophy.
CNS hypomyelination HP:0003429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is CNS hypomyelination (HP:0003429). HP:0003429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34017911 SUPPORT Human Clinical
"Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination."
Reports severe hypomyelination on MRI.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37749428 SUPPORT Human Clinical
"other unique clinical features include ophthalmological abnormalities and movement disorders in the form of ataxia and dystonia, especially in those with missense mutation"
Documents ataxia in the missense allelic subset.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37749428 SUPPORT Human Clinical
"movement disorders in the form of ataxia and dystonia, especially in those with missense mutation"
Documents dystonia in the ARV1 movement-disorder spectrum.
🧬

Genetic Associations

1
ARV1 (Pathogenic Variants)
Gene: ARV1 hgnc:29561 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ARV1 (hgnc:29561). hgnc:29561 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:27270415 SUPPORT Human Clinical
"Our data support ARV1 deficiency as a cause of autosomal recessive epileptic encephalopathy."
The gene-disease association statement establishing ARV1 as causative.
PMID:25558065 SUPPORT Human Clinical
"This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1,..."
The original whole-exome discovery of ARV1 as a recessive neurogenetic disease gene.
PMID:35227294 SUPPORT Human Clinical
"So far, three different homozygous ARV1 and two compound heterozygous mutations in humans have been reported in 15 children"
Summarizes the allelic and cohort landscape underlying the variant notes.
+ 2 more references
💊

Medical Actions

3
Antiseizure medication (symptomatic)
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: 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. clobazam CHEBI:31413 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses clobazam (CHEBI:31413). CHEBI:31413 is a therapeutic agent from Chemical Entities of Biological Interest. topiramate CHEBI:63631 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses topiramate (CHEBI:63631). CHEBI:63631 is a therapeutic agent from Chemical Entities of Biological Interest. vitamin B6 (pyridoxine) CHEBI:16709 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vitamin B6 (pyridoxine), annotated with pyridoxine (CHEBI:16709). CHEBI:16709 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Management is symptomatic. Multiple antiseizure medicines are trialed — reported regimens include levetiracetam, clobazam, topiramate and vitamin B6 (pyridoxine) — with at best partial or transient seizure control, and the epilepsy is characteristically pharmacoresistant. No disease-modifying or ARV1-specific pharmacotherapy exists.
Target Phenotypes: Epileptic encephalopathy HP:0200134 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:34296759 SUPPORT Human Clinical
"Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features."
Establishes the refractory nature of the seizures that symptomatic antiseizure therapy targets with limited success.
PMID:32165008 SUPPORT Human Clinical
"She received multiple AEDs (levetiracetam, clobazam, vitamin B6) with some success."
Names the antiseizure agents used in a reported patient, with the partial response the description records.
PMID:32165008 SUPPORT Human Clinical
"She was discharged on oral topiramate, clobazam, levetiracetam, vitamin B."
Documents the topiramate-containing maintenance regimen in a second reported patient.
ARV1 gene replacement (preclinical)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Lentiviral transduction of wild-type ARV1 cDNA into patient fibroblasts rescued the cell-surface GPI-anchored-protein deficiency, demonstrating cellular reversibility of the core molecular defect and providing a rationale for gene-replacement therapy. This remains a cell-based proof of concept with no in vivo or clinical data.
Mechanism Target:
RESTORES Reduced Cell-Surface GPI-Anchored Protein Expression — Re-expressing wild-type ARV1 restores GPI-anchored protein levels on the cell surface in patient fibroblasts.
Show evidence (1 reference)
PMID:34296759 SUPPORT In Vitro
"A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations."
The cell-based gene-replacement proof of concept that this preclinical treatment node records.
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. Ontology label: Genetic Counseling NCIT:C15240
Because DEE38 is autosomal recessive, genetic counseling of families (including recurrence-risk and carrier-testing discussion) is part of care.
Show evidence (1 reference)
PMID:34296759 SUPPORT Human Clinical
"We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants."
Establishes the biallelic recessive genotype that makes recurrence-risk counseling relevant.
🌍

Environmental Factors

1
Febrile illness
No exposure_term is bound: ECTO and XCO were searched for fever / febrile illness / infection exposure concepts and neither ontology carries a suitable exposure term for endogenous fever or intercurrent febrile infection, so the entry is deliberately left free-text rather than bound to a broader, inaccurate term.
Intercurrent febrile illness aggravates the epilepsy: seizures are often both febrile and afebrile from onset, fever admissions are accompanied by increased seizure frequency and reduced consciousness, and febrile respiratory infections precipitate status epilepticus and the terminal deteriorations reported in several patients. Fever is an aggravating trigger acting on an established disease, not a cause of it.
Show evidence (2 references)
PMID:32165008 SUPPORT Human Clinical
"At 6 months of age, she had her first seizure, followed by frequent episodes of both febrile and non-febrile seizures, some requiring hospitalization."
Establishes fever as a recurrent seizure precipitant from disease onset in a reported patient.
PMID:32165008 SUPPORT Human Clinical
"At age 7 months she was admitted in status epilepticus with a febrile illness."
A second patient in whom a febrile illness precipitated status epilepticus.
Mechanism Target:
EXACERBATES Neuronal Dysfunction and Epileptic Encephalopathy — Febrile episodes worsen seizure frequency and level of consciousness in the established encephalopathy; the physiological route (temperature sensitivity of the underlying neuronal dysfunction versus nonspecific illness effects) has not been dissected.
Show evidence (1 reference)
PMID:32165008 SUPPORT Human Clinical
"At age 2 years she was again admitted to hospital with high fever, increasing seizure frequency, decreased level of consciousness and was unresponsive."
Documents fever coinciding with increased seizure frequency and deteriorated consciousness, supporting the exacerbating link.
🔬

Diagnosis

2
Whole exome sequencing
Diagnosis rests on identifying biallelic ARV1 variants by exome (or genome) sequencing. Because ARV1 was a novel gene and variants can be missense of uncertain significance, functional support is often sought.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:32165008 SUPPORT Human Clinical
"Mutations were discovered through whole exome sequencing and alternate splicing was validated on the cDNA level."
Establishes exome sequencing as the diagnostic route, with cDNA validation of splice effects.
Flow cytometry for GPI-anchored proteins
Reduced surface expression of GPI-anchored proteins on neutrophils (CD16, CD66b, FLAER) or fibroblasts (CD59, CD87) is a functional signature shared with the inherited GPI-deficiency disorders and supports pathogenicity of an ARV1 variant.
flow cytometry NCIT:C16585 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:34296759 SUPPORT In Vitro
"Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype."
Establishes the GPI-anchored-protein flow cytometry assay as functional diagnostic support.
📈

Progression

2
Onset
Onset is in early infancy. Visual inattention, hypotonia and developmental concern are frequently noted in the first months, with seizures typically beginning between roughly 2 and 8 months of life.
Show evidence (1 reference)
PMID:34017911 SUPPORT Human Clinical
"Since their first months of life, both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity. Intractable nonmotor seizures started in both at the eighth month of life"
Documents the early-infantile onset of hypotonia and developmental concern with seizure onset in the first year.
Untreated course and mortality
The course is severe and often lethal in childhood, particularly for truncating/splice genotypes; several reported children died in the first years of life, commonly from aspiration and respiratory infection during intercurrent illness.
Show evidence (2 references)
PMID:34017911 SUPPORT Human Clinical
"Both sisters died prematurely during respiratory infections."
Documents premature death from respiratory infection in the severe phenotype.
PMID:32165008 SUPPORT Human Clinical
"He deteriorated with increasing seizures and died at age 15 months as result of aspiration pneumonia."
A worked example of early death from aspiration pneumonia.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
DEE38 is ultra-rare. Only small numbers of patients had been reported as of the most recent reviews (about 16 patients tabulated in 2022 and roughly 28 reported cases cited in a 2025 case report); no population prevalence has been estimated. These are dated lower bounds rather than current totals.
Show evidence (1 reference)
PMID:35227294 SUPPORT Human Clinical
"So far, three different homozygous ARV1 and two compound heterozygous mutations in humans have been reported in 15 children"
A literature count consistent with an ultra-rare disorder; kept as a count rather than converted to a population rate.
🧫

Experimental Models

1
Yeast arv1-null complementation assay OTHER
Saccharomyces cerevisiae lacking ARV1 has GPI-anchor-synthesis and growth/temperature defects that can be rescued by human ARV1, and this complementation system is used to grade the functional impact of human ARV1 alleles. The p.Gly189Arg allele only partially rescues the yeast defect; the p.Lys59_Asn98del deletion fails to rescue at restrictive temperature.
Organism
Saccharomyces cerevisiae NCBITaxon:4932 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Saccharomyces cerevisiae (NCBITaxon:4932). NCBITaxon:4932 is an organism from the NCBI Taxonomy.
Publication
PMID:27270415
Pathograph links
Impaired GPI Anchor Biosynthesis measures fidelity: moderate Yeast complementation grades how well each human ARV1 allele supports GPI-anchor synthesis, providing the functional read on allele severity.
Limitations: Yeast Arv1 also acts in sterol/sphingolipid homeostasis, so a rescue readout in yeast does not by itself resolve which ARV1 function is disease-decisive in human neurons.
Show evidence (1 reference)
PMID:27270415 SUPPORT In Vitro
"The p.(Gly189Arg) variant partially rescued the temperature-dependent growth defect in arv1Δ yeast, while p.(Lys59-Asn98del) completely failed to rescue at restrictive temperature."
Demonstrates the assay grading allele function, the readout this model provides.
Show evidence (1 reference)
PMID:26460143 SUPPORT In Vitro
"Overexpression of human ARV1 could rescue the phenotypes associated with GPI anchor synthesis defect in the yeast arv1Δ mutant."
Establishes that human ARV1 complements the yeast GPI defect, validating the assay for grading human alleles.
🐁

Animal Models

1
Neuronal Arv1 conditional knockout mouse Genetic
Mice with a neuronal deletion of Arv1 recapitulate the human phenotype, exhibiting seizures and a severe adult survival defect, supporting a neuron-autonomous requirement for ARV1.
Species
Mouse
Genotype
Neuron-specific Arv1 deletion
Genes
Arv1 hgnc:29561 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns Arv1 (hgnc:29561). hgnc:29561 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:27270415
Pathograph links
Neuronal Dysfunction and Epileptic Encephalopathy recapitulates fidelity: moderate Neuron-specific loss of Arv1 reproduces the seizure phenotype and a severe survival defect, isolating a neuronal requirement for ARV1.
Limitations: A conditional neuronal knockout models complete loss rather than the hypomorphic residual activity of many human missense/splice alleles, and the non-neural features of the human disorder (visual, cardiac, systemic) are not addressed by a neuron-restricted deletion.
Show evidence (1 reference)
PMID:27270415 SUPPORT Model Organism
"Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood."
Supports treating the neuronal Arv1 knockout as informative for the encephalopathy node.
Show evidence (1 reference)
PMID:27270415 SUPPORT Model Organism
"Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood."
Establishes the mouse model and its phenotypic recapitulation of the human disease.
{ }

Source YAML

click to show 
name: Developmental And Epileptic Encephalopathy 38
creation_date: "2026-09-02T13:30:00Z"
description: >-
  DEE38 (EIEE38) is an autosomal recessive developmental and epileptic
  encephalopathy caused by biallelic loss-of-function variants in ARV1, a
  multi-pass endoplasmic-reticulum transmembrane protein. ARV1 was first
  characterized in yeast as a sterol/lipid homeostasis factor, but its
  disease-relevant human role is as a facilitating component of the GPI
  N-acetylglucosaminyltransferase (GPI-GnT) complex that initiates
  glycosylphosphatidylinositol (GPI) anchor biosynthesis; loss of ARV1
  therefore reduces cell-surface expression of GPI-anchored proteins, placing
  DEE38 among the inherited GPI-deficiency disorders. Affected infants present
  in the first months of life with early-onset refractory seizures (including
  epilepsy of infancy with migrating focal seizures), profound global
  developmental delay with regression, axial hypotonia, cortical visual
  impairment, and progressive cerebral and cerebellar atrophy. A missense
  allelic subset shows a somewhat milder, ataxia-and-elevated-AFP presentation,
  and dilated cardiomyopathy has been reported in a minority. There is no
  disease-modifying therapy; the untreated course is frequently lethal in
  childhood, usually from aspiration and respiratory infection.
category: Mendelian
parents:
- Genetic Developmental and Epileptic Encephalopathy
synonyms:
- DEE38
- EIEE38
- early infantile epileptic encephalopathy 38
- ARV1 early infantile epileptic encephalopathy
- ARV1 deficiency
- ARV1-related encephalopathy
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 38
  term:
    id: MONDO:0014868
    label: developmental and epileptic encephalopathy, 38
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    DEE38 is autosomal recessive: affected individuals carry biallelic ARV1
    variants (homozygous in consanguineous families, or compound heterozygous).
    Reported alleles include missense (p.Gly189Arg), in-frame deletions
    (p.Lys59_Asn98del, p.Leu185del), splice variants (c.294+1G>A, c.674-2A>T)
    and truncating/frameshift variants (p.Ser122Glnfs*7, p.Trp163*,
    p.Phe144Argfs*5).
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe seven patients from two unrelated families with biallelic splice mutations in ARV1."
    explanation: >-
      Documents biallelic causation across two unrelated families, consistent
      with recessive inheritance.
  - reference: PMID:34296759
    reference_title: "Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants."
    explanation: >-
      Independent confirmation of biallelic recessive causation and of allelic
      heterogeneity.
pathophysiology:
- name: Biallelic ARV1 Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    ARV1 is a ubiquitously expressed ~271-residue multi-pass ER transmembrane
    protein with an N-terminal conserved ARV1 homology domain carrying a
    putative zinc-binding motif. Biallelic variants reduce or abolish functional
    ARV1: truncating and frameshift alleles trigger nonsense-mediated decay,
    splice variants reduce transcript and protein and delete conserved domains,
    and missense/in-frame-deletion alleles fail (or only partially rescue) the
    temperature-sensitive growth defect of arv1-null yeast. Neither the
    p.Lys59_Asn98del nor the previously reported p.Gly189Arg allele produced
    detectable protein in mammalian cells.
  genes:
  - preferred_term: ARV1
    term:
      id: hgnc:29561
      label: ARV1
  downstream:
  - target: Impaired GPI Anchor Biosynthesis
    causal_link_type: DIRECT
    description: >-
      Loss of ARV1 removes a facilitating component of the GPI-GnT complex that
      initiates GPI-anchor assembly.
    evidence:
    - reference: PMID:40378954
      reference_title: ARV1 is a component of the enzyme initiating glycosylphosphatidylinositol biosynthesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ARV1 acts as a component of the enzyme initiating GPI biosynthesis, GPI N-acetylglucosaminyltransferase (GPI-GnT) complex"
      explanation: >-
        Establishes the direct biochemical link from ARV1 to the GPI-initiating
        enzyme whose activity is lost when ARV1 is lost.
  evidence:
  - reference: PMID:27270415
    reference_title: Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast to wild type human ARV1, neither variant expressed detectable levels of protein in mammalian cells."
    explanation: >-
      Directly demonstrates loss of ARV1 protein for the disease-associated
      variants, grounding the loss-of-function trigger.
  - reference: PMID:35227294
    reference_title: "Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The human ARV1 encodes a ubiquitously expressed 271-amino-acid protein containing the N-terminal ARV1 homology domain (AHD), which also includes a putative zinc-binding motif and the first of six predicted transmembrane domains"
    explanation: >-
      Source for the protein architecture (length, AHD, zinc-binding motif,
      transmembrane topology) described in this node.
- name: Impaired GPI Anchor Biosynthesis
  biological_scale: MOLECULAR
  description: >-
    The disease-relevant consequence of ARV1 loss is impaired initiation of GPI
    anchor biosynthesis. ARV1 associates with PIGQ within the GPI-GnT complex
    and promotes efficient recruitment of the phosphatidylinositol substrate;
    an ARV1 mutant unable to associate with PIGQ loses the ability to enhance
    GPI-GnT activity. In a complementation assay the human p.Gly189Arg allele
    caused deficient maturation of the GPI-anchored protein Gas1 without
    affecting sphingolipid synthesis, isolating the GPI-anchoring defect as the
    mechanistically decisive lesion. Whether ARV1's ancestral sterol/sphingolipid
    trafficking role contributes independently to neuronal injury is unresolved
    (see gap_gpi_versus_lipid_driver).
  biological_processes:
  - preferred_term: GPI anchor biosynthetic process
    term:
      id: GO:0006506
      label: GPI anchor biosynthetic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: phosphatidylinositol N-acetylglucosaminyltransferase activity
    term:
      id: GO:0017176
      label: phosphatidylinositol N-acetylglucosaminyltransferase activity
    modifier: DECREASED
  downstream:
  - target: Reduced Cell-Surface GPI-Anchored Protein Expression
    causal_link_type: DIRECT
    description: >-
      Failure of GPI-anchor assembly reduces the amount of mature GPI available
      to anchor client proteins at the cell surface.
    evidence:
    - reference: PMID:32165008
      reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the loss of ARV1 protein, causing a significant decrease in membrane bound"
      explanation: >-
        Links the ARV1 defect to reduced membrane-bound GPI-anchored proteins,
        the next node.
  evidence:
  - reference: PMID:40378954
    reference_title: ARV1 is a component of the enzyme initiating glycosylphosphatidylinositol biosynthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ARV1 associates with PIGQ, a GPI-GnT component, and ARV1 mutants defective in this association lose their ability to enhance GPI-GnT activity, showing that association with PIGQ is critical for ARV1's function."
    explanation: >-
      Establishes the molecular mechanism by which ARV1 supports GPI-GnT
      activity and how its loss impairs the pathway.
  - reference: PMID:32462292
    reference_title: A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "complementation tests in yeast showed that the ARV1 p.Gly189Arg mutation leads to deficient maturation of Gas1, a GPI-anchored protein, but does not affect sphingolipid synthesis"
    explanation: >-
      Isolates the GPI-anchoring defect from the sphingolipid role for a
      patient allele, supporting GPI biosynthesis as the decisive lesion.
- name: Reduced Cell-Surface GPI-Anchored Protein Expression
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Patient neutrophils and fibroblasts show significantly reduced surface
    expression of multiple GPI-anchored proteins (CD16 with ~5% residual
    expression, CD66b, CD55/CD59, and reduced FLAER binding in neutrophils;
    CD59 and CD87/uPAR in fibroblasts). This cellular readout is what assigns
    ARV1 deficiency to the inherited GPI-deficiency disorders and is corrected
    by lentiviral re-expression of wild-type ARV1, establishing it as the
    reversible core molecular defect.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: Dermal fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  downstream:
  - target: Neuronal Dysfunction and Epileptic Encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of GPI-anchored signaling and adhesion proteins on developing
      neuronal membranes is the proposed route to the encephalopathy, by analogy
      to other inherited GPI-deficiency disorders that share the clinical and
      neuroimaging picture. The intervening steps are not demonstrated in human
      neural tissue.
    evidence:
    - reference: PMID:34017911
      reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "this severe syndrome can be assigned to the group of inherited GPI deficiency disorders, with which it shares remarkably similar clinical and neuroimaging features"
      explanation: >-
        Classified INDIRECT: supports the analogy to inherited GPI-deficiency
        disorders as the basis for the neuronal consequence, without
        demonstrating the intervening neuronal steps.
  evidence:
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The splice variants resulted in decreased ARV1 expression and significant decreases in GPI-anchored protein on the membranes of neutrophils and fibroblasts, indicating that the loss of ARV1 results in impaired GPI-anchor synthesis."
    explanation: >-
      Direct measurement of reduced surface GPI-anchored proteins in patient
      cells.
  - reference: PMID:34296759
    reference_title: "Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype. A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations."
    explanation: >-
      Independent confirmation of the surface deficit and its correction by
      wild-type ARV1, establishing reversibility of the core defect.
- name: Neuronal Dysfunction and Epileptic Encephalopathy
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The clinical endpoint is an early-infantile developmental and epileptic
    encephalopathy with drug-refractory seizures, profound developmental delay
    with regression, and progressive cerebral and cerebellar atrophy. A neuronal
    conditional knockout of Arv1 in mice recapitulates the seizure phenotype and
    a severe adult survival defect, supporting a neuron-autonomous requirement
    for ARV1. This entry does not declare conformance to the
    epilepsy_excitation_inhibition_imbalance module: no excitation-inhibition
    measurement exists in ARV1 deficiency and asserting that mechanism would
    substitute a plausible route for an evidenced one (see
    gap_excitation_inhibition_route).
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:27270415
    reference_title: Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood."
    explanation: >-
      Demonstrates that neuron-specific loss of Arv1 is sufficient for the
      seizure phenotype, supporting neuronal dysfunction as the disease endpoint.
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients presented with early onset epilepsy, global developmental delays, profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy."
    explanation: >-
      Characterizes the clinical endpoint syndrome across a multi-patient
      series.
phenotypes:
- name: Epileptic encephalopathy
  category: Neurologic
  description: >-
    A developmental and epileptic encephalopathy is the defining feature, with
    early-onset seizures accompanied by developmental impairment. Onset is
    typically in the first months of life.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:34296759
    reference_title: "Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features."
    explanation: >-
      Establishes the early-onset refractory-seizure encephalopathy as the core
      presentation.
- name: Refractory epilepsy
  category: Neurologic
  description: >-
    The epilepsy is characteristically drug-resistant, with seizures continuing
    despite multiple antiseizure medicines.
  phenotype_term:
    preferred_term: Refractory epilepsy
    term:
      id: HP:0020174
      label: Refractory drug response
  evidence:
  - reference: PMID:34017911
    reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intractable nonmotor seizures started in both at the eighth month of life, exhibiting the electroclinical characteristics of epilepsy of infancy with migrating focal seizures (EIMFS)."
    explanation: >-
      Documents intractable (refractory) seizures in the ARV1 spectrum.
- name: Migrating focal seizures
  category: Neurologic
  description: >-
    Epilepsy of infancy with migrating focal seizures (EIMFS) is part of the
    ARV1 epilepsy spectrum, described in a pair of compound-heterozygous sisters.
  phenotype_term:
    preferred_term: Migrating focal seizure
    term:
      id: HP:0032786
      label: Migrating focal seizure
  evidence:
  - reference: PMID:34017911
    reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "adds epilepsy with migrating focal seizures and myoclonic status to the spectrum of epilepsy phenotypes"
    explanation: >-
      Explicitly adds migrating focal seizures to the ARV1 epilepsy spectrum.
- name: Myoclonic status epilepticus
  category: Neurologic
  description: >-
    In the second year of life, continuous high-amplitude epileptiform activity
    with myoclonic status appeared, severely impairing alertness.
  phenotype_term:
    preferred_term: Status epilepticus
    term:
      id: HP:0002133
      label: Status epilepticus
  evidence:
  - reference: PMID:34017911
    reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "continuous epileptiform EEG activity of extremely high amplitude appeared in association with myoclonic status, leading to severely impaired alertness and responsiveness"
    explanation: >-
      Documents myoclonic status epilepticus in the ARV1 spectrum.
- name: Global developmental delay
  category: Neurologic
  description: >-
    Profound global developmental delay is near-universal; most patients never
    attain motor or social milestones, and regression of any acquired skills is
    typical.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients presented with early onset epilepsy, global developmental delays, profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy."
    explanation: >-
      Reports global developmental delay across the patient series.
- name: Developmental regression
  category: Neurologic
  description: >-
    Loss of previously emerging skills follows seizure onset, a feature the
    genotype-phenotype refinement study singles out.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:34296759
    reference_title: "Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early onset refractory seizures followed by regression and specific neuroimaging features"
    explanation: >-
      States that regression follows the refractory seizures.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Surviving older individuals have severe to profound intellectual disability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35227294
    reference_title: "Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we present a novel homozygous in-frame ARV1-deletion (c.554_556delTAT, p.L185del) in a 21-year old Caucasian man with developmental delay, intellectual disability, seizures, walking and speech impairments"
    explanation: >-
      Documents intellectual disability in a long-surviving affected adult.
- name: Axial hypotonia
  category: Neurologic
  description: >-
    Profound central/axial hypotonia is a consistent early feature, often noted
    before seizure onset.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:34017911
    reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity"
    explanation: >-
      Reports severe axial hypotonia as an early feature.
- name: Cortical visual impairment
  category: Ophthalmologic
  description: >-
    Cortical (cerebral) visual impairment is frequent; some patients also have
    retinal dystrophy or abnormal eye movements.
  phenotype_term:
    preferred_term: Cortical visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy"
    explanation: >-
      Reports cortical visual impairment in the patient series.
- name: Cerebral atrophy
  category: Neurologic
  description: >-
    Progressive generalized cerebral atrophy is a characteristic and worsening
    neuroimaging feature.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:34017911
    reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination."
    explanation: >-
      Documents progressive atrophic changes on serial imaging.
- name: Cerebellar atrophy
  category: Neurologic
  description: >-
    Cerebellar atrophy is prominent, and postmortem neuropathology in one
    patient showed atrophic change mainly involving the cerebellum.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:34017911
    reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postmortem neuropathologic examination of the brain, performed in one, revealed atrophic brain changes, mainly involving the cerebellum."
    explanation: >-
      Neuropathologic confirmation of cerebellar-predominant atrophy.
- name: CNS hypomyelination
  category: Neurologic
  description: >-
    Delayed myelination/hypomyelination accompanies the atrophic changes on MRI.
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:34017911
    reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination."
    explanation: >-
      Reports severe hypomyelination on MRI.
- name: Ataxia
  category: Neurologic
  description: >-
    A missense-associated subset presents with cerebellar ataxia (with
    oculomotor abnormalities and elevated alpha-fetoprotein), a phenotype that
    can mimic autosomal recessive cerebellar ataxias such as ataxia
    telangiectasia.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:37749428
    reference_title: "ARV1 Gene: A Novel Cause of Autosomal Recessive Cerebellar Ataxia with Elevated Alpha Fetoprotein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "other unique clinical features include ophthalmological abnormalities and movement disorders in the form of ataxia and dystonia, especially in those with missense mutation"
    explanation: >-
      Documents ataxia in the missense allelic subset.
- name: Dystonia
  category: Neurologic
  description: >-
    Dyskinetic/dystonic movements occur, particularly in the missense subset.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:37749428
    reference_title: "ARV1 Gene: A Novel Cause of Autosomal Recessive Cerebellar Ataxia with Elevated Alpha Fetoprotein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "movement disorders in the form of ataxia and dystonia, especially in those with missense mutation"
    explanation: >-
      Documents dystonia in the ARV1 movement-disorder spectrum.
- name: Elevated circulating alpha-fetoprotein concentration
  category: Laboratory
  description: >-
    Elevated serum alpha-fetoprotein has been reported in the ataxia-predominant
    missense subset and contributes to the ataxia-telangiectasia-like
    presentation.
  phenotype_term:
    preferred_term: Elevated circulating alpha-fetoprotein concentration
    term:
      id: HP:0006254
      label: Elevated circulating alpha-fetoprotein concentration
  evidence:
  - reference: PMID:37749428
    reference_title: "ARV1 Gene: A Novel Cause of Autosomal Recessive Cerebellar Ataxia with Elevated Alpha Fetoprotein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARV1 can also be associated with increased alpha-fetoprotein."
    explanation: >-
      States the alpha-fetoprotein elevation associated with ARV1.
- name: Dilated cardiomyopathy
  category: Cardiovascular
  description: >-
    Dilated cardiomyopathy has been reported in a minority of patients (about a
    quarter of the ~16 patients tabulated in 2022), and is proposed as part of
    the ARV1-associated phenotype, though the authors caution the evidence is
    not yet definitive.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:35227294
    reference_title: "Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The finding of dilated cardiomyopathy in the presented as well as in three previously reported patients from two different families indicates that dilated cardiomyopathy is a part of the ARV1-induced DEE38 phenotype. However, more data are needed to make this conclusion definitive."
    explanation: >-
      Reports dilated cardiomyopathy in a subset and flags it as not yet
      definitively established, which the description preserves.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Feeding difficulties are a consistent feature: reported patients required
    thickened feeds, nasogastric-tube or gastrostomy feeding, with choking
    episodes and aspiration. This is the substrate of the aspiration pneumonia
    that is the usual proximate cause of death in the severe genotypes (see the
    mortality phase under progression).
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our patients present with early onset seizures, central hypotonia, severe developmental delay, visual impairment and feeding difficulties, supporting the clinical diagnosis of IEE38"
    explanation: >-
      Names feeding difficulties among the features present across the series,
      the basis for the VERY_FREQUENT band.
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Poor feeding, choking episodes and probable aspiration pneumonia were managed with NG-feeding from age 17 months."
    explanation: >-
      A worked example connecting the feeding difficulty to aspiration, the
      mortality mechanism recorded under progression.
- name: Spasticity
  category: Neurologic
  description: >-
    Peripheral spasticity develops alongside the central hypotonia — the
    characteristic mixed picture of central hypotonia with peripherally
    increased tone and brisk reflexes — and is part of the progressive
    neurodegenerative course.
  phenotype_term:
    preferred_term: Peripheral spasticity
    term:
      id: HP:0001257
      label: Spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurodegenerative course (increasing seizures, central hypotonia, peripheral spasticity, ataxia and dystonia) appeared to be progressive in Family II"
    explanation: >-
      Names peripheral spasticity as part of the progressive neurodegenerative
      course, which the clinical_course qualifier records.
- name: Nystagmus
  category: Ophthalmologic
  description: >-
    Nystagmus and roving eye movements accompany the visual inattention, in
    some patients from birth, as part of the early visual phenotype.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An ophthalmological examination confirmed visual inattention, nystagmus, roving eye movements and small optic discs on fundoscopy."
    explanation: >-
      Documents nystagmus and roving eye movements on formal ophthalmological
      examination.
- name: Retinal dystrophy
  category: Ophthalmologic
  description: >-
    Retinal dystrophy was reported in the original p.Lys59_Asn98del patient, so
    the visual phenotype spans both cortical and retinal contributions in
    different patients.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:35227294
    reference_title: "Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one additional patient with the homozygous ARV1 p.K59_N98del splice variant who showed severe neurodevelopmental delay, an intractable infantile onset seizure, movement disorder, and retinal dystrophy and died at the age of 1 year"
    explanation: >-
      Documents retinal dystrophy in a reported patient, sourced from the
      case-summary review of the original report.
- name: Abnormal skeletal muscle morphology
  category: Musculoskeletal
  description: >-
    Muscle histology in patients (and in Arv1-knockout mice) indicates that
    skeletal muscle impairment is part of the ARV1-associated phenotype, beyond
    the central hypotonia.
  phenotype_term:
    preferred_term: Abnormal skeletal muscle morphology
    term:
      id: HP:0011805
      label: Abnormal skeletal muscle morphology
  evidence:
  - reference: PMID:35227294
    reference_title: "Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the muscle histology of ARV1 patients, as well as of ARV1-knockout mice, indicated that at least skeletal muscle impairment is also a part of the ARV1-associated phenotype"
    explanation: >-
      States the histological skeletal-muscle involvement in patients; the same
      sentence cites the concordant knockout-mouse histology.
genetic:
- name: ARV1
  gene_term:
    preferred_term: ARV1
    term:
      id: hgnc:29561
      label: ARV1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    ARV1 (ACAT-related enzyme 2 required for viability 1; MIM 611647) is the
    only gene implicated in DEE38 (MIM 617020). Reported biallelic alleles span
    homozygous missense (p.Gly189Arg), in-frame deletions (p.Lys59_Asn98del from
    the c.294+1G>A splice variant; p.Leu185del), a splice variant deleting the
    C-terminus (c.674-2A>T), and compound-heterozygous truncating variants
    (p.Ser122Glnfs*7 / p.Trp163*; p.Phe144Argfs*5). A rough genotype-phenotype
    trend has been proposed: truncating/null-predominant genotypes cluster with
    the most severe, early-lethal encephalopathy, whereas missense alleles can
    give a milder ataxia-with-elevated-AFP presentation. ARV1 was originally
    identified as a candidate disease gene by whole-exome sequencing of
    prescreened multiplex consanguineous families.
  evidence:
  - reference: PMID:27270415
    reference_title: Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data support ARV1 deficiency as a cause of autosomal recessive epileptic encephalopathy."
    explanation: >-
      The gene-disease association statement establishing ARV1 as causative.
  - reference: PMID:25558065
    reference_title: Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS)."
    explanation: >-
      The original whole-exome discovery of ARV1 as a recessive neurogenetic
      disease gene.
  - reference: PMID:35227294
    reference_title: "Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "So far, three different homozygous ARV1 and two compound heterozygous mutations in humans have been reported in 15 children"
    explanation: >-
      Summarizes the allelic and cohort landscape underlying the variant notes.
  - reference: PMID:35227294
    reference_title: "Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both these patients had no obvious ophthalmologic abnormalities, showed a milder neurocognitive phenotype compared with the patients with the p.K59_N98del splice mutation, described above, and had dilated cardiomyopathy (DCM), which has not been related to the ARV1-associated phenotype."
    explanation: >-
      Directly contrasts the milder p.Gly189Arg missense phenotype with the
      severe p.Lys59_Asn98del splice phenotype, the genotype-phenotype trend
      recorded in the notes.
  - reference: PMID:35227294
    reference_title: "Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All five children carrying the latter variant died by the age of 5 years."
    explanation: >-
      Documents the early lethality of the p.Lys59_Asn98del splice genotype,
      the severe end of the trend.
environmental:
- name: Febrile illness
  description: >-
    Intercurrent febrile illness aggravates the epilepsy: seizures are often
    both febrile and afebrile from onset, fever admissions are accompanied by
    increased seizure frequency and reduced consciousness, and febrile
    respiratory infections precipitate status epilepticus and the terminal
    deteriorations reported in several patients. Fever is an aggravating
    trigger acting on an established disease, not a cause of it.
  notes: >-
    No exposure_term is bound: ECTO and XCO were searched for fever / febrile
    illness / infection exposure concepts and neither ontology carries a
    suitable exposure term for endogenous fever or intercurrent febrile
    infection, so the entry is deliberately left free-text rather than bound to
    a broader, inaccurate term.
  influences_mechanisms:
  - target: Neuronal Dysfunction and Epileptic Encephalopathy
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Febrile episodes worsen seizure frequency and level of consciousness in
      the established encephalopathy; the physiological route (temperature
      sensitivity of the underlying neuronal dysfunction versus nonspecific
      illness effects) has not been dissected.
    evidence:
    - reference: PMID:32165008
      reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At age 2 years she was again admitted to hospital with high fever, increasing seizure frequency, decreased level of consciousness and was unresponsive."
      explanation: >-
        Documents fever coinciding with increased seizure frequency and
        deteriorated consciousness, supporting the exacerbating link.
  evidence:
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 6 months of age, she had her first seizure, followed by frequent episodes of both febrile and non-febrile seizures, some requiring hospitalization."
    explanation: >-
      Establishes fever as a recurrent seizure precipitant from disease onset
      in a reported patient.
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 7 months she was admitted in status epilepticus with a febrile illness."
    explanation: >-
      A second patient in whom a febrile illness precipitated status
      epilepticus.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    DEE38 is ultra-rare. Only small numbers of patients had been reported as of
    the most recent reviews (about 16 patients tabulated in 2022 and roughly 28
    reported cases cited in a 2025 case report); no population prevalence has
    been estimated. These are dated lower bounds rather than current totals.
  evidence:
  - reference: PMID:35227294
    reference_title: "Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "So far, three different homozygous ARV1 and two compound heterozygous mutations in humans have been reported in 15 children"
    explanation: >-
      A literature count consistent with an ultra-rare disorder; kept as a count
      rather than converted to a population rate.
progression:
- phase: Onset
  notes: >-
    Onset is in early infancy. Visual inattention, hypotonia and developmental
    concern are frequently noted in the first months, with seizures typically
    beginning between roughly 2 and 8 months of life.
  evidence:
  - reference: PMID:34017911
    reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since their first months of life, both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity. Intractable nonmotor seizures started in both at the eighth month of life"
    explanation: >-
      Documents the early-infantile onset of hypotonia and developmental
      concern with seizure onset in the first year.
- phase: Untreated course and mortality
  notes: >-
    The course is severe and often lethal in childhood, particularly for
    truncating/splice genotypes; several reported children died in the first
    years of life, commonly from aspiration and respiratory infection during
    intercurrent illness.
  evidence:
  - reference: PMID:34017911
    reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both sisters died prematurely during respiratory infections."
    explanation: >-
      Documents premature death from respiratory infection in the severe
      phenotype.
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He deteriorated with increasing seizures and died at age 15 months as result of aspiration pneumonia."
    explanation: >-
      A worked example of early death from aspiration pneumonia.
diagnosis:
- name: Whole exome sequencing
  description: >-
    Diagnosis rests on identifying biallelic ARV1 variants by exome (or genome)
    sequencing. Because ARV1 was a novel gene and variants can be missense of
    uncertain significance, functional support is often sought.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations were discovered through whole exome sequencing and alternate splicing was validated on the cDNA level."
    explanation: >-
      Establishes exome sequencing as the diagnostic route, with cDNA
      validation of splice effects.
- name: Flow cytometry for GPI-anchored proteins
  description: >-
    Reduced surface expression of GPI-anchored proteins on neutrophils (CD16,
    CD66b, FLAER) or fibroblasts (CD59, CD87) is a functional signature shared
    with the inherited GPI-deficiency disorders and supports pathogenicity of an
    ARV1 variant.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:34296759
    reference_title: "Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype."
    explanation: >-
      Establishes the GPI-anchored-protein flow cytometry assay as functional
      diagnostic support.
treatments:
- name: Antiseizure medication (symptomatic)
  description: >-
    Management is symptomatic. Multiple antiseizure medicines are trialed —
    reported regimens include levetiracetam, clobazam, topiramate and vitamin
    B6 (pyridoxine) — with at best partial or transient seizure control, and
    the epilepsy is characteristically pharmacoresistant. No disease-modifying
    or ARV1-specific pharmacotherapy exists.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: clobazam
      term:
        id: CHEBI:31413
        label: clobazam
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
    - preferred_term: vitamin B6 (pyridoxine)
      term:
        id: CHEBI:16709
        label: pyridoxine
  target_phenotypes:
  - preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:34296759
    reference_title: "Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features."
    explanation: >-
      Establishes the refractory nature of the seizures that symptomatic
      antiseizure therapy targets with limited success.
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She received multiple AEDs (levetiracetam, clobazam, vitamin B6) with some success."
    explanation: >-
      Names the antiseizure agents used in a reported patient, with the partial
      response the description records.
  - reference: PMID:32165008
    reference_title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was discharged on oral topiramate, clobazam, levetiracetam, vitamin B."
    explanation: >-
      Documents the topiramate-containing maintenance regimen in a second
      reported patient.
- name: ARV1 gene replacement (preclinical)
  description: >-
    Lentiviral transduction of wild-type ARV1 cDNA into patient fibroblasts
    rescued the cell-surface GPI-anchored-protein deficiency, demonstrating
    cellular reversibility of the core molecular defect and providing a rationale
    for gene-replacement therapy. This remains a cell-based proof of concept with
    no in vivo or clinical data.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Reduced Cell-Surface GPI-Anchored Protein Expression
    treatment_effect: RESTORES
    description: >-
      Re-expressing wild-type ARV1 restores GPI-anchored protein levels on the
      cell surface in patient fibroblasts.
  evidence:
  - reference: PMID:34296759
    reference_title: "Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations."
    explanation: >-
      The cell-based gene-replacement proof of concept that this preclinical
      treatment node records.
- name: Genetic counseling
  description: >-
    Because DEE38 is autosomal recessive, genetic counseling of families
    (including recurrence-risk and carrier-testing discussion) is part of care.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34296759
    reference_title: "Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants."
    explanation: >-
      Establishes the biallelic recessive genotype that makes recurrence-risk
      counseling relevant.
animal_models:
- name: Neuronal Arv1 conditional knockout mouse
  species: Mouse
  genotype: Neuron-specific Arv1 deletion
  category: Genetic
  description: >-
    Mice with a neuronal deletion of Arv1 recapitulate the human phenotype,
    exhibiting seizures and a severe adult survival defect, supporting a
    neuron-autonomous requirement for ARV1.
  publication: PMID:27270415
  genes:
  - preferred_term: Arv1
    term:
      id: hgnc:29561
      label: ARV1
  modeled_mechanisms:
  - target: Neuronal Dysfunction and Epileptic Encephalopathy
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Neuron-specific loss of Arv1 reproduces the seizure phenotype and a severe
      survival defect, isolating a neuronal requirement for ARV1.
    limitations: >-
      A conditional neuronal knockout models complete loss rather than the
      hypomorphic residual activity of many human missense/splice alleles, and
      the non-neural features of the human disorder (visual, cardiac, systemic)
      are not addressed by a neuron-restricted deletion.
    evidence:
    - reference: PMID:27270415
      reference_title: Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood."
      explanation: >-
        Supports treating the neuronal Arv1 knockout as informative for the
        encephalopathy node.
  evidence:
  - reference: PMID:27270415
    reference_title: Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood."
    explanation: >-
      Establishes the mouse model and its phenotypic recapitulation of the human
      disease.
experimental_models:
- name: Yeast arv1-null complementation assay
  description: >-
    Saccharomyces cerevisiae lacking ARV1 has GPI-anchor-synthesis and
    growth/temperature defects that can be rescued by human ARV1, and this
    complementation system is used to grade the functional impact of human ARV1
    alleles. The p.Gly189Arg allele only partially rescues the yeast defect;
    the p.Lys59_Asn98del deletion fails to rescue at restrictive temperature.
  experimental_model_type: OTHER
  organism:
    preferred_term: Saccharomyces cerevisiae
    term:
      id: NCBITaxon:4932
      label: Saccharomyces cerevisiae
  publication: PMID:27270415
  modeled_mechanisms:
  - target: Impaired GPI Anchor Biosynthesis
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Yeast complementation grades how well each human ARV1 allele supports
      GPI-anchor synthesis, providing the functional read on allele severity.
    limitations: >-
      Yeast Arv1 also acts in sterol/sphingolipid homeostasis, so a rescue
      readout in yeast does not by itself resolve which ARV1 function is
      disease-decisive in human neurons.
    evidence:
    - reference: PMID:27270415
      reference_title: Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The p.(Gly189Arg) variant partially rescued the temperature-dependent growth defect in arv1Δ yeast, while p.(Lys59-Asn98del) completely failed to rescue at restrictive temperature."
      explanation: >-
        Demonstrates the assay grading allele function, the readout this model
        provides.
  evidence:
  - reference: PMID:26460143
    reference_title: Complementation analysis reveals a potential role of human ARV1 in GPI anchor biosynthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overexpression of human ARV1 could rescue the phenotypes associated with GPI anchor synthesis defect in the yeast arv1Δ mutant."
    explanation: >-
      Establishes that human ARV1 complements the yeast GPI defect, validating
      the assay for grading human alleles.
discussions:
- discussion_id: gap_gpi_versus_lipid_driver
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the neuronal injury in ARV1 deficiency driven mainly by the GPI-anchor
    biosynthesis defect, by disruption of ARV1's ancestral sterol/sphingolipid
    trafficking role, or by both acting together?
  attaches_to:
  - "pathophysiology#Impaired GPI Anchor Biosynthesis"
  - "pathophysiology#Neuronal Dysfunction and Epileptic Encephalopathy"
  rationale: >-
    Yeast Arv1 has documented roles in both GPI-anchor flow and sterol/sphingolipid
    homeostasis, and human ARV1 conserves both. The strongest direct human
    evidence points at the GPI-anchoring branch: patient cells show reduced
    surface GPI-anchored proteins, the 2025 reconstitution work places ARV1 in
    the GPI-GnT complex, and a patient allele impaired GPI-anchored Gas1
    maturation without affecting sphingolipid synthesis. But whether residual
    lipid dyshomeostasis contributes independently to neuronal injury is not
    resolved, and the branch point is stated as open in the literature.
  proposed_experiments:
  - experiment_id: exp_neuronal_gpi_vs_lipid_dissection
    name: Dissecting GPI versus lipid contributions in ARV1-null neurons
    description: >-
      In ARV1-null human iPSC-derived neurons, separately restore GPI-anchoring
      (e.g. by re-expressing an ARV1 mutant competent for GPI-GnT support but
      not lipid handling, or vice versa) and measure rescue of neuronal
      excitability, survival and GPI-anchored protein levels, to attribute the
      neuronal phenotype to each function.
  evidence:
  - reference: PMID:32462292
    reference_title: A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "complementation tests in yeast showed that the ARV1 p.Gly189Arg mutation leads to deficient maturation of Gas1, a GPI-anchored protein, but does not affect sphingolipid synthesis"
    explanation: >-
      Evidence that at least one patient allele separates the GPI defect from the
      sphingolipid role, which is the crux of this open question.
- discussion_id: gap_excitation_inhibition_route
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what route does reduced surface expression of GPI-anchored proteins
    produce neuronal hyperexcitability and seizures in the developing brain?
  attaches_to:
  - "pathophysiology#Reduced Cell-Surface GPI-Anchored Protein Expression"
  - "pathophysiology#Neuronal Dysfunction and Epileptic Encephalopathy"
  rationale: >-
    The link from the measured cellular defect to seizures is drawn by analogy to
    other inherited GPI-deficiency disorders that share the clinical and imaging
    picture, and to a proposed role for ER stress from immature GPI-anchored
    proteins. No excitation-inhibition measurement exists in ARV1 deficiency, so
    the entry deliberately does not conform to the
    epilepsy_excitation_inhibition_imbalance module: doing so would assert a
    mechanism that has not been measured here.
  proposed_experiments:
  - experiment_id: exp_arv1_neuronal_excitability
    name: Excitation-inhibition measurement in ARV1-deficient neural models
    description: >-
      Use multi-electrode array or patch-clamp recordings in ARV1-null iPSC
      neuronal networks (and the neuronal Arv1 knockout mouse) to test whether a
      measurable excitation-inhibition imbalance underlies the seizures, and
      whether it tracks with loss of specific GPI-anchored synaptic/adhesion
      proteins.
  evidence:
  - reference: PMID:34017911
    reference_title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this severe syndrome can be assigned to the group of inherited GPI deficiency disorders, with which it shares remarkably similar clinical and neuroimaging features"
    explanation: >-
      The analogy-based reasoning that stands in for a demonstrated
      excitation-inhibition route, which is what this gap flags.
notes: >-
  Scope note on identity. MONDO:0014868 (developmental and epileptic
  encephalopathy, 38; OMIM 617020) is the ARV1-related autosomal recessive DEE.
  It is distinct from the ALG13-related X-linked DEE (a separate MONDO/OMIM
  entity), which the numbering can invite confusion with; every primary source
  cited here concerns ARV1.

  Deliberate non-conformances. This entry does not declare conformance to the
  epilepsy_excitation_inhibition_imbalance module (no E-I measurement exists in
  ARV1 deficiency; see gap_excitation_inhibition_route) nor to the
  congenital_disorder_of_glycosylation module, which models N-linked
  glycoprotein hypoglycosylation rather than the GPI-anchor lesion central to
  DEE38. DEE38 belongs mechanistically with the inherited GPI-deficiency
  disorders and is listed as a member of the Disorders_of_GPI_Anchor_Biosynthesis
  grouping on that mechanism basis (MONDO does not yet classify MONDO:0014868
  under its disorder-of-GPI-anchor-biosynthesis class, which is recorded there
  as an upstream MONDO gap rather than a membership problem).

  Ketogenic diet. The full text of the two-sister report (PMID:34017911)
  describes a temporary reduction in seizure frequency on a ketogenic diet
  before efficacy was lost with disease progression. The observation is
  full-text-only — the cached record for that paper is abstract-only, so no
  exact quote can be validated — and it is therefore recorded here as a note
  rather than as a cited treatment entry.
references:
- reference: PMID:27270415
  title: Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.
- reference: PMID:25558065
  title: Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
- reference: PMID:32165008
  title: Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
- reference: PMID:34296759
  title: "Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins."
- reference: PMID:34017911
  title: Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
- reference: PMID:40378954
  title: ARV1 is a component of the enzyme initiating glycosylphosphatidylinositol biosynthesis.
- reference: PMID:32462292
  title: A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures.
- reference: PMID:26460143
  title: Complementation analysis reveals a potential role of human ARV1 in GPI anchor biosynthesis.
- reference: PMID:35227294
  title: "Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report."
- reference: PMID:37749428
  title: "ARV1 Gene: A Novel Cause of Autosomal Recessive Cerebellar Ataxia with Elevated Alpha Fetoprotein."
📚

References & Deep Research

References

10
PMID:27270415
Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.
No top-level findings curated for this source.
PMID:25558065
Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
No top-level findings curated for this source.
PMID:32165008
Homozygous splice-variants in human ARV1 cause GPI-anchor synthesis deficiency.
No top-level findings curated for this source.
PMID:34296759
Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins.
No top-level findings curated for this source.
PMID:34017911
Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.
No top-level findings curated for this source.
PMID:40378954
ARV1 is a component of the enzyme initiating glycosylphosphatidylinositol biosynthesis.
No top-level findings curated for this source.
PMID:32462292
A defect in GPI synthesis as a suggested mechanism for the role of ARV1 in intellectual disability and seizures.
No top-level findings curated for this source.
PMID:26460143
Complementation analysis reveals a potential role of human ARV1 in GPI anchor biosynthesis.
No top-level findings curated for this source.
PMID:35227294
Dilated cardiomyopathy is a part of the ARV1-associated phenotype: a case report.
No top-level findings curated for this source.
PMID:37749428
ARV1 Gene: A Novel Cause of Autosomal Recessive Cerebellar Ataxia with Elevated Alpha Fetoprotein.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Developmental And Epileptic Encephalopathy 38 · 2026-09-02T13:44:35Z · View source

Curated ARV1-related autosomal recessive DEE38 (MONDO:0014868, OMIM 617020) de novo. Deep research via claude_code provider (needs_review flag was for one unsupported full-text-only quote, PMID:34017911 'Purkinje cell loss', which was not used). preflight-dr returned WARN because the GPI abbreviation is frequent; resolved by inspection (canonical gene ARV1, OMIM 617020 match). NOTE: the claim-issue/stub clinical description was for ALG13 X-linked DEE, a different disorder; the actual MONDO:0014868 entity is ARV1, confirmed by MONDO record, OMIM 617020, and all primary literature. Curated 4-node GPI-anchor pathophysiology chain (ARV1 LoF -> impaired GPI-GnT/GPI biosynthesis -> reduced surface GPI-anchored proteins -> neuronal dysfunction/DEE), 15 phenotypes, genetic, inheritance, prevalence, progression, diagnosis, 4 treatments, neuronal Arv1-KO mouse and yeast complementation models, and two knowledge-gap discussions (GPI-vs-lipid driver; E-I route). Did not declare conformance to epilepsy_excitation_inhibition_imbalance or congenital_disorder_of_glycosylation modules (GPI-anchor lesion, not N-glycosylation; no E-I measurement). Validation: just validate PASS (48/48 snippets verified), validate-terms PASS, check-entity-refs/check-duplicate-keys PASS, validate-disorders PASS.

Claude Code ▸
Developmental and Epileptic Encephalopathy 38 (DEE38 / EIEE38): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 3 citations 2026-09-02T13:24:08.703099

Developmental and Epileptic Encephalopathy 38 (DEE38 / EIEE38): Comprehensive Research Report

1. Disease Information

Overview. Developmental and Epileptic Encephalopathy 38 (DEE38; formerly designated Early Infantile Epileptic Encephalopathy 38, EIEE38) is an autosomal recessive neurologic/neurodegenerative disorder caused by biallelic loss-of-function variants in ARV1 (ARV1 Fatty Acid Homeostasis Modulator), an endoplasmic reticulum transmembrane protein. It presents in early infancy with severe global developmental impairment followed by onset of refractory, multifocal/migrating seizures, and follows a progressive, usually fatal, neurodegenerative course [OMIM #617020; PMID:27270415].

Key identifiers: - OMIM: #617020 (DEE38), gene locus ARV1 OMIM 611647, chromosome 1q42 - Gene: ARV1 (HGNC — "ARV1 fatty acid homeostasis modulator"; historically annotated "acyl-CoA cholesterol acyltransferase [ACAT]-related enzyme 2, required for viability 1") - Inheritance: Autosomal recessive - Synonyms: Early Infantile Epileptic Encephalopathy 38 (EIEE38); ARV1-related developmental and epileptic encephalopathy; ARV1 deficiency - Note: MONDO and dedicated GeneReviews/Orphanet entries were not directly retrievable in this search session (site access blocked); the OMIM entry #617020 is the authoritative primary identifier and should be used to cross-reference MONDO on curation.

Evidence basis: Nearly all published knowledge on DEE38 derives from individual case reports and small case series (single families or trios of patients) rather than large aggregated registries — as of the most recent literature identified (2024–2025), only on the order of ~20–30 molecularly confirmed cases have been reported worldwide, virtually all from consanguineous or compound-heterozygous pedigrees [PMC12080507].

Sources: - OMIM #617020 — DEE38 - Palmer et al. 2016, Hum Mol Genet, PMID:27270415 - PMC12080507 — "When Genes Misfire" review

2. Etiology

Disease causal factors

DEE38 is caused exclusively by biallelic (homozygous or compound heterozygous) pathogenic variants in ARV1. No environmental, infectious, or purely mechanistic (non-genetic) cause has been described; this is a monogenic Mendelian disorder.

Genetic risk factors

  • Causal variants reported to date span multiple mutation classes:
  • Missense: p.Cys61Tyr (recurrent, seen in 2 of 3 cases in one Egyptian series) [PMC12103100]; p.Gly189Arg (homozygous, 3 related children) [Neurogenetics 2020]
  • Nonsense: p.Trp163* [PMID:34017911]; p.Gln62Ter [Springer J Rare Dis 2025]
  • Frameshift: p.Phe144Argfs*5 (novel) [PMC12103100]
  • Splice-site: c.294+1G>A (exon 2 skipping, ~45% mRNA reduction, ~20% protein reduction) and c.674-2A>T (exon 5 skipping, ~40-50% protein reduction) [PMID:32165008]; c.363_364del (p.Ser122Glnfs*7) [PMID:34017911]
  • In-frame deletion: c.554_556delTAT (p.Leu185del), in the fourth predicted transmembrane domain — associated with a dilated cardiomyopathy phenotype [PMID:35227294]
  • Founder/recurrent alleles: p.Cys61Tyr and the exon-2/exon-5 splice variants recur across unrelated consanguineous families, consistent with regional founder effects (reported in Middle Eastern/North African and South Asian cohorts) [PMC12103100; PMID:32165008].
  • Modifier genes: None established; phenotypic variability (e.g., presence/absence of cardiomyopathy, retinal dystrophy, or skeletal dysplasia) is not yet linked to specific modifier loci — likely reflects allelic severity (null vs hypomorphic) and possibly genetic background.

Environmental risk factors

None identified — parental consanguinity is the dominant epidemiological risk factor (nearly all reported families), consistent with autosomal recessive inheritance and variant enrichment in consanguineous populations, not a true environmental exposure.

Protective factors

No genetic or environmental protective factors have been reported. No protective alleles are documented in population databases for ARV1 loss-of-function variants (specific gnomAD constraint metrics for ARV1, e.g., pLI/LOEUF, were not retrievable in this search but should be checked directly on the gnomAD browser during curation).

Gene-environment interactions

Not described; disease penetrance and expressivity appear driven by variant type/residual protein function rather than documented environmental modulation. Fever has been reported as a trigger for seizure exacerbation in affected patients (not a causal environmental factor) [PMID:34017911].

3. Phenotypes

DEE38 phenotypes are best organized along the disease's stereotyped pre-seizure prodrome → seizure-onset → progressive regression timeline.

Pre-seizure (neonatal–early infantile) phenotypes

  • Global developmental delay / failure to achieve milestones — onset in first weeks to months of life, universal, severe [OMIM #617020; PMID:27270415]
  • Central hypotonia with poor head control — onset weeks 4–8, universal
  • Visual inattention with roving eye movements / nystagmus — universal in the prodromal phase; some patients diagnosed with Leber congenital amaurosis / retinal dystrophy on electrophysiology [PMID:27270415]
  • Cortical visual impairment progressing over time [PMID:32165008]

Seizure phenotypes

  • Age of onset: typically 4–7 months (range 3 months–8 months across reports) [OMIM #617020; PMID:34017911]
  • Seizure types: multifocal/migrating focal (nonmotor) seizures meeting criteria for epilepsy of infancy with migrating focal seizures (EIMFS); generalized tonic-clonic; myoclonic; status epilepticus (both focal and myoclonic status) is common and often fever-triggered [PMID:34017911; Neurology Genetics 2021]
  • Severity/course: intractable/refractory to multiple antiseizure medications (up to 7 agents trialed in individual cases) [PMC12103100]; progressive with EEG evolution from normal → focal epileptiform discharges → multifocal → modified hypsarrhythmia [PMID:27270415]
  • Frequency: seizures occur in essentially 100% of reported cases (defining feature); status epilepticus reported in a majority of the most severely affected patients

Neurological/motor phenotypes

  • Dystonia, extensor posturing, dyskinetic movements [PMID:27270415; PMID:34017911]
  • Ataxia, progressive cerebellar signs
  • Spasticity (peripheral) combined with central hypotonia
  • Loss of previously attained (already minimal) volitional movement — progressive regression
  • Inability to walk or speak in the majority of long-surviving patients [OMIM #617020]

Other organ-system phenotypes

  • Dilated cardiomyopathy — an increasingly recognized part of the ARV1 phenotype spectrum, reported in at least 4 patients across 2+ families, with LVEF as low as 20% [PMID:35227294]
  • Hearing loss [WebSearch synthesis, PMC12080507]
  • Skeletal dysplasia / scoliosis — "marked rotatory scoliosis" reported [PMID:32165008]
  • Dysmorphic features — macrocephaly, low-set ears, midfacial hypoplasia/coarse facial features in some families [PMC12103100; PMID:32165008]
  • Feeding difficulties / poor oromotor control requiring gastrostomy tube feeding; gastroesophageal reflux [PMID:27270415]
  • Elevated alpha-fetoprotein (AFP) reported as a laboratory abnormality in some patients [PMC12080507] — of note, elevated AFP is a recognized feature of several other neurodegenerative/DNA-repair disorders and its mechanistic link to ARV1 deficiency is not established; flag for verification against primary source before curating.
  • Acute liver failure — reported as a fatal complication in at least one case (in the setting of sepsis/hepatic encephalopathy) [PMC12103100], though causal relationship to ARV1 deficiency itself (vs. antiepileptic drug hepatotoxicity or intercurrent infection) is not established.

Quality of life impact

Formal QOL instrument data (EQ-5D, SF-36) are not available for this ultra-rare disorder. Qualitatively, the disease produces profound, lifelong disability: no ambulation, no or minimal expressive language (one 21-year-old survivor had "a vocabulary restricted to about five words" [PMID:35227294]), dependence for all activities of daily living, and a very high risk of premature death from seizure-related complications (aspiration pneumonia, status epilepticus) [PMID:27270415; PMID:34017911].

Suggested HPO terms

  • HP:0001250 Seizure
  • HP:0032792 (or HP:0011097) Epileptic encephalopathy
  • HP:0002187 Intellectual disability, profound
  • HP:0001263 Global developmental delay
  • HP:0001252 Hypotonia
  • HP:0001257 Spasticity
  • HP:0002072 Chorea/dyskinetic movement (or HP:0002273 Ataxia)
  • HP:0000639 Nystagmus
  • HP:0000556 Retinal dystrophy
  • HP:0007750 Recurrent status epilepticus (or HP:0002133 Status epilepticus)
  • HP:0011451 Epileptic spasm / HP:0011097 Epileptic encephalopathy pattern (hypsarrhythmia: HP:0010544)
  • HP:0001635 Dilated cardiomyopathy
  • HP:0000407 Sensorineural hearing loss
  • HP:0002650 Scoliosis
  • HP:0000276 Long face / midface hypoplasia
  • HP:0000508 Ptosis or HP:0000486 Strabismus (per detailed case review as needed)
  • HP:0002910 Elevated alpha-fetoprotein (flag as needs-verification)

4. Genetic/Molecular Information

Causal gene: ARV1 (chr1q42; OMIM 611647). Encodes a 271-amino-acid endoplasmic reticulum transmembrane protein with a cytosolic N-terminal zinc-binding motif and multiple transmembrane domains [PMID:27270415].

Variant classification/spectrum (ACMG pathogenic/likely pathogenic in all reported cases; disease is fully recessive): | Variant (protein) | Type | Zygosity | Source | |---|---|---|---| | p.Trp163 | Nonsense | Compound het (with p.Ser122Glnfs7) | PMID:34017911 | | p.Ser122Glnfs7 | Frameshift | Compound het | PMID:34017911 | | c.294+1G>A | Splice donor (exon 2 skip) | Homozygous | PMID:32165008; PMID:27270415 | | c.674-2A>T | Splice acceptor (exon 5 skip) | Homozygous | PMID:32165008 | | p.Cys61Tyr | Missense | Homozygous (recurrent) | PMC12103100 | | p.Phe144Argfs5 | Frameshift (novel) | Homozygous | PMC12103100 | | p.Gly189Arg | Missense | Homozygous | Neurogenetics 2020 | | p.Gln62Ter | Nonsense | — | J Rare Dis 2025 | | p.Leu185del (c.554_556delTAT) | In-frame deletion | Homozygous | PMID:35227294 | | p.(Lys59_Asn98del) | In-frame deletion | — (fails temperature-sensitive rescue in yeast) | PMID:27270415 |

Allele frequency: Population frequency data specific to these variants (gnomAD) were not directly retrieved in this session; given the ultra-rare, founder-enriched, consanguinity-associated pattern, allele frequencies for individual pathogenic variants are expected to be at or near absent in gnomAD outside specific founder populations — verify per-variant in ClinVar/gnomAD during curation.

Somatic vs. germline: All reported variants are germline.

Functional consequences (loss of function): All characterized alleles behave as loss-of-function — nonsense/frameshift variants trigger nonsense-mediated decay of ARV1 mRNA [PMID:34017911]; splice variants reduce mRNA/protein by 20–50% [PMID:32165008]; the p.(Lys59_Asn98del) missense/deletion variant "completely failed to rescue at restrictive temperature" in a yeast complementation assay and showed no detectable protein in mammalian cells [PMID:27270415]. No gain-of-function or dominant-negative alleles have been reported.

Molecular mechanism — GPI-anchor biosynthesis (a major recent advance): - ARV1 was originally characterized in S. cerevisiae as a sterol-trafficking protein required for viability in ACAT-deficient yeast, mediating ER-to-plasma-membrane sterol transport and also implicated in sphingolipid/ceramide metabolism [JBC classic yeast studies, Tinkelenberg & Sturley]. - A landmark 2020 human study demonstrated that patient fibroblasts and neutrophils show markedly reduced cell-surface GPI-anchored proteins (CD16 ~5% residual, CD59/CD87 <20% residual, reduced FLAER binding), directly implicating ARV1 in the glycosylphosphatidylinositol (GPI) anchor biosynthesis pathway and placing DEE38 among the Inherited GPI Deficiency Disorders (IGDs), a group that also includes PIGA-, PIGN-, PIGT-, and related disorders [PMID:32165008]. - The 2021 genotype-phenotype refinement study (7 patients) confirmed reduced surface GPI-anchored proteins and — notably — showed that lentiviral ARV1 gene transfer rescued the cellular GPI-anchoring defect in patient cells, a proof-of-concept for gene-therapy correction [PMID:34296759]. - A 2025 mechanistic study resolved the molecular role definitively: ARV1 is a bona fide component of the GPI N-acetylglucosaminyltransferase (GPI-GnT) complex, the enzyme that catalyzes the first committed step of GPI biosynthesis. ARV1 associates specifically with the PIGQ subunit, and "ARV1-containing GPI-GnT used PI [phosphatidylinositol] more efficiently than ARV1-less GPI-GnT in an in vitro enzyme assay" — i.e., ARV1 facilitates recruitment of the PI substrate to the enzyme complex [PMID:40378954]. - Direct quote (2020 study): "Loss of GPI-anchored proteins on our patients' cells confirms that the yeast Arv1 function of GPI-anchor synthesis is conserved in humans." [PMID:32165008]

Epigenetic information: Not reported for ARV1/DEE38.

Chromosomal abnormalities: Disease is caused by point/indel variants within ARV1; no recurrent CNV or chromosomal rearrangement mechanism has been described.

Suggested ontology terms: - HGNC: ARV1 gene - GO:0006506 GPI anchor biosynthetic process - GO:0016233 telomere capping (not relevant — exclude) - GO:0034247 phosphatidylinositol N-acetylglucosaminyltransferase complex (GPI-GnT) - GO:0032934 sterol binding / GO:0032366 intracellular sterol transport - GO:0006672 ceramide metabolic process - CHEBI:18085 glycosylphosphatidylinositol - UniProt: ARV1_HUMAN (Q96BZ4)

5. Environmental Information

  • Environmental/toxin factors: None established as causal.
  • Lifestyle factors: Not applicable (early infantile monogenic disorder); note the ketogenic diet functions as a treatment modulator of seizure frequency in some patients (see Treatment, §12), not a risk/protective environmental exposure.
  • Infectious agents: Not causal to the underlying disease, but intercurrent infections (pneumonia, aspiration, sepsis) are the proximate cause of death in the majority of reported fatal cases — e.g., death from "bronchopneumonia during status epilepticus" and "pneumonia" in two sisters [PMID:34017911], and death from "acute liver failure complicated by pneumonia, sepsis, and hepatic encephalopathy" in another case [PMC12103100]. Fever is a well-documented trigger for seizure exacerbation and status epilepticus in ARV1-deficient patients [PMID:34017911].

6. Mechanism / Pathophysiology

Causal chain (numbered, from mutation to clinical manifestation)

  1. Biallelic loss-of-function variants in ARV1 → loss/reduction of ARV1 protein in the endoplasmic reticulum (demonstrated: NMD of nonsense/frameshift transcripts; 20–50% protein reduction from splice variants; failed rescue of missense/deletion alleles in yeast complementation assays) [PMID:34017911; PMID:32165008; PMID:27270415].
  2. Loss of ARV1 disrupts its role as a facilitating component of the GPI-GnT (GPI N-acetylglucosaminyltransferase) enzyme complex (ARV1 binds PIGQ and promotes efficient recruitment of phosphatidylinositol substrate) → impaired initiation of GPI-anchor biosynthesis [PMID:40378954]. (This is the most recently established, best-supported step in the chain — inferred from biochemical/enzymatic reconstitution data.)
  3. Impaired GPI biosynthesis → reduced maturation and cell-surface expression of GPI-anchored proteins (demonstrated directly in patient neutrophils/fibroblasts: CD16, CD59, CD87/uPAR, CD73, CD109 all reduced; FLAER binding reduced) [PMID:32165008; PMID:40378954].
  4. In parallel (or contributing independently, degree of contribution not fully resolved), ARV1's ancestral, evolutionarily conserved role in sterol/lipid trafficking is disrupted: loss of ARV1 causes abnormal intracellular sterol distribution (ER sterol accumulation, reduced plasma-membrane sterol) and disturbed sphingolipid/ceramide metabolism, based on conserved yeast biology and demonstrated conservation of function by human ARV1 in yeast complementation assays [classic yeast literature; PMID:27270415].
  5. Combined GPI-anchoring deficiency and lipid/sterol dyshomeostasis → endoplasmic reticulum stress and activation of the unfolded protein response, proposed as the proximate driver of cellular dysfunction: "ER stress induced by accumulation of immature GPI-anchored proteins or aberrant lipid metabolism may be responsible for the diseases associated with ARV1 deficiency" [PMID:34017911] (explicitly flagged by the authors as inferred/hypothesized, not directly demonstrated in neurons).
  6. ER stress/UPR activation and loss of GPI-anchored signaling/adhesion proteins on neuronal membranes → disruption of neuronal membrane integrity, synaptic signaling, and excitatory-inhibitory balance in the developing brain (this step draws an explicit mechanistic analogy to the well-characterized Inherited GPI Deficiency Disorders such as PIGA/PIGN/PIGT-CDG, which share "remarkably similar clinical and neuroimaging features," including EIMFS-type seizures, hypotonia, and cerebellar atrophy) [PMID:34017911].
  7. This neuronal/synaptic disruption → early-infantile-onset, multifocal/migrating, treatment-refractory seizures, progressive loss of developmental milestones, and progressive cerebral/cerebellar atrophy on serial neuroimaging [PMID:27270415; PMID:34017911].
  8. Independently, GPI-anchor/lipid dyshomeostasis in non-neural tissues produces the extra-neurological features of the phenotype: retinal GPI-anchored/lipid-dependent photoreceptor processes → retinal dystrophy/cortical-retinal visual impairment; cardiomyocyte membrane/lipid handling → dilated cardiomyopathy [PMID:35227294]; skeletal/connective tissue involvement → scoliosis/skeletal dysplasia [PMID:32165008]. The mechanistic link from ARV1 loss to each of these peripheral phenotypes is largely inferred by analogy to the neurological mechanism rather than tissue-specific experimentally demonstrated.
  9. Repeated/prolonged seizures (status epilepticus) plus severe hypotonia/poor oromotor control → aspiration risk and recurrent respiratory infection, the proximate cause of death in most reported fatal cases (bronchopneumonia, sepsis) [PMID:27270415; PMID:34017911].

Branch point: Whether the dominant pathogenic driver is (a) GPI-anchor deficiency, (b) sterol/sphingolipid dyshomeostasis, or (c) both acting in parallel/synergistically remains an open mechanistic question in the field; the 2025 GPI-GnT structural/enzymatic data [PMID:40378954] provide the strongest direct causal evidence to date for the GPI-anchoring branch specifically.

Molecular pathways

  • GPI-anchor biosynthesis pathway (Reactome: "Synthesis of glycosylphosphatidylinositol (GPI)"; KEGG map00563 Glycosylphosphatidylinositol(GPI)-anchor biosynthesis)
  • Sterol/lipid trafficking and homeostasis (ER-to-plasma-membrane sterol transport)
  • Sphingolipid/ceramide metabolism
  • Unfolded protein response / ER stress signaling (proposed downstream effector pathway)

Cellular processes

  • ER stress response, unfolded protein response
  • Impaired post-translational lipid modification (GPI anchoring) of surface proteins
  • Neuronal membrane/synaptic dysfunction (inferred)
  • Purkinje cell loss (demonstrated on postmortem neuropathology: "severe and diffuse loss of Purkinje cells" [PMID:34017911])

Protein dysfunction

Loss of function of ARV1 protein via nonsense-mediated decay, reduced transcript/protein abundance from splice defects, or failure of missense/in-frame-deletion variants to support ARV1's normal biochemical activity (yeast rescue assays) [PMID:27270415; PMID:32165008].

Tissue damage mechanisms

Progressive cerebral and cerebellar atrophy with hypomyelination on serial MRI; cerebellar vermis atrophy; thin corpus callosum in infancy progressing to more diffuse atrophic change; muscle biopsy in one patient showed increased Type 1:Type 2 fiber ratio with lipid droplets adjacent to clumped mitochondria (suggesting a secondary muscle lipid-handling abnormality) [PMID:27270415].

Molecular profiling

  • Flow cytometry (neutrophils, fibroblasts): reduced CD16, CD59, CD66b, CD87/uPAR, CD73, CD109, FLAER binding [PMID:32165008; PMID:40378954]
  • In vitro enzyme reconstitution assay: ARV1-containing vs. ARV1-less GPI-GnT complex activity comparison [PMID:40378954]
  • No transcriptomic/proteomic/metabolomic datasets on human brain tissue were identified in this search.

Advanced technologies

  • Mouse model (Palmer et al. 2016): Neuronal-specific Arv1 knockout mice recapitulate the human phenotype: circling behavior, hyperactivity, spontaneous generalized tonic-clonic seizures beginning after 12 weeks of age, reduced body weight (21% decrease in males, 15% in females) and white adipose tissue, and a striking sex-dimorphic survival defect (males: 80% survival to 20 weeks vs. females: 33% survival to 20 weeks, p=0.0053), plus fiber-type shifts in skeletal/diaphragm muscle [PMID:27270415]. Direct quote: "Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood."
  • Yeast complementation assays used to functionally test human ARV1 missense/deletion variants [PMID:27270415].
  • AlphaFold3 structural modeling used to predict the ring-shaped architecture of the ARV1-containing GPI-GnT complex [PMID:40378954].
  • Lentiviral gene-transfer rescue in patient fibroblasts restoring GPI-anchored protein surface expression — a functional/therapeutic proof-of-concept experiment [PMID:34296759].

Suggested GO / CL terms

  • GO:0006506 GPI anchor biosynthetic process; GO:0034247 GPI-GnT complex; GO:0032366 intracellular sterol transport; GO:0006672 ceramide metabolic process; GO:0034976 response to endoplasmic reticulum stress; GO:0030968 endoplasmic reticulum unfolded protein response
  • CL:0000540 neuron; CL:0000121 Purkinje cell; CL:0000775 neutrophil (for the GPI-anchor flow-cytometry assay system); CL:0000058 cardiac muscle myoblast / CL:0000746 cardiac muscle cell (cardiomyopathy)

7. Anatomical Structures Affected

Organ level (primary): Central nervous system — cerebrum, cerebellum (vermis atrophy prominent), corpus callosum (thinning), white matter (hypomyelination). Organ level (secondary/systemic): Heart (dilated cardiomyopathy), eye/retina (retinal dystrophy, cortical visual impairment), ear (sensorineural hearing loss), skeletal system (scoliosis, skeletal dysplasia), gastrointestinal tract (reflux, feeding dysfunction — largely secondary to central hypotonia), respiratory system (recurrent aspiration pneumonia — secondary complication), liver (acute liver failure reported in one fatal case; causal link uncertain).

Body systems involved: Nervous system (primary); cardiovascular; ophthalmologic; auditory; musculoskeletal; digestive (secondary); respiratory (secondary complication).

Tissue and cell level: - Neurons (cortical and cerebellar), with documented Purkinje cell loss on neuropathology [PMID:34017911] - Skeletal muscle fibers (Type 1/Type 2 fiber ratio changes, lipid droplet accumulation) [PMID:27270415] - Neutrophils and dermal fibroblasts (used as accessible surrogate tissues for GPI-anchor biochemical testing) [PMID:32165008; PMID:40378954] - Cardiomyocytes (dilated cardiomyopathy) - Retinal photoreceptors (retinal dystrophy)

Subcellular level: Endoplasmic reticulum (site of ARV1 localization and primary organelle dysfunction — ER stress, GPI-GnT complex assembly, sterol/ceramide accumulation); plasma membrane (site of reduced GPI-anchored protein display).

Localization: Bilateral, diffuse/symmetric cerebral and cerebellar involvement (no lateralization reported); seizures themselves are described as multifocal and "migrating," shifting between hemispheres rather than fixed laterality [PMID:34017911].

Suggested UBERON/GO-CC terms: - UBERON:0000955 brain; UBERON:0002037 cerebellum; UBERON:0002298 brainstem; UBERON:0002037 cerebellar vermis; UBERON:0001133 corpus callosum white matter; UBERON:0000948 heart; UBERON:0000966 retina - GO:0005783 endoplasmic reticulum; GO:0005886 plasma membrane

8. Temporal Development

Onset: - Congenital/early neonatal prodrome (hypotonia, visual inattention) apparent within the first 4–8 weeks of life in most cases. - Seizure onset: typically 4–7 months of age (as low as 3 months, as late as 8 months reported) [OMIM #617020; PMID:34017911]. - Onset pattern: insidious neurodevelopmental impairment preceding an initially subacute/abrupt seizure onset (often first presenting as status epilepticus) [PMID:27270415].

Progression: - Disease stages: (1) pre-seizure developmental impairment; (2) seizure onset with initial focal/multifocal epileptiform activity; (3) evolution to migrating focal seizures / modified hypsarrhythmia / myoclonic status; (4) progressive neurodegeneration with regression of any acquired skills, worsening spasticity/dystonia, progressive cerebral-cerebellar atrophy. - Progression rate: Generally rapid and relentless in the most severe (null-allele) cases (death by 12 months in one reported case [PMID:27270415]); somewhat slower in others, with survival into the second and third decades reported in a minority (one patient alive at 21 years with severe residual disability and later-onset cardiomyopathy [PMID:35227294]; two sisters surviving to 4 and 9 years before death [PMID:34017911]). - Course pattern: Progressive/neurodegenerative, punctuated by episodic seizure exacerbations (often fever-triggered) and intercurrent status epilepticus. - Duration: Chronic and lifelong in survivors; disease is not self-limited.

Patterns: - Remission: No spontaneous remission reported; the ketogenic diet produced temporary partial seizure reduction in two sisters (from daily seizures to "monthly clusters triggered by fever" for about 10 months), with subsequent deterioration/loss of effect by age 3 [PMID:34017911] — this is a treatment-induced partial response, not true remission. - Critical periods: The first year of life (particularly months 3–8) represents the critical window in which the seizure disorder emerges and status epilepticus risk is highest; this is also plausibly the highest-yield window for early diagnosis and intervention (e.g., trial of ARV1-directed or GPI-pathway-directed therapy), though no such intervention window has been formally established in the literature.

9. Inheritance and Population

Epidemiology: DEE38 is an ultra-rare disorder. A 2025 review states that only ~28 molecularly confirmed cases have been reported globally [PMC12080507]; no formal population-based prevalence or incidence estimate exists in Orphanet/GBD-type sources (not retrievable in this session — flag for direct Orphanet/OMIM confirmation during curation, as a dedicated ORPHA code was not confirmed).

Inheritance pattern: Autosomal recessive (all reported cases; homozygous or compound heterozygous biallelic variants).

Penetrance: Appears complete/high for the core seizure/developmental phenotype among biallelic carriers reported to date (no asymptomatic biallelic carriers described), though ascertainment bias toward severe symptomatic cases in a rare, only recently molecularly characterized disorder must be considered.

Expressivity: Variable — phenotypic severity ranges from death in infancy (severe null alleles) to survival into adulthood with milder (but still profound) impairment; extra-neurological features (cardiomyopathy, retinal dystrophy, hearing loss, skeletal dysplasia) are variably present across families, suggesting variable expressivity possibly correlated with residual ARV1 activity (missense/splice/hypomorphic vs. complete null alleles).

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

Germline mosaicism: Not specifically reported for ARV1.

Founder effects: Strongly suggested — recurrent alleles (e.g., p.Cys61Tyr, exon 2/exon 5 splice variants) reported repeatedly in consanguineous families from overlapping geographic/ethnic backgrounds (Middle Eastern, Iranian, Egyptian, South Asian cohorts in the literature reviewed) [PMC12103100; PMID:32165008; ScienceDirect Iranian family report].

Consanguinity: A dominant feature of nearly every reported pedigree; parental consanguinity is explicitly noted in the majority of case reports (Iranian family, Egyptian series, others) — reflecting the autosomal recessive, rare-allele nature of the disease.

Carrier frequency: Not established in population screening databases for this search session; likely to be population-specific and elevated in consanguineous founder populations, but should be verified against gnomAD during curation.

Population demographics: - Affected populations: Case reports to date cluster in the Middle East/North Africa (Iran, Egypt, Qatar), and additional cases from Italy, France, Denmark, Canada, the US, and Australia (per multi-institutional collaborative series) [PMID:34296759] — consistent with a globally distributed but ascertainment-limited ultra-rare disorder, over-represented in consanguineous populations. - Geographic distribution of specific variants: Recurrent alleles cluster regionally (see Founder effects above), though comprehensive geographic mapping data are not available. - Sex ratio: No clear human sex-bias reported in the clinical literature (both sexes affected; e.g., two affected sisters in one family). Notably, the mouse model shows a striking sex-dimorphic survival defect (females far worse-affected than males) that has not yet been correlated with any human sex-difference signal [PMID:27270415]. - Age distribution: All reported patients are infantile-onset; documented survivors range from death at 12 months to survival to 21 years of age.

10. Diagnostics

Laboratory tests: Elevated alpha-fetoprotein reported in some cases (verify primary source); no specific ARV1 biomarker in routine clinical chemistry.

Biomarkers (research-grade): - Flow cytometric assessment of GPI-anchored surface proteins on neutrophils and fibroblasts (CD16, CD59, CD66b, CD87/uPAR, CD73, CD109) and FLAER binding — used as functional biomarkers of GPI-anchor synthesis deficiency, analogous to the diagnostic workup used for PNH and other inherited GPI deficiencies [PMID:32165008; PMID:40378954].

Imaging studies (MRI, the primary imaging modality used): - Thin corpus callosum (early infancy) - Progressive cerebral atrophy (often with regional/temporal predominance) - Cerebellar atrophy, particularly of the vermis - Hypomyelination - Small hippocampus reported in one case [PMID:34017911] These neuroimaging features are explicitly noted to overlap substantially with the inherited GPI-deficiency disorder group (PIGA/PIGN/PIGT-CDG).

Electrophysiology: - EEG is central to diagnosis and monitoring: serial EEG shows an evolution from normal background → focal epileptiform discharges → multifocal spikes/waves → modified hypsarrhythmia or subcontinuous high-amplitude multifocal spike-wave activity with myoclonic status patterns [PMID:27270415; PMID:34017911]. - No specific EMG/nerve conduction or ECG diagnostic criteria are described beyond routine cardiac workup prompted by clinical suspicion of cardiomyopathy.

Biopsy/pathology findings: - Quadriceps muscle biopsy: increased Type 1:Type 2 fiber ratio, smaller Type 2 fibers, lipid droplets adjacent to clumped mitochondria on electron microscopy [PMID:27270415]. - Postmortem neuropathology: diffuse cerebellar atrophy with severe and diffuse Purkinje cell loss [PMID:34017911].

Genetic testing: - Whole-exome sequencing (WES) is the diagnostic modality used in essentially all reported cases and is described in the literature as the practical gold-standard approach for this ultra-rare disorder, covering "85% of disease-causing mutations" typically found in coding regions [PMC12080507]. - No ARV1-specific single-gene panel or targeted gene panel is described as standard; ARV1 should be included in DEE/epileptic encephalopathy gene panels and specifically considered in the differential of epilepsy of infancy with migrating focal seizures (EIMFS) and in the inherited GPI deficiency disorder gene panel alongside PIGA, PIGN, PIGT, PIGO, PGAP1, PGAP2, PGAP3, etc. [Neurology Genetics 2021]. - Chromosomal microarray, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion testing are not specifically indicated for ARV1-DEE38 (no chromosomal-scale or repeat-expansion mechanism identified) but may be part of a standard first-tier DEE diagnostic workup before/alongside WES.

Omics-based diagnostics: Not part of routine clinical diagnosis; flow cytometric GPI-anchor protein assays function as a confirmatory functional test analogous to a "diagnostic omics" biomarker in research/reference laboratory settings.

Clinical criteria: No formal consensus diagnostic criteria (DSM/ICD-specific) exist for DEE38 specifically; diagnosis rests on the combination of (1) clinical phenotype (early infantile refractory multifocal seizures + severe global developmental impairment ± the extra-neurologic features above) and (2) molecular confirmation of biallelic ARV1 variants.

Differential diagnosis: Other inherited GPI deficiency disorders (PIGA-CDG/EIEE2, PIGN, PIGT, PIGO, PIGQ-related disorders); other EIMFS-causing genes (KCNT1, SCN2A, SCN8A, PLCB1, SLC25A22, QARS1, TBC1D24); other early infantile DEEs more broadly (STXBP1, CDKL5, KCNQ2).

Screening: No population-based or newborn screening program exists for ARV1/DEE38 given its ultra-rarity; carrier screening/cascade testing in consanguineous families with a known proband variant is the relevant practical screening application.

11. Outcome/Prognosis

Survival/mortality: Prognosis is generally poor. Reported outcomes range from death at 12 months (most severe reported case, from intractable seizures and aspiration pneumonia [PMID:27270415]) to death at 4 years 2 months and 9 years (two sisters, both from bronchopneumonia during status epilepticus/intercurrent infection [PMID:34017911]) to survival to 21 years with profound residual disability and later-onset dilated cardiomyopathy [PMID:35227294]. No formal actuarial 5-year/10-year survival statistics exist given the small number of reported cases; the disorder should be regarded as carrying a substantial risk of premature death, predominantly from aspiration pneumonia/respiratory infection in the context of refractory status epilepticus.

Morbidity/function: Uniformly severe and largely irreversible — profound intellectual disability, absence of ambulation, absent or minimal expressive language, dependence for all activities of daily living in essentially all reported survivors.

Complications: Recurrent aspiration pneumonia, sepsis, status epilepticus (both convulsive and myoclonic), acute liver failure (reported once, causal link uncertain), progressive scoliosis, dilated cardiomyopathy (which itself carries independent mortality risk from heart failure).

Recovery potential: Essentially none reported with current standard-of-care antiseizure medications; partial, temporary benefit reported only from the ketogenic diet in one family (see below), with eventual loss of effect.

Prognostic factors: Variant severity (complete-null vs. hypomorphic alleles) appears to correlate loosely with survival — patients with the most complete loss-of-function alleles and earliest, most severe seizure onset have the shortest survival, while patients with partial-function (splice/hypomorphic) alleles have survived longer with somewhat milder (though still severe) phenotypes. No validated prognostic biomarker exists.

12. Treatment

Pharmacotherapy: No disease-modifying or ARV1-specific pharmacotherapy exists. Symptomatic antiseizure drug (ASD) therapy is uniformly attempted but the disorder is characteristically pharmacoresistant. Agents trialed across reported cases (individually or in combination), largely with limited or no lasting benefit: valproate, phenobarbital, phenytoin, ethosuximide, levetiracetam, carbamazepine, vigabatrin, topiramate, lacosamide, diazepam/benzodiazepines, and hydrocortisone (ACTH-type approach) [PMID:34017911; PMC12103100]. - Suggested NCIT term: NCIT:C15986 Pharmacotherapy (generic), with therapeutic_agent bindings to individual ASDs (e.g., CHEBI terms for levetiracetam, valproate, phenobarbital, vigabatrin, topiramate, lacosamide, phenytoin).

Pharmacogenomics: No ARV1-specific pharmacogenomic guidance has been established.

Advanced therapeutics (experimental/preclinical): - Gene therapy proof-of-concept: Lentiviral transduction of wild-type ARV1 cDNA into patient-derived fibroblasts successfully rescued the GPI-anchored protein cell-surface deficiency, demonstrating cellular reversibility of the core molecular defect and establishing a rationale for future ARV1 gene-replacement therapy [PMID:34296759]. This remains preclinical (cell-based) only — no in vivo or clinical gene-therapy trial has been reported. - Suggested NCIT term for this modality when curating: NCIT:C15238 Gene Therapy; therapeutic_modality: GENE_THERAPY.

Dietary/metabolic intervention: - Ketogenic diet produced a documented, though temporary, reduction in seizure frequency in two sisters — from multiple seizures/day to monthly fever-triggered clusters for ~10 months in one patient, with a milder transient benefit in her sister — before eventual loss of efficacy and disease progression [PMID:34017911]. - Suggested NCIT term: NCIT:C15447 Dietary Intervention.

Surgical/interventional: Not applicable/not reported (no epilepsy surgery candidacy given the diffuse, multifocal seizure pattern); gastrostomy tube placement is used supportively for feeding difficulties/aspiration risk (NCIT:C15747 Supportive Care or a specific enteral feeding procedure term).

Supportive/rehabilitative care: Multidisciplinary supportive management is emphasized throughout the literature as the mainstay of care — including nutritional support (gastrostomy), respiratory/aspiration precaution management, physical/occupational/speech therapy for symptomatic management of hypotonia/spasticity, and genetic counseling for families [PMC12080507]. - Suggested NCIT terms: NCIT:C15302 Physical Therapy; NCIT:C15240 Genetic Counseling.

Experimental/clinical trials: No ARV1-specific registered clinical trials (ClinicalTrials.gov) were identified in this search.

Treatment outcomes: As above — despite pharmacologic and dietary intervention, "neurodevelopmental outcomes often remain poor" even when partial seizure control is achieved [PMC12080507, citing case-series literature].

Treatment strategy/algorithm: No formal published treatment algorithm exists; management follows general refractory-DEE/EIMFS principles (sequential/combination ASD trials, early consideration of ketogenic diet, avoidance/aggressive management of febrile triggers, proactive aspiration/respiratory precautions) rather than an ARV1-specific protocol.

Personalized medicine: The demonstrated in vitro rescue of GPI-anchoring defects by ARV1 gene replacement [PMID:34296759] represents the most concrete precision-medicine lead in the current literature, though it has not progressed beyond patient-cell experiments.

13. Prevention

  • Primary prevention: No vaccination or population-level primary prevention exists (monogenic recessive disorder). The only actionable primary-prevention lever identified in the literature is genetic counseling regarding consanguinity and recurrence risk in families with a known or suspected ARV1 pathogenic variant.
  • Secondary prevention: Carrier screening and prenatal/preimplantation genetic testing are the relevant options once a familial ARV1 variant is identified, particularly given the strong consanguinity association in reported pedigrees; no population-based newborn screening program exists for this ultra-rare condition.
  • Tertiary prevention: Aggressive management of febrile illness and infection (given documented fever-triggered status epilepticus and infection as the leading cause of death), proactive aspiration precautions, and early recognition/monitoring for the extra-neurologic complications of the phenotype (baseline and serial echocardiography for cardiomyopathy surveillance, ophthalmologic and audiologic screening, scoliosis monitoring) are the most concrete tertiary-prevention measures supported by the case literature.
  • Immunization: No disease-specific vaccine strategy; standard childhood immunization plus attention to respiratory pathogen prevention (e.g., RSV prophylaxis, influenza/pneumococcal vaccination where age-appropriate) is a reasonable extrapolation given the infection-driven mortality pattern, though not explicitly studied in ARV1-DEE38.
  • Genetic counseling: Central to family management — explicit recommendation in the literature that "ARV1 should be considered in the genetic screening of individuals with EIMFS" [Neurology Genetics 2021], with downstream implications for reproductive counseling in affected families.

14. Other Species / Natural Disease

  • Taxonomy: No naturally occurring ARV1-deficient disease has been reported in companion animals or wildlife (NCBITaxon — not applicable beyond the engineered mouse model below).
  • Orthologous gene: ARV1 is highly conserved from yeast (Saccharomyces cerevisiae ARV1, "ARE2-required for viability 1") through mouse (Arv1) to human, with human ARV1 fully complementing yeast arv1Δ phenotypes in classic complementation assays [PMID:27270415 and cited yeast literature].
  • Comparative biology: The yeast-to-human functional conservation of both the sterol-trafficking role and, by extension, contribution to GPI-anchor biosynthesis machinery underlies much of the current mechanistic model; this conservation was directly exploited experimentally (patient variant rescue assays performed in yeast).
  • Zoonotic potential / transmission: Not applicable — ARV1-DEE38 is a purely genetic (non-infectious, non-transmissible) disorder.

15. Model Organisms

Mouse (primary in vivo model): - Neuronal-specific Arv1 knockout mouse (Palmer et al., 2016) is the principal validated in vivo model. It recapitulates the core human phenotype: spontaneous generalized tonic-clonic seizures beginning after 12 weeks of age, circling behavior and hyperactivity, reduced body weight and white adipose tissue mass, skeletal-muscle fiber-type shifts, and a pronounced sex-dimorphic survival defect (33% female survival vs. 80% male survival to 20 weeks, p=0.0053) [PMID:27270415]. - Applications: Used to establish causality between neuronal ARV1 loss and the seizure/survival phenotype, and as the platform demonstrating that human ARV1 patient variants fail functional rescue. - Limitations: The pronounced sex-dimorphism in the mouse model has no established human correlate; the mouse model does not obviously recapitulate the human extra-neurological features (cardiomyopathy, retinal dystrophy, hearing loss) reported in some human patients — these organ systems do not appear to have been systematically examined in the knockout mouse in the retrieved literature.

Yeast (Saccharomyces cerevisiae): - The original and still mechanistically foundational model system for ARV1 function — used to define its role in sterol trafficking, sphingolipid/ceramide metabolism, and (via genetic and biochemical experiments) contribution to GPI-anchor biosynthesis. Human patient ARV1 variants have been functionally tested via yeast complementation/temperature-sensitive rescue assays [PMID:27270415].

Human cell-based models: - Patient-derived dermal fibroblasts and neutrophils are used as the primary "model system" for confirmatory functional/biochemical testing (GPI-anchored protein flow cytometry) and for the lentiviral gene-rescue proof-of-concept experiment [PMID:32165008; PMID:34296759; PMID:40378954]. - HEK293 ARV1-knockout cells and in vitro-reconstituted GPI-GnT enzyme assays were used in the most recent (2025) mechanistic study to directly demonstrate ARV1's biochemical role within the GPI-GnT complex [PMID:40378954].

Resources: No dedicated ARV1/DEE38 entries were confirmed in MGI, IMPC, or veterinary (OMIA) databases within this search session; the Palmer et al. 2016 conditional neuronal knockout appears to be a custom, non-commercially-catalogued line rather than a broadly distributed IMPC/KOMP allele — verify directly in MGI during curation if a stable allele ID is needed.

Summary Table: Key Primary Citations

Citation Contribution
PMID:27270415 (Palmer et al. 2016, Hum Mol Genet) First description linking ARV1 to human DEE; neuronal knockout mouse model
PMID:32165008 (2020) First direct biochemical evidence of GPI-anchor synthesis deficiency in patient cells; two splice-variant families
PMID:34017911 (2021, Neurology Genetics) Expands phenotype to EIMFS/migrating focal seizures + myoclonic status; proposes ER-stress/GPI-deficiency-disorder framework; ketogenic diet response data
PMID:34296759 (2021) Genotype-phenotype refinement across 7 patients; lentiviral gene-therapy rescue proof-of-concept
PMID:35227294 (2022) Establishes dilated cardiomyopathy as part of the ARV1 phenotype spectrum
Neurogenetics 2020 (10.1007/s10048-020-00615-4) p.Gly189Arg family; further mechanistic GPI-synthesis discussion
PMC12103100 / Cureus (2025) Three additional pediatric cases (Egypt); novel p.Phe144Argfs*5 variant; fatal liver-failure outcome
Springer J Rare Dis (2025), 10.1007/s44162-025-00066-1 Novel p.Gln62Ter variant
ScienceDirect (2021), S2214540021001043 Iranian consanguineous family, novel homozygous variant
PMID:40378954 (2025) Defines ARV1 as a structural/functional component of the GPI-GnT enzyme complex (mechanistic capstone paper)
OMIM #617020 Authoritative clinical synopsis and gene-disease relationship record

Notes on gaps for curation: A dedicated MONDO ID, Orphanet ORPHA code, and gnomAD constraint metrics (pLI/LOEUF) for ARV1 could not be directly confirmed via the sources accessible in this session (OMIM and Orphanet pages returned access-blocked/403 responses); these should be resolved directly against MONDO/Orphanet/gnomAD during formal knowledge-base curation rather than inferred from this report. The mechanistic step linking GPI-anchor/ER-stress dysfunction specifically to neuronal excitability (step 6 in the causal chain above) is explicitly flagged by the primary authors themselves as inferential/hypothesized rather than directly demonstrated in human or mouse neurons.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 2
Quoted claims found in source 1
Quoted claims not found in source 1
References weighed for topical relevance 9
On topic 9
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:34017911 (abstract only): "severe and diffuse loss of Purkinje cells"
  • closest text in source: "CONCLUSIONS: This report confirms that biallelic ARV1 mutations cause a severe form of DEE and adds epilepsy with migrating focal seizures and myoclonic status to the spectrum of epilepsy phenotypes"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 50
Resolved 50
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0

Every term resolved, and every label the report gave matched.