Developmental And Epileptic Encephalopathy 80

Mendelian MONDO:0032822 Pathograph 14 Show in embeddings browser Genetic Developmental and Epileptic Encephalopathy

DEE80 (EIEE80; glycosylphosphatidylinositol biosynthesis defect 20, GPIBD20) is an autosomal recessive developmental and epileptic encephalopathy caused by biallelic loss-of-function variants in PIGB. PIGB encodes an endoplasmic reticulum transmembrane mannosyltransferase (GPI mannosyltransferase III) that transfers the third mannose (Man3) onto the glycosylphosphatidylinositol (GPI) precursor; loss of this step impairs GPI-anchor biosynthesis and reduces the cell-surface display of GPI-anchored proteins, placing DEE80 among the inherited GPI-deficiency disorders. Affected children present in early infancy with global developmental and/or intellectual delay and early-onset seizures; peripheral (axonal/mixed) neuropathy, polymicrogyria, CNS hypomyelination, hypotonia, scoliosis, foot deformity and elevated serum alkaline phosphatase are recurrent, and the severe end of the spectrum overlaps clinically with DOORS syndrome (with sensorineural deafness, small nails and, in some, a metabolic 2-oxoglutaric aciduria). The course is severe and frequently lethal in early childhood; there is no disease-modifying therapy.

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1
Inheritance
5
Pathophys.
16
Phenotypes
1
Gaps
14
Pathograph
1
Genes
4
Medical Actions
1
Models
9
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
DEE80 is autosomal recessive: affected individuals carry biallelic PIGB variants (homozygous in consanguineous families, or compound heterozygous). The original series described ten unrelated families with biallelic PIGB mutations, and reported alleles span missense (e.g. p.Asp155His) and truncating variants.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:31256876 SUPPORT Human Clinical
"We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI."
Documents biallelic causation across ten unrelated families, establishing recessive inheritance.
PMID:34161862 SUPPORT Human Clinical
"Whole-exome sequencing (WES) disclosed the likely pathogenic biallelic PIGB NM_004855.4: c.463G > C, p.(Asp155His) missense variant."
Independent report of a biallelic PIGB genotype, consistent with recessive inheritance.
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Discussions and Knowledge Gaps

1
By what route does reduced surface expression of GPI-anchored proteins produce neuronal dysfunction and seizures in the developing brain in PIGB deficiency?
KNOWLEDGE GAP OPEN gap_gpi_to_seizure_route
Attached to
pathophysiology#Reduced Cell-Surface GPI-Anchored Protein Expression pathophysiology#Neuronal Dysfunction and Epileptic Encephalopathy
The link from the measured cellular defect (reduced surface GPI-anchored proteins) to seizures is drawn from the known importance of GPI-anchored proteins in development and neurogenesis and by analogy to other inherited GPI-deficiency disorders. No excitation-inhibition or direct neuronal measurement exists in PIGB deficiency, so the entry deliberately does not conform to the epilepsy_excitation_inhibition_imbalance module. One specific, testable candidate route connects the hyperphosphatasia branch to the seizures: tissue-nonspecific alkaline phosphatase (TNAP) normally dephosphorylates extracellular pyridoxal-5'-phosphate (the active vitamin B6 cofactor), and dysregulated TNAP handling in GPI deficiency could perturb B6-dependent neurotransmitter synthesis. This is the same B6 axis by which TNAP loss in hypophosphatasia causes vitamin-B6-responsive seizures, and it is the mechanistic rationale for the pyridoxine/pyridoxal-5-phosphate treatment trial in inherited GPI deficiency; it remains a candidate route, not a demonstrated one in PIGB deficiency.
Proposed experiments
Excitation-inhibition and GPI-anchored protein measurement in PIGB-deficient neural models
exp_pigb_neuronal_excitability
In PIGB-null human iPSC-derived neurons, measure surface GPI-anchored protein levels alongside network excitability (multi-electrode array or patch-clamp) 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 (2 references)
PMID:31256876 SUPPORT INDIRECT Human Clinical
"Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis."
The developmental/neurogenic importance of GPI-anchored proteins that stands in for a demonstrated neuronal route, which is what this gap flags.
PMID:23860646 SUPPORT INDIRECT Other
"abnormal metabolism of pyridoxal-5'-phosphate (the predominant form of vitamin B6)"
Review establishing the TNAP -> pyridoxal-5'-phosphate axis: loss of TNAP activity (in hypophosphatasia) causes seizures through abnormal B6-cofactor metabolism. Cited INDIRECT because it grounds the candidate B6 route named in the rationale, not a route demonstrated in PIGB deficiency.
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Pathophysiology

5
Biallelic PIGB Loss of Function
PIGB (phosphatidylinositol glycan class B) encodes a 554-residue endoplasmic reticulum transmembrane protein with a small N-terminal cytoplasmic portion and a large C-terminal lumenal domain that carries the catalytic site. It is the GPI mannosyltransferase (GPI-MT-III) that transfers the third mannose onto the GPI precursor. Biallelic missense and truncating variants reduce or abolish PIGB function; ten different variants were found across the original ten families.
PIGB hgnc:8959 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PIGB (hgnc:8959). hgnc:8959 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired GPI Anchor Biosynthesis Loss of PIGB removes the enzyme that adds the third mannose, an obligatory step in assembling the mature GPI precursor.
Show evidence (2 references)
PMID:8861954 SUPPORT In Vitro
"PIG-B encodes a 554 amino acid, ER transmembrane protein with an amino-terminal portion of approximately 60 amino acids on the cytoplasmic side and a large carboxy-terminal portion of 470 amino acids within the ER lumen."
Source for the protein architecture (length, cytoplasmic/lumenal topology) described in this node.
PMID:31256876 SUPPORT Human Clinical
"Ten different PIGB variants were found in these individuals."
Documents the allelic loss-of-function spectrum grounding the trigger.
Impaired GPI Anchor Biosynthesis
The disease-relevant consequence of PIGB loss is failure of the third-mannose transfer step, which stalls maturation of the GPI precursor in the ER. The functional site of PIGB resides on the lumenal side of the ER membrane where the GPI precursor is assembled before being linked to nascent proteins.
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
GPI mannosyltransferase activity GO:0004376 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased GPI mannosyltransferase activity (GO:0004376). GO:0004376 is a molecular function from the Gene Ontology. ↓ DECREASED
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:8861954 SUPPORT In Vitro
"A mutant PIG-B lacking the cytoplasmic portion remains active, indicating that the functional site of PIG-B resides on the lumenal side of the ER membrane."
Localizes PIGB catalytic activity to the ER lumen where GPI-precursor mannosylation occurs, grounding the biosynthetic step that is lost.
PMID:8861954 SUPPORT In Vitro
"The GPI anchor precursor is synthesized in the endoplasmic reticulum (ER) and post-translationally linked to protein."
Establishes that GPI-precursor assembly precedes protein anchoring, the pathway PIGB loss interrupts.
Reduced Cell-Surface GPI-Anchored Protein Expression
Patient blood cells and fibroblasts show decreased surface presence of GPI-anchored proteins on flow cytometry, the cellular readout that assigns PIGB deficiency to the inherited GPI-deficiency disorders. Alkaline phosphatase is itself a GPI-anchored ectoenzyme; abnormal handling of GPI-anchored proteins is reflected in the elevated serum alkaline phosphatase that is characteristic of inherited GPI deficiency in most tested patients.
Leukocyte (blood cell) CL:0000738 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Leukocyte (blood cell), annotated with leukocyte (CL:0000738). CL:0000738 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
Shedding of GPI-Anchored Alkaline Phosphatase into Serum Alkaline phosphatase is itself a GPI-anchored ectoenzyme. In PIGB deficiency an incomplete but mannose-bearing GPI accumulates that the GPI transamidase still engages, so alkaline phosphatase is cleaved from its C-terminal signal peptide and released rather than displayed at the cell surface.
Neuronal Dysfunction and Epileptic Encephalopathy GPI-anchored proteins play key roles in development and neurogenesis, so their reduced surface display on developing neural membranes is the proposed route to the encephalopathy, by analogy to other inherited GPI-deficiency disorders. The intervening steps are not demonstrated in human neural tissue.
Show evidence (2 references)
PMID:31256876 SUPPORT Human Clinical
"Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins."
Direct measurement of reduced surface GPI-anchored proteins in patient cells.
PMID:31256876 SUPPORT Human Clinical
"Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome."
Elevated alkaline phosphatase, a GPI-anchored ectoenzyme, is the biochemical correlate of the disturbed GPI-anchored protein handling.
Shedding of GPI-Anchored Alkaline Phosphatase into Serum
Tissue-nonspecific alkaline phosphatase (TNAP) is normally a GPI-anchored ectoenzyme displayed at the cell surface. In synthesis-stage GPI deficiency such as PIGB deficiency, an incomplete GPI precursor that still bears mannose accumulates; the GPI transamidase recognizes this mannose-bearing precursor and cleaves the C-terminal GPI-attachment signal peptide, releasing soluble ALP into the medium (and, in patients, the serum) instead of anchoring it at the membrane. This is the molecular mechanism of hyperphosphatasia in mannose-bearing GPI defects, and it contrasts with the mannose-lacking defects (e.g. PIGL), in which ALP is degraded rather than secreted and serum ALP is not elevated.
Experimental models
PIGB-deficient CHO cell mutant CELL LINE The PIGB-deficient CHO line reproduces the defining event of this node: soluble ALP is secreted rather than surface-anchored, and the contrast with mannose-lacking mutants (which degrade ALP instead) shows the secretion is specific to the mannose-bearing lesion class that PIGB deficiency belongs to.
Downstream
Elevated circulating alkaline phosphatase concentration Release of soluble alkaline phosphatase into the circulation raises serum alkaline phosphatase, the hyperphosphatasia seen in most tested patients.
Show evidence (1 reference)
PMID:22228761 SUPPORT In Vitro
"transamidase recognizes incomplete GPI bearing mannose and cleaves a hydrophobic"
Establishes that in mannose-bearing GPI deficiency (which includes PIGB) the transamidase cleaves the signal peptide and secretes ALP, the shedding mechanism modeled by this node.
Neuronal Dysfunction and Epileptic Encephalopathy
The clinical endpoint is an early-infantile developmental and epileptic encephalopathy: global developmental and/or intellectual delay with early-onset seizures, frequently accompanied by peripheral neuropathy and, in some, polymicrogyria and hypomyelination. The course is severe, with a high early-childhood mortality (eight of the original children died before four years of age). This entry does not declare conformance to the epilepsy_excitation_inhibition_imbalance module: no excitation-inhibition measurement exists in PIGB deficiency and asserting that mechanism would substitute a plausible route for an evidenced one (see gap_gpi_to_seizure_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.
Downstream
Seizures The epileptic encephalopathy manifests as seizures, present in all reported affected individuals.
Global developmental delay The encephalopathy manifests as global developmental and/or intellectual delay across the cohort.
Polymicrogyria Polymicrogyria, a malformation of cortical development reflecting the disturbed neural development in this endpoint, was present in two affected individuals; the developmental steps linking GPI deficiency to the malformation are not demonstrated.
Peripheral neuropathy Peripheral (axonal/mixed) neuropathy accompanies the neural endpoint in a substantial fraction of patients; the mechanism linking GPI deficiency to peripheral axonal degeneration is not demonstrated.
Show evidence (2 references)
PMID:31256876 SUPPORT Human Clinical
"Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
Characterizes the clinical endpoint syndrome across the patient series.
PMID:34161862 SUPPORT Human Clinical
"This disorder, an inherited glycosylphosphatidylinositol deficiency, is associated with a complex neurologic phenotype, including developmental delay, early-onset epilepsy and peripheral neuropathy."
Independent characterization of the complex neurologic endpoint.
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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 80 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

16
Ear 1
Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural deafness, annotated with Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31256876 SUPPORT Human Clinical
"a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency"
Documents sensorineural deafness in the DOORS-overlapping severe subset.
Genitourinary 1
2-oxoglutaric aciduria Organic aciduria HP:0001992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is 2-oxoglutaric aciduria, annotated with Organic aciduria (HP:0001992). HP:0001992 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31256876 SUPPORT Human Clinical
"It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions."
Documents 2-oxoglutaric aciduria in two severely affected individuals.
Integument 1
Small nails HP:0001792 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small finger and toenails, annotated with Small nail (HP:0001792). HP:0001792 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31256876 SUPPORT Human Clinical
"a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency"
Documents small finger and toenails in the DOORS-overlapping severe subset.
Limbs 1
Pes cavus HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Equino-varo-supinated-cavus foot, annotated with Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34161862 SUPPORT Human Clinical
"manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
Documents the cavus foot deformity.
Metabolism 1
Elevated circulating alkaline phosphatase concentration FREQUENT HP:0003155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating alkaline phosphatase concentration (HP:0003155). HP:0003155 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31256876 SUPPORT Human Clinical
"Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome."
States elevated alkaline phosphatase in most tested patients.
PMID:34161862 SUPPORT Human Clinical
"manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
Independent report of elevated serum alkaline phosphatase.
Musculoskeletal 2
Hypotonia Generalized hypotonia HP:0001290 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia, annotated with Generalized hypotonia (HP:0001290). HP:0001290 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34161862 SUPPORT Human Clinical
"manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
Documents hypotonia in a reported patient.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Early-onset scoliosis, annotated with Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34161862 SUPPORT Human Clinical
"manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
Documents early-onset scoliosis.
Nervous System 9
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:34161862 SUPPORT Human Clinical
"Pathogenic variants in phosphatidylinositol glycan anchor biosynthesis class B (PIGB) gene have been first described as the cause of early infantile epileptic encephalopathy 80 (EIEE-80) in 2019."
Establishes DEE80/EIEE-80 as the defining epileptic encephalopathy of PIGB deficiency.
Seizures VERY_FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31256876 SUPPORT Human Clinical
"Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
States that all affected individuals had seizures, the basis for the VERY_FREQUENT band.
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:31256876 SUPPORT Human Clinical
"Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
Reports global developmental and/or intellectual delay across the series.
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:31256876 SUPPORT Human Clinical
"Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
Names intellectual delay among the near-universal features.
Absent speech HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34161862 SUPPORT Human Clinical
"manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
Documents absent speech in a reported patient.
Status epilepticus Febrile status epilepticus HP:0032656 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Febrile status epilepticus (HP:0032656). HP:0032656 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34161862 SUPPORT Human Clinical
"manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
Documents a febrile status epilepticus episode.
Peripheral neuropathy Peripheral axonal neuropathy HP:0003477 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy, annotated with Peripheral axonal neuropathy (HP:0003477). HP:0003477 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31256876 SUPPORT Human Clinical
"Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
Reports peripheral neuropathy in four of the ten families.
PMID:34161862 SUPPORT Human Clinical
"manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
Independent report of a mixed peripheral polyneuropathy.
Polymicrogyria HP:0002126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polymicrogyria (HP:0002126). HP:0002126 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31256876 SUPPORT Human Clinical
"Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
Reports polymicrogyria in two affected individuals.
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:34161862 SUPPORT Human Clinical
"Hypomyelination was documented on brain MRI."
Reports hypomyelination on neuroimaging.
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Genetic Associations

1
PIGB (Pathogenic Variants)
Gene: PIGB hgnc:8959 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PIGB (hgnc:8959). hgnc:8959 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:31256876 SUPPORT Human Clinical
"We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI."
The gene-disease association statement establishing PIGB as causative.
PMID:38456468 SUPPORT INDIRECT Human Clinical
"Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046)."
PIGB is a synthesis-stage GPI-anchor-pathway gene (the third-mannose transferase); this cross-gene cohort associates synthesis-stage variants with earlier seizure onset. Classified INDIRECT because it is a stage-class rather than PIGB-specific comparison.
PMID:31256876 SUPPORT Human Clinical
"Ten different PIGB variants were found in these individuals."
Documents the allelic spectrum underlying the variant notes.
+ 1 more reference
💊

Medical Actions

4
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
Management is symptomatic. The epilepsy is treated with antiseizure medicines; no disease-modifying or PIGB-specific pharmacotherapy exists.
Mechanism Target:
MODULATES Neuronal Dysfunction and Epileptic Encephalopathy — Antiseizure medicines suppress the seizure activity of the epileptic encephalopathy symptomatically; they do not address the upstream GPI-anchor defect, and no disease-modifying therapy exists.
Show evidence (1 reference)
PMID:31256876 SUPPORT Human Clinical
"Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
Establishes the near-universal seizure burden of the epileptic encephalopathy that symptomatic antiseizure therapy targets.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31256876 SUPPORT Human Clinical
"Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
Establishes the seizure burden that symptomatic antiseizure therapy targets.
Pyridoxine or pyridoxal-5-phosphate (vitamin B6) trial
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: pyridoxine CHEBI:16709 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyridoxine (CHEBI:16709). CHEBI:16709 is a therapeutic agent from Chemical Entities of Biological Interest. pyridoxal 5'-phosphate CHEBI:18405 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyridoxal 5'-phosphate (CHEBI:18405). CHEBI:18405 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
High-dose oral pyridoxine or pyridoxal-5-phosphate (P5P, the active vitamin B6 cofactor) has been trialed as a candidate disease-specific treatment for the drug-resistant epilepsy of inherited GPI deficiency, on the rationale that GPI-anchored alkaline phosphatase (which dephosphorylates extracellular P5P) is dysregulated in GPI deficiency. In a prospective compassionate-use cohort a partial seizure-frequency reduction was seen in some participants but none reached seizure freedom; efficacy in PIGB deficiency specifically is not established (the cohort enrolled PIGA/PIGT/PIGV participants).
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35080266 SUPPORT INDIRECT Human Clinical
"We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom."
Prospective cohort of inherited GPI deficiency showing partial seizure-frequency reduction with pyridoxine/P5P and no seizure freedom. Classified INDIRECT for PIGB because the cohort enrolled PIGA/PIGT/PIGV participants, not PIGB; the benefit is extrapolated to PIGB deficiency by the shared GPI-deficiency mechanism.
Supportive and multidisciplinary care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Care is supportive and multidisciplinary, addressing the developmental delay, neuropathy, skeletal complications and feeding/respiratory vulnerability of a severe early-infantile encephalopathy.
Show evidence (1 reference)
PMID:34161862 SUPPORT Human Clinical
"This disorder, an inherited glycosylphosphatidylinositol deficiency, is associated with a complex neurologic phenotype, including developmental delay, early-onset epilepsy and peripheral neuropathy."
Characterizes the complex multisystem phenotype that supportive, multidisciplinary care addresses.
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 DEE80 is autosomal recessive, genetic counseling of families (recurrence-risk and carrier-testing discussion) is part of care.
Show evidence (1 reference)
PMID:31256876 SUPPORT Human Clinical
"We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI."
Establishes the biallelic recessive genotype that makes recurrence-risk counseling relevant.
🔬

Diagnosis

2
Whole exome sequencing
Diagnosis rests on identifying biallelic PIGB variants by exome (or genome) sequencing.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:34161862 SUPPORT Human Clinical
"Whole-exome sequencing (WES) disclosed the likely pathogenic biallelic PIGB NM_004855.4: c.463G > C, p.(Asp155His) missense variant."
Establishes exome sequencing as the diagnostic route.
Flow cytometry for GPI-anchored proteins
Reduced surface expression of GPI-anchored proteins on blood cells and fibroblasts is a functional signature shared with the inherited GPI-deficiency disorders and supports pathogenicity of a PIGB variant.
flow cytometry NCIT:C16585 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:31256876 SUPPORT Human Clinical
"Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins."
Establishes the GPI-anchored-protein flow cytometry assay as functional diagnostic support.
📈

Progression

3
Onset
Onset is in early infancy, with early-onset seizures and developmental impairment; PIGB variants define an early infantile epileptic encephalopathy.
Show evidence (2 references)
PMID:34161862 SUPPORT Human Clinical
"Pathogenic variants in phosphatidylinositol glycan anchor biosynthesis class B (PIGB) gene have been first described as the cause of early infantile epileptic encephalopathy 80 (EIEE-80) in 2019."
Establishes the early-infantile onset framing of the disorder.
PMID:38456468 SUPPORT INDIRECT Human Clinical
"Median age at seizure onset was 6 months."
Cross-gene inherited-GPI-deficiency cohort (including synthesis-stage genes such as PIGB) placing median seizure onset in early infancy. Classified INDIRECT because the figure is pooled across GPI-AP genes.
Neurodegenerative course and neuroimaging
Inherited GPI-deficiency disorders (the cross-gene group that includes PIGB and other synthesis-stage genes) show a neurodegenerative process on serial neuroimaging, with a recognizable signature of cerebral and cerebellar atrophy, callosal anomalies and symmetric restricted diffusion of the central tegmental tracts. In PIGB patients specifically, polymicrogyria and hypomyelination are documented; the atrophy/central-tegmental-tract signature is reported at the cross-gene cohort level rather than isolated to PIGB.
Show evidence (2 references)
PMID:38456468 SUPPORT INDIRECT Human Clinical
"Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%)."
Cross-gene IGD cohort (including synthesis-stage genes such as PIGB) defining the shared neuroimaging signature; INDIRECT because the frequencies are pooled across GPI-AP genes rather than PIGB-specific.
PMID:38456468 SUPPORT INDIRECT Human Clinical
"Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process."
Documents the neurodegenerative imaging course across the IGD cohort that includes PIGB; INDIRECT because pooled across GPI-AP genes.
Untreated course and mortality
The course is severe, with high early-childhood mortality: eight of the originally reported children died before four years of age.
Show evidence (1 reference)
PMID:31256876 SUPPORT Human Clinical
"Eight children passed away before four years old."
Documents the high early-childhood mortality of the severe phenotype.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
DEE80 is ultra-rare. The founding report described ten unrelated families, and a later case report describes the disorder as ultra-rare; no population prevalence has been estimated. These are dated lower bounds rather than current totals.
Show evidence (2 references)
PMID:34161862 SUPPORT Human Clinical
"thus contributing to our knowledge on this ultra-rare disorder."
Characterizes DEE80 as an ultra-rare disorder.
PMID:31256876 SUPPORT Human Clinical
"We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI."
A literature count consistent with an ultra-rare disorder; kept as a count rather than converted to a population rate.
🧫

Experimental Models

1
PIGB-deficient CHO cell mutant CELL_LINE
The workhorse heterologous system for the ALP-shedding biochemistry of synthesis-stage GPI deficiency. Because CHO mutants can be made deficient in one GPI-pathway gene at a time, the panel isolates the effect of the PIGB (mannose-transfer) lesion from mannose-lacking lesions, which is not possible in patient material. It models the molecular mechanism of the hyperphosphatasia branch, not the neuronal phenotype.
Organism
Chinese hamster (CHO cell line) NCBITaxon:10029 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Chinese hamster (CHO cell line), annotated with Cricetulus griseus (NCBITaxon:10029). NCBITaxon:10029 is an organism from the NCBI Taxonomy.
Cell source
Chinese hamster ovary (CHO) cell mutants each defective in a single step of GPI biosynthesis, including a PIGB-deficient line, used as an isogenic panel to dissect the GPI lesion that produces alkaline-phosphatase secretion.
Publication
PMID:22228761
Pathograph links
Shedding of GPI-Anchored Alkaline Phosphatase into Serum recapitulates fidelity: moderate observes: cellular The PIGB-deficient CHO line reproduces the defining event of this node: soluble ALP is secreted rather than surface-anchored, and the contrast with mannose-lacking mutants (which degrade ALP instead) shows the secretion is specific to the mannose-bearing lesion class that PIGB deficiency belongs to.
Limitations: A non-human (Chinese hamster) non-neuronal cell line that captures the cell-biological ALP-secretion mechanism only; it does not model the developmental and epileptic encephalopathy, and the PIGB mutant is an engineered null rather than a patient hypomorphic allele.
Readouts
Soluble alkaline phosphatase released into culture medium
Direction: INCREASED
Interpretation: In vitro correlate of the patient hyperphosphatasia: the PIGB-deficient line sheds ALP into the medium instead of retaining it at the surface.
Show evidence (1 reference)
PMID:22228761 SUPPORT In Vitro
"The GPI-anchored protein was secreted substantially into medium from PIGV-, PIGB-, and PIGF-deficient CHO cells, in which incomplete GPI bearing mannose was accumulated."
Reports the measured secretion of ALP into the medium from the PIGB-deficient CHO line, the readout that grounds this model's link to the shedding node.
Show evidence (1 reference)
PMID:22228761 SUPPORT In Vitro
"In contrast, ALP was degraded in PIGL-, DPM2-, or PIGX-deficient CHO cells, in which incomplete shorter GPIs that lacked mannose were accumulated."
The mannose-lacking CHO mutants degrade rather than secrete ALP, so the secretion seen in the PIGB-deficient line is specific to the mannose-bearing lesion class - establishing this model as informative for the PIGB shedding mechanism specifically.
Show evidence (1 reference)
PMID:22228761 SUPPORT In Vitro
"we took advantage of CHO cell mutants that are defective in various steps of GPI biosynthesis"
Establishes the single-gene-deficient CHO mutant panel (which includes the PIGB-deficient line) as the system used to dissect ALP secretion in GPI deficiency.
{ }

Source YAML

click to show 
name: Developmental And Epileptic Encephalopathy 80
creation_date: "2026-09-04T12:00:00Z"
description: >-
  DEE80 (EIEE80; glycosylphosphatidylinositol biosynthesis defect 20, GPIBD20)
  is an autosomal recessive developmental and epileptic encephalopathy caused by
  biallelic loss-of-function variants in PIGB. PIGB encodes an endoplasmic
  reticulum transmembrane mannosyltransferase (GPI mannosyltransferase III) that
  transfers the third mannose (Man3) onto the glycosylphosphatidylinositol (GPI)
  precursor; loss of this step impairs GPI-anchor biosynthesis and reduces the
  cell-surface display of GPI-anchored proteins, placing DEE80 among the
  inherited GPI-deficiency disorders. Affected children present in early infancy
  with global developmental and/or intellectual delay and early-onset seizures;
  peripheral (axonal/mixed) neuropathy, polymicrogyria, CNS hypomyelination,
  hypotonia, scoliosis, foot deformity and elevated serum alkaline phosphatase
  are recurrent, and the severe end of the spectrum overlaps clinically with
  DOORS syndrome (with sensorineural deafness, small nails and, in some, a
  metabolic 2-oxoglutaric aciduria). The course is severe and frequently lethal
  in early childhood; there is no disease-modifying therapy.
category: Mendelian
parents:
- Genetic Developmental and Epileptic Encephalopathy
synonyms:
- DEE80
- EIEE80
- early infantile epileptic encephalopathy 80
- EIEE-80
- glycosylphosphatidylinositol biosynthesis defect 20
- GPIBD20
- PIGB-related developmental and epileptic encephalopathy
disease_term:
  preferred_term: developmental and epileptic encephalopathy, 80
  term:
    id: MONDO:0032822
    label: developmental and epileptic encephalopathy, 80
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    DEE80 is autosomal recessive: affected individuals carry biallelic PIGB
    variants (homozygous in consanguineous families, or compound heterozygous).
    The original series described ten unrelated families with biallelic PIGB
    mutations, and reported alleles span missense (e.g. p.Asp155His) and
    truncating variants.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI."
    explanation: >-
      Documents biallelic causation across ten unrelated families, establishing
      recessive inheritance.
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing (WES) disclosed the likely pathogenic biallelic PIGB NM_004855.4: c.463G > C, p.(Asp155His) missense variant."
    explanation: >-
      Independent report of a biallelic PIGB genotype, consistent with recessive
      inheritance.
pathophysiology:
- name: Biallelic PIGB Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    PIGB (phosphatidylinositol glycan class B) encodes a 554-residue endoplasmic
    reticulum transmembrane protein with a small N-terminal cytoplasmic portion
    and a large C-terminal lumenal domain that carries the catalytic site. It is
    the GPI mannosyltransferase (GPI-MT-III) that transfers the third mannose
    onto the GPI precursor. Biallelic missense and truncating variants reduce or
    abolish PIGB function; ten different variants were found across the original
    ten families.
  genes:
  - preferred_term: PIGB
    term:
      id: hgnc:8959
      label: PIGB
  downstream:
  - target: Impaired GPI Anchor Biosynthesis
    causal_link_type: DIRECT
    description: >-
      Loss of PIGB removes the enzyme that adds the third mannose, an obligatory
      step in assembling the mature GPI precursor.
    evidence:
    - reference: PMID:8861954
      reference_title: "PIG-B, a membrane protein of the endoplasmic reticulum with a large lumenal domain, is involved in transferring the third mannose of the GPI anchor."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We cloned a human gene termed PIG-B (phosphatidylinositol glycan of complementation class B) that is involved in transferring the third mannose."
      explanation: >-
        Establishes the direct biochemical role of PIGB in GPI-anchor assembly
        whose loss impairs the pathway.
  evidence:
  - reference: PMID:8861954
    reference_title: "PIG-B, a membrane protein of the endoplasmic reticulum with a large lumenal domain, is involved in transferring the third mannose of the GPI anchor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PIG-B encodes a 554 amino acid, ER transmembrane protein with an amino-terminal portion of approximately 60 amino acids on the cytoplasmic side and a large carboxy-terminal portion of 470 amino acids within the ER lumen."
    explanation: >-
      Source for the protein architecture (length, cytoplasmic/lumenal topology)
      described in this node.
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten different PIGB variants were found in these individuals."
    explanation: >-
      Documents the allelic loss-of-function spectrum grounding the trigger.
- name: Impaired GPI Anchor Biosynthesis
  biological_scale: MOLECULAR
  description: >-
    The disease-relevant consequence of PIGB loss is failure of the
    third-mannose transfer step, which stalls maturation of the GPI precursor in
    the ER. The functional site of PIGB resides on the lumenal side of the ER
    membrane where the GPI precursor is assembled before being linked to nascent
    proteins.
  biological_processes:
  - preferred_term: GPI anchor biosynthetic process
    term:
      id: GO:0006506
      label: GPI anchor biosynthetic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: GPI mannosyltransferase activity
    term:
      id: GO:0004376
      label: GPI mannosyltransferase 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:31256876
      reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins."
      explanation: >-
        Directly links the PIGB biosynthesis defect to reduced surface
        GPI-anchored proteins, the next node.
  evidence:
  - reference: PMID:8861954
    reference_title: "PIG-B, a membrane protein of the endoplasmic reticulum with a large lumenal domain, is involved in transferring the third mannose of the GPI anchor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A mutant PIG-B lacking the cytoplasmic portion remains active, indicating that the functional site of PIG-B resides on the lumenal side of the ER membrane."
    explanation: >-
      Localizes PIGB catalytic activity to the ER lumen where GPI-precursor
      mannosylation occurs, grounding the biosynthetic step that is lost.
  - reference: PMID:8861954
    reference_title: "PIG-B, a membrane protein of the endoplasmic reticulum with a large lumenal domain, is involved in transferring the third mannose of the GPI anchor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The GPI anchor precursor is synthesized in the endoplasmic reticulum (ER) and post-translationally linked to protein."
    explanation: >-
      Establishes that GPI-precursor assembly precedes protein anchoring, the
      pathway PIGB loss interrupts.
- name: Reduced Cell-Surface GPI-Anchored Protein Expression
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Patient blood cells and fibroblasts show decreased surface presence of
    GPI-anchored proteins on flow cytometry, the cellular readout that assigns
    PIGB deficiency to the inherited GPI-deficiency disorders. Alkaline
    phosphatase is itself a GPI-anchored ectoenzyme; abnormal handling of
    GPI-anchored proteins is reflected in the elevated serum alkaline phosphatase
    that is characteristic of inherited GPI deficiency in most tested patients.
  cell_types:
  - preferred_term: Leukocyte (blood cell)
    term:
      id: CL:0000738
      label: leukocyte
  - preferred_term: Dermal fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  downstream:
  - target: Shedding of GPI-Anchored Alkaline Phosphatase into Serum
    causal_link_type: DIRECT
    description: >-
      Alkaline phosphatase is itself a GPI-anchored ectoenzyme. In PIGB
      deficiency an incomplete but mannose-bearing GPI accumulates that the GPI
      transamidase still engages, so alkaline phosphatase is cleaved from its
      C-terminal signal peptide and released rather than displayed at the cell
      surface.
    evidence:
    - reference: PMID:22228761
      reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "secreted substantially into medium from PIGV-, PIGB-, and PIGF-deficient CHO"
      explanation: >-
        In PIGB-deficient CHO cells the GPI-anchored protein (alkaline
        phosphatase) is secreted into the medium rather than surface-anchored,
        the shedding step wired by this edge.
  - target: Neuronal Dysfunction and Epileptic Encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      GPI-anchored proteins play key roles in development and neurogenesis, so
      their reduced surface display on developing neural membranes is the
      proposed route to the encephalopathy, by analogy to other inherited
      GPI-deficiency disorders. The intervening steps are not demonstrated in
      human neural tissue.
    evidence:
    - reference: PMID:31256876
      reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis."
      explanation: >-
        Classified INDIRECT: supports the developmental/neurogenic importance of
        GPI-anchored proteins that motivates the neuronal consequence, without
        demonstrating the intervening neuronal steps.
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins."
    explanation: >-
      Direct measurement of reduced surface GPI-anchored proteins in patient
      cells.
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome."
    explanation: >-
      Elevated alkaline phosphatase, a GPI-anchored ectoenzyme, is the
      biochemical correlate of the disturbed GPI-anchored protein handling.
- name: Shedding of GPI-Anchored Alkaline Phosphatase into Serum
  biological_scale: CELLULAR
  description: >-
    Tissue-nonspecific alkaline phosphatase (TNAP) is normally a GPI-anchored
    ectoenzyme displayed at the cell surface. In synthesis-stage GPI deficiency
    such as PIGB deficiency, an incomplete GPI precursor that still bears mannose
    accumulates; the GPI transamidase recognizes this mannose-bearing precursor
    and cleaves the C-terminal GPI-attachment signal peptide, releasing soluble
    ALP into the medium (and, in patients, the serum) instead of anchoring it at
    the membrane. This is the molecular mechanism of hyperphosphatasia in
    mannose-bearing GPI defects, and it contrasts with the mannose-lacking
    defects (e.g. PIGL), in which ALP is degraded rather than secreted and serum
    ALP is not elevated.
  downstream:
  - target: Elevated circulating alkaline phosphatase concentration
    causal_link_type: DIRECT
    description: >-
      Release of soluble alkaline phosphatase into the circulation raises serum
      alkaline phosphatase, the hyperphosphatasia seen in most tested patients.
    evidence:
    - reference: PMID:22228761
      reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "from secretion of ALP, a GPI-anchored protein normally expressed on the cell"
      explanation: >-
        Attributes the elevated (serum) alkaline phosphatase to secretion of the
        normally surface-anchored enzyme, the mechanism producing the elevated
        alkaline phosphatase phenotype.
  evidence:
  - reference: PMID:22228761
    reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "transamidase recognizes incomplete GPI bearing mannose and cleaves a hydrophobic"
    explanation: >-
      Establishes that in mannose-bearing GPI deficiency (which includes PIGB)
      the transamidase cleaves the signal peptide and secretes ALP, the shedding
      mechanism modeled by this node.
- name: Neuronal Dysfunction and Epileptic Encephalopathy
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The clinical endpoint is an early-infantile developmental and epileptic
    encephalopathy: global developmental and/or intellectual delay with
    early-onset seizures, frequently accompanied by peripheral neuropathy and, in
    some, polymicrogyria and hypomyelination. The course is severe, with a high
    early-childhood mortality (eight of the original children died before four
    years of age). This entry does not declare conformance to the
    epilepsy_excitation_inhibition_imbalance module: no excitation-inhibition
    measurement exists in PIGB deficiency and asserting that mechanism would
    substitute a plausible route for an evidenced one (see
    gap_gpi_to_seizure_route).
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Seizures
    causal_link_type: DIRECT
    description: >-
      The epileptic encephalopathy manifests as seizures, present in all reported
      affected individuals.
    evidence:
    - reference: PMID:31256876
      reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
      explanation: >-
        Reports that all affected individuals had seizures, the seizure
        manifestation of the encephalopathy.
  - target: Global developmental delay
    causal_link_type: DIRECT
    description: >-
      The encephalopathy manifests as global developmental and/or intellectual
      delay across the cohort.
    evidence:
    - reference: PMID:31256876
      reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
      explanation: >-
        Reports global developmental and/or intellectual delay, the
        developmental manifestation of the neuronal endpoint.
  - target: Polymicrogyria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Polymicrogyria, a malformation of cortical development reflecting the
      disturbed neural development in this endpoint, was present in two affected
      individuals; the developmental steps linking GPI deficiency to the
      malformation are not demonstrated.
    evidence:
    - reference: PMID:31256876
      reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
      explanation: >-
        Reports polymicrogyria in two affected individuals, the cortical
        malformation of the neural endpoint.
  - target: Peripheral neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Peripheral (axonal/mixed) neuropathy accompanies the neural endpoint in a
      substantial fraction of patients; the mechanism linking GPI deficiency to
      peripheral axonal degeneration is not demonstrated.
    evidence:
    - reference: PMID:31256876
      reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
      explanation: >-
        Reports peripheral neuropathy in four of the ten families, the
        peripheral-nerve manifestation of the neural endpoint.
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
    explanation: >-
      Characterizes the clinical endpoint syndrome across the patient series.
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder, an inherited glycosylphosphatidylinositol deficiency, is associated with a complex neurologic phenotype, including developmental delay, early-onset epilepsy and peripheral neuropathy."
    explanation: >-
      Independent characterization of the complex neurologic endpoint.
phenotypes:
- name: Epileptic encephalopathy
  category: Neurologic
  description: >-
    A developmental and epileptic encephalopathy is the defining feature; PIGB
    variants were first described as the cause of early infantile epileptic
    encephalopathy 80 (EIEE-80). Seizures are early in onset and combined with
    developmental impairment.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in phosphatidylinositol glycan anchor biosynthesis class B (PIGB) gene have been first described as the cause of early infantile epileptic encephalopathy 80 (EIEE-80) in 2019."
    explanation: >-
      Establishes DEE80/EIEE-80 as the defining epileptic encephalopathy of PIGB
      deficiency.
- name: Seizures
  category: Neurologic
  description: >-
    Seizures were present in all originally reported affected individuals, with
    onset in infancy.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
    explanation: >-
      States that all affected individuals had seizures, the basis for the
      VERY_FREQUENT band.
- name: Global developmental delay
  category: Neurologic
  description: >-
    Most affected children have global developmental and/or intellectual delay;
    severely affected individuals never attain speech.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
    explanation: >-
      Reports global developmental and/or intellectual delay across the series.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Intellectual disability is part of the global developmental and/or
    intellectual delay reported across the cohort and of the DOORS-overlapping
    severe phenotype.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
    explanation: >-
      Names intellectual delay among the near-universal features.
- name: Absent speech
  category: Neurologic
  description: >-
    Severely affected individuals have absent speech, part of the profound
    developmental impairment.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
    explanation: >-
      Documents absent speech in a reported patient.
- name: Status epilepticus
  category: Neurologic
  description: >-
    Febrile status epilepticus has been documented in the PIGB spectrum, even in
    a patient in whom seizures were otherwise not a major clinical issue.
  phenotype_term:
    preferred_term: Febrile status epilepticus
    term:
      id: HP:0032656
      label: Febrile status epilepticus
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
    explanation: >-
      Documents a febrile status epilepticus episode.
- name: Peripheral neuropathy
  category: Neurologic
  description: >-
    Peripheral neuropathy is a recurrent feature (four of the ten original
    families); the neuropathy has been characterized as axonal in the index
    series and as a mixed polyneuropathy in a later case.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
    explanation: >-
      Reports peripheral neuropathy in four of the ten families.
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
    explanation: >-
      Independent report of a mixed peripheral polyneuropathy.
- name: Polymicrogyria
  category: Neurologic
  description: >-
    Polymicrogyria, a malformation of cortical development, was present in two of
    the originally reported affected individuals.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
    explanation: >-
      Reports polymicrogyria in two affected individuals.
- name: CNS hypomyelination
  category: Neurologic
  description: >-
    Hypomyelination has been documented on brain MRI in the PIGB spectrum.
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypomyelination was documented on brain MRI."
    explanation: >-
      Reports hypomyelination on neuroimaging.
- name: Hypotonia
  category: Neurologic
  description: >-
    Hypotonia is part of the neurologic presentation.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
    explanation: >-
      Documents hypotonia in a reported patient.
- name: Scoliosis
  category: Musculoskeletal
  description: >-
    Early-onset scoliosis has been reported, consistent with the neuromuscular
    and skeletal involvement in the disorder.
  phenotype_term:
    preferred_term: Early-onset scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
    explanation: >-
      Documents early-onset scoliosis.
- name: Pes cavus
  category: Musculoskeletal
  description: >-
    A bilateral equino-varo-supinated-cavus foot deformity has been reported,
    consistent with the peripheral neuropathy.
  phenotype_term:
    preferred_term: Equino-varo-supinated-cavus foot
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
    explanation: >-
      Documents the cavus foot deformity.
- name: Elevated circulating alkaline phosphatase concentration
  category: Laboratory
  description: >-
    Elevated serum alkaline phosphatase (hyperphosphatasia) is seen in most
    tested patients and is characteristic of inherited GPI deficiency; alkaline
    phosphatase is itself a GPI-anchored ectoenzyme. It is a useful biochemical
    clue that also distinguishes the GPI-deficiency phenotype from DOORS
    syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase concentration
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome."
    explanation: >-
      States elevated alkaline phosphatase in most tested patients.
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus."
    explanation: >-
      Independent report of elevated serum alkaline phosphatase.
- name: Sensorineural hearing impairment
  category: Otologic
  description: >-
    Sensorineural deafness is part of the severe, DOORS-overlapping end of the
    PIGB spectrum.
  phenotype_term:
    preferred_term: Sensorineural deafness
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency"
    explanation: >-
      Documents sensorineural deafness in the DOORS-overlapping severe subset.
- name: Small nails
  category: Integumentary
  description: >-
    Small finger and toenails (with shortened terminal phalanges) are part of the
    DOORS-overlapping severe phenotype.
  phenotype_term:
    preferred_term: Small finger and toenails
    term:
      id: HP:0001792
      label: Small nail
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency"
    explanation: >-
      Documents small finger and toenails in the DOORS-overlapping severe subset.
- name: 2-oxoglutaric aciduria
  category: Laboratory
  description: >-
    A metabolic abnormality, 2-oxoglutaric aciduria, was found in two severely
    affected individuals and can also be seen in DOORS syndrome, suggesting
    shared molecular-pathway disruption at the severe end of the spectrum.
  phenotype_term:
    preferred_term: 2-oxoglutaric aciduria
    term:
      id: HP:0001992
      label: Organic aciduria
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions."
    explanation: >-
      Documents 2-oxoglutaric aciduria in two severely affected individuals.
genetic:
- name: PIGB
  gene_term:
    preferred_term: PIGB
    term:
      id: hgnc:8959
      label: PIGB
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    PIGB (phosphatidylinositol glycan class B; the GPI mannosyltransferase that
    transfers the third mannose) is the only gene implicated in DEE80/EIEE80
    (glycosylphosphatidylinositol biosynthesis defect 20). The variants are
    loss-of-function. The founding series reported ten different biallelic
    variants across ten unrelated families, spanning missense and truncating
    alleles; a later case added the biallelic p.Asp155His missense allele. A
    rough genotype-severity trend is described: the most severe cases (early
    death, peripheral neuropathy, and a metabolic 2-oxoglutaric aciduria
    overlapping DOORS syndrome) cluster at the loss-of-function end of the
    spectrum. PIGB is a synthesis-stage GPI-anchor-pathway gene; in the largest
    cross-gene inherited-GPI-deficiency cohort, synthesis-stage variants were
    associated with a significantly shorter time to seizure onset than
    transamidase- and remodelling-stage variants, consistent with the early
    infantile onset seen in PIGB deficiency. Biallelic PIGB variants also extend
    beyond the classic DEE80 phenotype: a recessively-inherited intronic PIGB
    variant causing exon skipping was identified in acrofrontofacionasal
    dysostosis type 1 (AFFND1), placing that dysostosis among the
    GPI-biosynthesis defects and broadening the PIGB phenotypic spectrum
    (Palagano et al., PMID:34400385).
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI."
    explanation: >-
      The gene-disease association statement establishing PIGB as causative.
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046)."
    explanation: >-
      PIGB is a synthesis-stage GPI-anchor-pathway gene (the third-mannose
      transferase); this cross-gene cohort associates synthesis-stage variants
      with earlier seizure onset. Classified INDIRECT because it is a
      stage-class rather than PIGB-specific comparison.
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten different PIGB variants were found in these individuals."
    explanation: >-
      Documents the allelic spectrum underlying the variant notes.
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing (WES) disclosed the likely pathogenic biallelic PIGB NM_004855.4: c.463G > C, p.(Asp155His) missense variant."
    explanation: >-
      Adds the p.Asp155His missense allele to the reported variant spectrum.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    DEE80 is ultra-rare. The founding report described ten unrelated families,
    and a later case report describes the disorder as ultra-rare; no population
    prevalence has been estimated. These are dated lower bounds rather than
    current totals.
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thus contributing to our knowledge on this ultra-rare disorder."
    explanation: >-
      Characterizes DEE80 as an ultra-rare disorder.
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI."
    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, with early-onset seizures and developmental
    impairment; PIGB variants define an early infantile epileptic encephalopathy.
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic variants in phosphatidylinositol glycan anchor biosynthesis class B (PIGB) gene have been first described as the cause of early infantile epileptic encephalopathy 80 (EIEE-80) in 2019."
    explanation: >-
      Establishes the early-infantile onset framing of the disorder.
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median age at seizure onset was 6 months."
    explanation: >-
      Cross-gene inherited-GPI-deficiency cohort (including synthesis-stage
      genes such as PIGB) placing median seizure onset in early infancy.
      Classified INDIRECT because the figure is pooled across GPI-AP genes.
- phase: Neurodegenerative course and neuroimaging
  notes: >-
    Inherited GPI-deficiency disorders (the cross-gene group that includes PIGB
    and other synthesis-stage genes) show a neurodegenerative process on serial
    neuroimaging, with a recognizable signature of cerebral and cerebellar
    atrophy, callosal anomalies and symmetric restricted diffusion of the
    central tegmental tracts. In PIGB patients specifically, polymicrogyria and
    hypomyelination are documented; the atrophy/central-tegmental-tract signature
    is reported at the cross-gene cohort level rather than isolated to PIGB.
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%)."
    explanation: >-
      Cross-gene IGD cohort (including synthesis-stage genes such as PIGB)
      defining the shared neuroimaging signature; INDIRECT because the
      frequencies are pooled across GPI-AP genes rather than PIGB-specific.
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process."
    explanation: >-
      Documents the neurodegenerative imaging course across the IGD cohort that
      includes PIGB; INDIRECT because pooled across GPI-AP genes.
- phase: Untreated course and mortality
  notes: >-
    The course is severe, with high early-childhood mortality: eight of the
    originally reported children died before four years of age.
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight children passed away before four years old."
    explanation: >-
      Documents the high early-childhood mortality of the severe phenotype.
experimental_models:
- name: PIGB-deficient CHO cell mutant
  experimental_model_type: CELL_LINE
  publication: PMID:22228761
  organism:
    preferred_term: Chinese hamster (CHO cell line)
    term:
      id: NCBITaxon:10029
      label: Cricetulus griseus
  cell_source: >-
    Chinese hamster ovary (CHO) cell mutants each defective in a single step of
    GPI biosynthesis, including a PIGB-deficient line, used as an isogenic panel
    to dissect the GPI lesion that produces alkaline-phosphatase secretion.
  description: >-
    The workhorse heterologous system for the ALP-shedding biochemistry of
    synthesis-stage GPI deficiency. Because CHO mutants can be made deficient in
    one GPI-pathway gene at a time, the panel isolates the effect of the PIGB
    (mannose-transfer) lesion from mannose-lacking lesions, which is not possible
    in patient material. It models the molecular mechanism of the
    hyperphosphatasia branch, not the neuronal phenotype.
  modeled_mechanisms:
  - target: Shedding of GPI-Anchored Alkaline Phosphatase into Serum
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The PIGB-deficient CHO line reproduces the defining event of this node:
      soluble ALP is secreted rather than surface-anchored, and the contrast with
      mannose-lacking mutants (which degrade ALP instead) shows the secretion is
      specific to the mannose-bearing lesion class that PIGB deficiency belongs to.
    limitations: >-
      A non-human (Chinese hamster) non-neuronal cell line that captures the
      cell-biological ALP-secretion mechanism only; it does not model the
      developmental and epileptic encephalopathy, and the PIGB mutant is an
      engineered null rather than a patient hypomorphic allele.
    readouts:
    - name: Soluble alkaline phosphatase released into culture medium
      target: Shedding of GPI-Anchored Alkaline Phosphatase into Serum
      direction: INCREASED
      interpretation: >-
        In vitro correlate of the patient hyperphosphatasia: the PIGB-deficient
        line sheds ALP into the medium instead of retaining it at the surface.
      evidence:
      - reference: PMID:22228761
        reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "The GPI-anchored protein was secreted substantially into medium from PIGV-, PIGB-, and PIGF-deficient CHO cells, in which incomplete GPI bearing mannose was accumulated."
        explanation: >-
          Reports the measured secretion of ALP into the medium from the
          PIGB-deficient CHO line, the readout that grounds this model's link to
          the shedding node.
    evidence:
    - reference: PMID:22228761
      reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In contrast, ALP was degraded in PIGL-, DPM2-, or PIGX-deficient CHO cells, in which incomplete shorter GPIs that lacked mannose were accumulated."
      explanation: >-
        The mannose-lacking CHO mutants degrade rather than secrete ALP, so the
        secretion seen in the PIGB-deficient line is specific to the
        mannose-bearing lesion class - establishing this model as informative for
        the PIGB shedding mechanism specifically.
  evidence:
  - reference: PMID:22228761
    reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we took advantage of CHO cell mutants that are defective in various steps of GPI biosynthesis"
    explanation: >-
      Establishes the single-gene-deficient CHO mutant panel (which includes the
      PIGB-deficient line) as the system used to dissect ALP secretion in GPI
      deficiency.
diagnosis:
- name: Whole exome sequencing
  description: >-
    Diagnosis rests on identifying biallelic PIGB variants by exome (or genome)
    sequencing.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing (WES) disclosed the likely pathogenic biallelic PIGB NM_004855.4: c.463G > C, p.(Asp155His) missense variant."
    explanation: >-
      Establishes exome sequencing as the diagnostic route.
- name: Flow cytometry for GPI-anchored proteins
  description: >-
    Reduced surface expression of GPI-anchored proteins on blood cells and
    fibroblasts is a functional signature shared with the inherited
    GPI-deficiency disorders and supports pathogenicity of a PIGB variant.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins."
    explanation: >-
      Establishes the GPI-anchored-protein flow cytometry assay as functional
      diagnostic support.
treatments:
- name: Antiseizure medication (symptomatic)
  description: >-
    Management is symptomatic. The epilepsy is treated with antiseizure
    medicines; no disease-modifying or PIGB-specific pharmacotherapy exists.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  target_mechanisms:
  - target: Neuronal Dysfunction and Epileptic Encephalopathy
    treatment_effect: MODULATES
    description: >-
      Antiseizure medicines suppress the seizure activity of the epileptic
      encephalopathy symptomatically; they do not address the upstream GPI-anchor
      defect, and no disease-modifying therapy exists.
    evidence:
    - reference: PMID:31256876
      reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
      explanation: >-
        Establishes the near-universal seizure burden of the epileptic
        encephalopathy that symptomatic antiseizure therapy targets.
  evidence:
  - reference: PMID:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy."
    explanation: >-
      Establishes the seizure burden that symptomatic antiseizure therapy
      targets.
- name: Pyridoxine or pyridoxal-5-phosphate (vitamin B6) trial
  description: >-
    High-dose oral pyridoxine or pyridoxal-5-phosphate (P5P, the active vitamin
    B6 cofactor) has been trialed as a candidate disease-specific treatment for
    the drug-resistant epilepsy of inherited GPI deficiency, on the rationale
    that GPI-anchored alkaline phosphatase (which dephosphorylates extracellular
    P5P) is dysregulated in GPI deficiency. In a prospective compassionate-use
    cohort a partial seizure-frequency reduction was seen in some participants
    but none reached seizure freedom; efficacy in PIGB deficiency specifically is
    not established (the cohort enrolled PIGA/PIGT/PIGV participants).
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridoxine
      term:
        id: CHEBI:16709
        label: pyridoxine
    - preferred_term: pyridoxal 5'-phosphate
      term:
        id: CHEBI:18405
        label: pyridoxal 5'-phosphate
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35080266
    reference_title: "Pyridoxine or pyridoxal-5-phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom."
    explanation: >-
      Prospective cohort of inherited GPI deficiency showing partial
      seizure-frequency reduction with pyridoxine/P5P and no seizure freedom.
      Classified INDIRECT for PIGB because the cohort enrolled PIGA/PIGT/PIGV
      participants, not PIGB; the benefit is extrapolated to PIGB deficiency by
      the shared GPI-deficiency mechanism.
- name: Supportive and multidisciplinary care
  description: >-
    Care is supportive and multidisciplinary, addressing the developmental
    delay, neuropathy, skeletal complications and feeding/respiratory
    vulnerability of a severe early-infantile encephalopathy.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:34161862
    reference_title: "Further delineation of PIGB-related early infantile epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This disorder, an inherited glycosylphosphatidylinositol deficiency, is associated with a complex neurologic phenotype, including developmental delay, early-onset epilepsy and peripheral neuropathy."
    explanation: >-
      Characterizes the complex multisystem phenotype that supportive,
      multidisciplinary care addresses.
- name: Genetic counseling
  description: >-
    Because DEE80 is autosomal recessive, genetic counseling of families
    (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:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI."
    explanation: >-
      Establishes the biallelic recessive genotype that makes recurrence-risk
      counseling relevant.
discussions:
- discussion_id: gap_gpi_to_seizure_route
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what route does reduced surface expression of GPI-anchored proteins
    produce neuronal dysfunction and seizures in the developing brain in PIGB
    deficiency?
  attaches_to:
  - "pathophysiology#Reduced Cell-Surface GPI-Anchored Protein Expression"
  - "pathophysiology#Neuronal Dysfunction and Epileptic Encephalopathy"
  rationale: >-
    The link from the measured cellular defect (reduced surface GPI-anchored
    proteins) to seizures is drawn from the known importance of GPI-anchored
    proteins in development and neurogenesis and by analogy to other inherited
    GPI-deficiency disorders. No excitation-inhibition or direct neuronal
    measurement exists in PIGB deficiency, so the entry deliberately does not
    conform to the epilepsy_excitation_inhibition_imbalance module. One specific,
    testable candidate route connects the hyperphosphatasia branch to the
    seizures: tissue-nonspecific alkaline phosphatase (TNAP) normally
    dephosphorylates extracellular pyridoxal-5'-phosphate (the active vitamin B6
    cofactor), and dysregulated TNAP handling in GPI deficiency could perturb
    B6-dependent neurotransmitter synthesis. This is the same B6 axis by which
    TNAP loss in hypophosphatasia causes vitamin-B6-responsive seizures, and it
    is the mechanistic rationale for the pyridoxine/pyridoxal-5-phosphate
    treatment trial in inherited GPI deficiency; it remains a candidate route,
    not a demonstrated one in PIGB deficiency.
  proposed_experiments:
  - experiment_id: exp_pigb_neuronal_excitability
    name: Excitation-inhibition and GPI-anchored protein measurement in PIGB-deficient neural models
    description: >-
      In PIGB-null human iPSC-derived neurons, measure surface GPI-anchored
      protein levels alongside network excitability (multi-electrode array or
      patch-clamp) 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:31256876
    reference_title: "Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis."
    explanation: >-
      The developmental/neurogenic importance of GPI-anchored proteins that
      stands in for a demonstrated neuronal route, which is what this gap flags.
  - reference: PMID:23860646
    reference_title: "Multisystemic functions of alkaline phosphatases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "abnormal metabolism of pyridoxal-5'-phosphate (the predominant form of vitamin B6)"
    explanation: >-
      Review establishing the TNAP -> pyridoxal-5'-phosphate axis: loss of TNAP
      activity (in hypophosphatasia) causes seizures through abnormal B6-cofactor
      metabolism. Cited INDIRECT because it grounds the candidate B6 route named
      in the rationale, not a route demonstrated in PIGB deficiency.
notes: >-
  Scope note on identity. MONDO:0032822 (developmental and epileptic
  encephalopathy, 80; EIEE80; glycosylphosphatidylinositol biosynthesis defect
  20, GPIBD20) is the PIGB-related autosomal recessive DEE. The severe end of the
  spectrum overlaps clinically with DOORS syndrome (deafness, onychodystrophy,
  osteodystrophy, intellectual disability, seizures), but DOORS is a distinct
  entity; the elevated alkaline phosphatase of inherited GPI deficiency helps
  distinguish PIGB deficiency from DOORS. PIGB deficiency differs from classic
  paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder caused by
  somatic mutation of the X-linked PIGA gene: DEE80 is a constitutional
  autosomal-recessive encephalopathy. The boundary is not absolute, however -
  one report describes a familial PNH in which a germline heterozygous PIGB
  variant was rendered homozygous by somatic copy-number-neutral loss of
  heterozygosity, producing a GPI-deficient PNH clone (Langemeijer et al.,
  PMID:33216889).

  Grouping membership. DEE80 is an inherited GPI-deficiency disorder and is an
  individual member of the Disorders_of_GPI_Anchor_Biosynthesis grouping
  (cf. Developmental_And_Epileptic_Encephalopathy_38, an ARV1-related member of
  the same grouping). This entry does not recreate that grouping.

  Deliberate non-conformances. This entry does not declare conformance to the
  epilepsy_excitation_inhibition_imbalance module (no excitation-inhibition
  measurement exists in PIGB deficiency; see gap_gpi_to_seizure_route) nor to the
  congenital_disorder_of_glycosylation module, which models N-linked
  glycoprotein hypoglycosylation rather than the GPI-anchor lesion central to
  DEE80.

  Provider note. A falcon (Edison) deep-research run was requested with
  --fallback; falcon returned a billing error (out of credits) and the run fell
  back to openscientist, which succeeded (report references validated 26/26).
  Curation is grounded in the primary literature (Murakami et al. 2019,
  PMID:31256876; Schiavoni et al. 2021, PMID:34161862), the founding PIGB
  biochemistry (Takahashi et al. 1996, PMID:8861954), and the largest cross-gene
  inherited-GPI-deficiency cohort for onset, genotype-stage and neuroimaging
  context (Sidpra et al. 2024, PMID:38456468, used with INDIRECT directness). No
  PIGB-specific GeneReviews chapter exists (PubMed searched).
references:
- reference: PMID:31256876
  title: Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.
- reference: PMID:34161862
  title: Further delineation of PIGB-related early infantile epileptic encephalopathy.
- reference: PMID:8861954
  title: "PIG-B, a membrane protein of the endoplasmic reticulum with a large lumenal domain, is involved in transferring the third mannose of the GPI anchor."
- reference: PMID:38456468
  title: The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.
- reference: PMID:22228761
  title: Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome.
- reference: PMID:35080266
  title: "Pyridoxine or pyridoxal-5-phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study."
- reference: PMID:23860646
  title: Multisystemic functions of alkaline phosphatases.
- reference: PMID:33216889
  title: Paroxysmal nocturnal hemoglobinuria caused by CN-LOH of constitutional PIGB mutation and 70-kbp microdeletion on 15q.
- reference: PMID:34400385
  title: A novel intronic variant in PIGB in Acrofrontofacionasal dysostosis type 1 patients expands the spectrum of phenotypes associated with GPI biosynthesis defects.
📚

References & Deep Research

References

9
PMID:31256876
Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.
No top-level findings curated for this source.
PMID:34161862
Further delineation of PIGB-related early infantile epileptic encephalopathy.
No top-level findings curated for this source.
PMID:8861954
PIG-B, a membrane protein of the endoplasmic reticulum with a large lumenal domain, is involved in transferring the third mannose of the GPI anchor.
No top-level findings curated for this source.
PMID:38456468
The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.
No top-level findings curated for this source.
PMID:22228761
Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome.
No top-level findings curated for this source.
PMID:35080266
Pyridoxine or pyridoxal-5-phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study.
No top-level findings curated for this source.
PMID:23860646
Multisystemic functions of alkaline phosphatases.
No top-level findings curated for this source.
PMID:33216889
Paroxysmal nocturnal hemoglobinuria caused by CN-LOH of constitutional PIGB mutation and 70-kbp microdeletion on 15q.
No top-level findings curated for this source.
PMID:34400385
A novel intronic variant in PIGB in Acrofrontofacionasal dysostosis type 1 patients expands the spectrum of phenotypes associated with GPI biosynthesis defects.
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 (2)

Record notes

Scope note on identity. MONDO:0032822 (developmental and epileptic encephalopathy, 80; EIEE80; glycosylphosphatidylinositol biosynthesis defect 20, GPIBD20) is the PIGB-related autosomal recessive DEE. The severe end of the spectrum overlaps clinically with DOORS syndrome (deafness, onychodystrophy, osteodystrophy, intellectual disability, seizures), but DOORS is a distinct entity; the elevated alkaline phosphatase of inherited GPI deficiency helps distinguish PIGB deficiency from DOORS. PIGB deficiency differs from classic paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder caused by somatic mutation of the X-linked PIGA gene: DEE80 is a constitutional autosomal-recessive encephalopathy. The boundary is not absolute, however - one report describes a familial PNH in which a germline heterozygous PIGB variant was rendered homozygous by somatic copy-number-neutral loss of heterozygosity, producing a GPI-deficient PNH clone (Langemeijer et al., PMID:33216889). Grouping membership. DEE80 is an inherited GPI-deficiency disorder and is an individual member of the Disorders_of_GPI_Anchor_Biosynthesis grouping (cf. Developmental_And_Epileptic_Encephalopathy_38, an ARV1-related member of the same grouping). This entry does not recreate that grouping. Deliberate non-conformances. This entry does not declare conformance to the epilepsy_excitation_inhibition_imbalance module (no excitation-inhibition measurement exists in PIGB deficiency; see gap_gpi_to_seizure_route) nor to the congenital_disorder_of_glycosylation module, which models N-linked glycoprotein hypoglycosylation rather than the GPI-anchor lesion central to DEE80. Provider note. A falcon (Edison) deep-research run was requested with --fallback; falcon returned a billing error (out of credits) and the run fell back to openscientist, which succeeded (report references validated 26/26). Curation is grounded in the primary literature (Murakami et al. 2019, PMID:31256876; Schiavoni et al. 2021, PMID:34161862), the founding PIGB biochemistry (Takahashi et al. 1996, PMID:8861954), and the largest cross-gene inherited-GPI-deficiency cohort for onset, genotype-stage and neuroimaging context (Sidpra et al. 2024, PMID:38456468, used with INDIRECT directness). No PIGB-specific GeneReviews chapter exists (PubMed searched).

Create: Developmental And Epileptic Encephalopathy 80 (PIGB) · 2026-09-04T02:46:18Z · View source

New AR PIGB-related GPI-anchor-deficiency DEE (GPIBD20). Deep-research: falcon (Edison) was requested with --fallback but returned HTTP 402 (account out of credits); openscientist produced the report (24 citations, provenance fell_back=true). Entry grounded in primary literature: Murakami et al. 2019 (PMID:31256876, index 10-family series), Schiavoni et al. 2021 (PMID:34161862, further delineation), and founding PIGB biochemistry Takahashi et al. 1996 (PMID:8861954). Pathograph built as a causal chain PIGB LOF -> impaired GPI-anchor biosynthesis -> reduced surface GPI-anchored proteins -> neuronal dysfunction/DEE; the final edge is directness INDIRECT with a KNOWLEDGE_GAP discussion (no human neural E/I data) and the entry deliberately does not conform to the epilepsy E/I or CDG modules. NEC preflight-dr WARN for rival gene 'GPI' is a false positive (GPI = the glycosylphosphatidylinositol anchor abbreviation, not the GPI gene); OMIM matched 618580. No PIGB-specific GeneReviews chapter (PubMed searched). Validated: just validate PASS; count-verified-snippets 44/44; check-entity-refs OK; check-causal-targets OK; validate-disorders PASS. Curated in worktree by Claude Code.

OpenScientist ▸
Developmental and Epileptic Encephalopathy 80 (DEE80 / PIGB-related GPI Deficiency): A Comprehensive Disease Report
openscientist-autonomous 24 citations 2026-09-04T02:42:05.755191

Developmental and Epileptic Encephalopathy 80 (DEE80 / PIGB-related GPI Deficiency): A Comprehensive Disease Report

Summary

Developmental and Epileptic Encephalopathy 80 (DEE80; OMIM #618580; also EIEE80, GPI biosynthesis defect 21) is an ultra-rare, autosomal-recessive inherited glycosylphosphatidylinositol (GPI) deficiency disorder (IGD) caused by biallelic loss-of-function variants in PIGB (phosphatidylinositol glycan anchor biosynthesis class B; HGNC:8959; chromosome 15q21.3). PIGB encodes the endoplasmic-reticulum mannosyltransferase that transfers the third mannose to the growing GPI core glycan. Because roughly 150 human cell-surface proteins are attached to the plasma membrane through a GPI anchor — many of them adhesion, guidance and signaling molecules essential for brain development — the loss of PIGB function reduces surface presentation of all of them simultaneously. The clinical consequence is a severe neurodevelopmental disorder combining early-onset, often intractable epilepsy, global developmental delay/intellectual disability, hypotonia, axonal peripheral neuropathy, variable brain malformations (polymicrogyria, hypomyelination) and, in most patients, elevated serum alkaline phosphatase (hyperphosphatasia), with high mortality in early childhood in severe cases.

The disease was first delineated by Murakami et al. in 2019, who described 10 unrelated families with biallelic PIGB mutations; all affected individuals had seizures, most had developmental/intellectual delay, and eight children died before four years of age. Subsequent case reports (e.g., Schiavoni 2021) and large cross-gene IGD cohorts (Bellai-Dussault 2019; Sidpra 2024) have broadened the phenotypic spectrum from lethal neonatal encephalopathy to milder presentations with survival into later childhood, and have defined a shared neuroimaging signature including cerebral/cerebellar atrophy and symmetric restricted diffusion of the central tegmental tracts.

This report synthesizes eight confirmed findings and 29 reviewed papers into a coherent mechanistic and clinical picture. The two most mechanistically satisfying insights are: (1) why serum alkaline phosphatase is elevated — PIGB deficiency accumulates an incomplete but mannose-bearing GPI that the transamidase still attaches to, resulting in secretion (shedding) rather than membrane anchoring of tissue-nonspecific alkaline phosphatase (TNAP); and (2) why vitamin B6 partially helps seizures — TNAP is the ectoenzyme that dephosphorylates circulating pyridoxal-5′-phosphate (PLP), so perturbed surface TNAP disturbs vitamin B6 handling, providing a biochemical rationale for supraphysiologic pyridoxine/PLP supplementation. There is no cure; management is supportive with mechanism-based, partially effective high-dose pyridoxine/pyridoxal-5′-phosphate for seizures.

1. Disease Information

Overview. DEE80 is a Mendelian, autosomal-recessive congenital disorder of glycosylation belonging to the inherited GPI deficiency (IGD) subgroup. It is a developmental and epileptic encephalopathy — meaning both the underlying developmental disturbance and the recurrent epileptic activity contribute to the encephalopathy — of prenatal/early-infantile onset.

Key identifiers:

Resource Identifier
OMIM (phenotype) #618580 (Developmental and epileptic encephalopathy 80)
Gene PIGB — OMIM *604122; HGNC:8959; NCBI Gene 9488; Ensembl ENSG00000069943; UniProt Q92521
Locus 15q21.3
Suggested MONDO Inherited GPI deficiency / DEE80 (MONDO term for EIEE80)
ICD-11 8A61 (Developmental and epileptic encephalopathies) — closest applicable code
Inheritance Autosomal recessive

Synonyms / alternative names: EIEE80 (Epileptic encephalopathy, early infantile, 80); Developmental and epileptic encephalopathy 80; PIGB-related GPI biosynthesis defect; GPI biosynthesis defect 21 (GPIBD21); PIGB-CDG. Note that a broader allelic spectrum exists: biallelic PIGB variants have also been linked to Acrofrontofacionasal dysostosis type 1 (AFFND1) (PMID: 34400385), and a distinct constitutional PIGB mechanism can predispose to paroxysmal nocturnal hemoglobinuria (PNH) via somatic copy-number-neutral loss of heterozygosity (PMID: 33216889).

Source of information. Disease-level aggregated resources (OMIM, Orphanet) combined with individual-patient primary literature (case series and cohort studies). The founding evidence is individual-patient data from ~16 affected individuals across 10 families (PMID: 31256876), augmented by cross-gene IGD cohorts of 202 (PMID: 30054924) and 83 individuals (PMID: 38456468).

2. Etiology

Primary cause — genetic (Finding F001). DEE80 is caused exclusively by biallelic (homozygous or compound heterozygous) pathogenic variants in PIGB. Murakami et al. (2019) described ten unrelated families each carrying different PIGB mutations (10 distinct variants), and demonstrated by flow cytometry that blood cells and fibroblasts had decreased cell-surface GPI-anchored proteins, confirming causality.

"We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI." — PMID: 31256876

"Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins." — PMID: 31256876

Genetic risk factors. The only established risk factor is inheritance of two damaging PIGB alleles. Consanguinity increases risk of homozygosity (several reported families are consanguineous). No common susceptibility loci or GWAS signals apply — this is a monogenic disorder.

Environmental / infectious factors. No environmental, toxic, infectious, or lifestyle cause contributes to disease onset. As with other IGDs, fever and intercurrent infection can worsen seizures and precipitate status epilepticus (documented in the related PIGW disorder, PMID: 38055078), but these are triggers of symptoms, not causes of disease.

Protective factors. None genetically defined. Supraphysiologic vitamin B6 (pyridoxine/pyridoxal-5′-phosphate) mitigates seizures in a subset (see Treatment).

Gene–environment interactions. Limited; the principal clinically relevant interaction is fever/infection as a seizure-provoking factor superimposed on the genetic lesion.

3. Phenotypes

DEE80 phenotypes span neurological, metabolic and multisystem domains. Frequencies below combine the founding PIGB cohort (PMID: 31256876), a milder single case (PMID: 34161862), and cross-gene IGD cohorts (PMID: 30054924; PMID: 38456468).

Phenotype Type Onset Frequency Suggested HPO
Seizures / epilepsy Clinical sign Early infantile (median ~6 mo in IGDs) ~100% (PIGB cohort); 83% (IGD cohort) HP:0001250 (Seizure); HP:0011097 (Epileptic spasms)
Global developmental delay / intellectual disability Clinical sign Congenital/infantile Most; 90% (IGD cohort) HP:0001263; HP:0001249
Hypotonia Clinical sign Infantile 72% (IGD cohort) HP:0001252
Motor symptoms Clinical sign Infantile 64% (IGD cohort) HP:0100022
Peripheral (axonal) neuropathy Clinical sign Childhood 4/~16 (PIGB) HP:0000762; HP:0003477
Polymicrogyria Physical/imaging Congenital 2/~16 (PIGB) HP:0002126
Hypomyelination Imaging Congenital/infantile Reported (milder case) HP:0006808
Elevated alkaline phosphatase (hyperphosphatasia) Laboratory Congenital Most HP:0003155
2-oxoglutaric aciduria Laboratory — 2 severe cases (PIGB) HP:0003355 (Organic aciduria)
Scoliosis Physical Childhood Reported (milder case) HP:0002650
Foot deformity (equino-varo-cavus) Physical Childhood Reported (milder case) HP:0001760
Dysmorphic features Physical Congenital 82% (IGD cohort), variable HP:0001999
Early mortality Outcome <4 years 8 children (PIGB); 15/83 (IGD) —

Phenotype characteristics (Finding F002). In the founding cohort, "most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old" (PMID: 31256876). Two severely affected individuals showed 2-oxoglutaric aciduria, indicating a metabolic derangement in the most severe end of the spectrum. Two individuals carried a clinical diagnosis of DOORS syndrome (Deafness, Onycho-Osteodystrophy, mental Retardation, Seizures) before the molecular cause was known.

Severity is variable. Schiavoni et al. (2021) reported the milder end: "severe global developmental delay with absent speech, mixed peripheral polyneuropathy, hypotonia, bilateral equino-varo-supinated-cavus foot, early-onset scoliosis, elevated serum alkaline phosphatase and a single episode of febrile status epilepticus. Hypomyelination was documented on brain MRI" (PMID: 34161862). Progression is generally static-to-progressive; Murakami & Kinoshita note the disease "progresses even after birth" (PMID: 26165085).

Quality-of-life impact. Profound. Affected children typically have absent or minimal speech, are non-ambulatory or motor-impaired, require anticonvulsant therapy, and depend on full caregiving. No disease-specific EQ-5D/SF-36 data exist given rarity.

4. Genetic / Molecular Information

Causal gene. PIGB — phosphatidylinositol glycan anchor biosynthesis, class B (HGNC:8959; NCBI Gene 9488; OMIM 604122; UniProt Q92521; 15q21.3). PIGB is a GT-C superfamily mannosyltransferase* (GPI mannosyltransferase III / GPI-MT-III) that transfers the third mannose (Man3) onto the GPI intermediate in the ER membrane (PMID: 31256876; topology reviewed in PMID: 31569500). It shares a conserved membrane-embedded "BindGPILA" domain with PIG-M, PIG-V, PIG-Z, PIG-U and PIG-W (PMID: 29764287).

Pathogenic variants. At least 10 distinct biallelic variants were reported in the founding families, including missense and predicted loss-of-function alleles; an intronic splice variant causing exon skipping (a null allele) was found in AFFND1 families (PMID: 34400385). Variant classification follows ACMG/AMP; most are classified pathogenic/likely pathogenic in ClinVar. Functional consequence is loss of function — reduced or absent third-mannose transfer, leading to reduced GPI-anchored protein surface expression (PMID: 31256876). Transfection rescue assays confirm variant PIGB fails to restore GPI-anchored protein surface expression in PIGB-deficient CHO cells (PMID: 33216889).

Allele frequency. Pathogenic alleles are individually ultra-rare in gnomAD (consistent with a recessive, severe disorder). Origin: germline (constitutional). Notably, a constitutional heterozygous PIGB variant rendered homozygous by somatic copy-number-neutral loss of heterozygosity can produce a PNH clone (PMID: 33216889) — a distinct, non-DEE80 phenomenon.

Modifier genes / epigenetics. No specific modifier genes or epigenetic mechanisms are established for DEE80. Phenotypic variability (lethal vs milder) likely reflects residual PIGB enzymatic activity (hypomorphic vs null alleles), analogous to other IGDs.

Chromosomal abnormalities. Not a feature of DEE80 itself; the associated 70-kbp 15q microdeletion in the PNH report involves TM2D3/TARSL2, unrelated to the encephalopathy (PMID: 33216889).

Subcellular localization note. PIGB is normally an ER/nuclear-envelope membrane enzyme; work in fungal systems shows nuclear-envelope localization can be essential for its activity (PMID: 30266758; PMID: 32051283).

5. Environmental Information

DEE80 is a purely genetic disorder. No environmental toxins, radiation, pollution, occupational exposures, lifestyle factors, or infectious agents cause it. The only clinically relevant environmental modifiers are fever and infection, which can lower seizure threshold and precipitate status epilepticus. Dietary vitamin B6 status is relevant only as a therapeutic lever (see Treatment).

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function PIGB variants → loss of GPI mannosyltransferase-III activity in the ER (fails to add the third mannose to the GPI glycan core). (Demonstrated — enzyme function and rescue assays.)
  2. Loss of Man3 addition → accumulation of an incomplete, mannose-bearing GPI intermediate and globally reduced surface presentation of GPI-anchored proteins (GPI-APs) on all cell types (shown by flow cytometry). (Demonstrated.) 3a. Branch A (neurodevelopment): Reduced surface GPI-APs → loss of GPI-anchored adhesion/guidance/signaling molecules (glypicans, contactins, RGMa, and ~150 others) → impaired cortical progenitor proliferation, neuronal migration, axon guidance and myelination → polymicrogyria, hypomyelination, axonal neuropathy, developmental delay. (Mechanistically inferred from the established roles of individual GPI-APs.) 3b. Branch B (network excitability): Developmental disorganization + altered GPI-anchored receptor signaling → cortical hyperexcitability → early-onset, often intractable seizures → epileptic encephalopathy compounding the developmental deficit. (Inferred.) 3c. Branch C (alkaline phosphatase / vitamin B6): Because the accumulated GPI still bears mannose, the transamidase attaches TNAP to it, but the incomplete anchor causes TNAP to be secreted/shed rather than membrane-retained → serum hyperphosphatasia and reduced surface TNAP → perturbed dephosphorylation of pyridoxal-5′-phosphate (PLP) → disturbed vitamin B6 homeostasis contributing to seizures. (Branch C "secretion" step demonstrated in CHO cells; the PLP-handling link is biochemically inferred.)
  3. Net result: developmental and epileptic encephalopathy with multisystem involvement and high early mortality.

Molecular detail

Loss of GPI-anchored guidance/adhesion proteins drives cortical maldevelopment (Finding F005). Many GPI-APs are master regulators of corticogenesis. Glypicans: GPC4 (expressed in cortical progenitors) "promotes their proliferation and the generation of intermediate progenitors, whereas neuronal GPC2 acts as a brake on radial neuronal migration" (PMID: 42275470); the GPI-anchored morphogen receptor GPC3 forms a complex with Unc5 to "guide migrating pyramidal neurons in the mouse cortex" (PMID: 36240740). Contactins (CNTN2/TAG-1, CNTN4) mark and modulate migrating neurons and neurite elongation (PMID: 40580015; PMID: 38745463; PMID: 30629639), and RGMa is a GPI-anchored guidance molecule regulating neuronal differentiation and survival (PMID: 36089003). Because PIGB loss reduces surface presentation of all GPI-APs simultaneously (PMID: 31256876), these pathways are impaired in parallel — explaining polymicrogyria, migration defects, hypomyelination and neuropathy.

Hyperphosphatasia mechanism (Finding F006). Murakami et al. (2012) directly demonstrated the molecular basis in CHO mutants: "The GPI-anchored protein was secreted substantially into medium from PIGV-, PIGB-, and PIGF-deficient CHO cells, in which incomplete GPI bearing mannose was accumulated. In contrast, ALP was degraded in PIGL-, DPM2-, or PIGX-deficient CHO cells, in which incomplete shorter GPIs that lacked mannose were accumulated" (PMID: 22228761). Thus PIGB deficiency accumulates a mannose-bearing (but incomplete) GPI that the transamidase still uses, releasing TNAP into serum — the direct molecular cause of hyperphosphatasia in DEE80.

Vitamin B6 rationale (Finding F007). TNAP is itself a GPI-anchored ectoenzyme that dephosphorylates pyridoxal-5′-phosphate (PLP) — the predominant circulating form of vitamin B6 — to pyridoxal, which alone can cross the neuronal membrane to be re-phosphorylated intracellularly. Buchet, Millán & Magne (2013): TNAP deficiency (hypophosphatasia) "leads to ... epileptic seizures in the most severe cases, caused by abnormal metabolism of pyridoxal-5'-phosphate (the predominant form of vitamin B6)" (PMID: 23860646); TNAP's broad substrate range including PLP is confirmed by Imam et al. (2024) (PMID: 39728440). In GPI deficiencies the surface TNAP pool is reduced/shed, perturbing B6 handling — providing the biochemical rationale for supraphysiologic pyridoxine/PLP supplementation, which partially reduces seizures (PMID: 35080266).

Upstream vs downstream, cell types, GO/CL terms

  • Upstream (initiating): ER GPI biosynthesis defect (GO:0006506 GPI anchor biosynthetic process; GO:0000030 mannosyltransferase activity). Compartment: endoplasmic reticulum (GO:0005783); nuclear envelope (GO:0005635).
  • Downstream (effector): neuronal migration (GO:0001764), axon guidance (GO:0007411), central nervous system myelination (GO:0022010), regulation of neuron differentiation (GO:0045664); dephosphorylation of PLP (GO:0016791 phosphatase activity).
  • Cell types (CL): neural progenitor/radial glia (CL:0000031 neuroblast; CL:0000681 radial glial cell), pyramidal neuron (CL:0000598), oligodendrocyte (CL:0000128), peripheral neuron/Schwann-associated axons (CL:0002573).

7. Anatomical Structures Affected

Organ / system level. Primary organ: brain (central nervous system) — cerebral cortex, white matter, cerebellum, brainstem. Secondary: peripheral nervous system (axonal neuropathy). Multisystem involvement is common in IGDs — Sidpra et al. found systemic involvement in 61/83, with gastrointestinal 66%, cardiac 19%, renal 14% (PMID: 38456468). Musculoskeletal features (scoliosis, foot deformity) reflect neuromuscular and connective-tissue involvement.

Neuroimaging signature (Finding F008). In the largest IGD cohort, prognostically significant features were "cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%)" (PMID: 38456468). Polymicrogyria and hypomyelination are specifically documented in PIGB patients.

Tissue / cell level. Nervous tissue predominantly: cortical neurons, radial glia/progenitors, oligodendrocytes (hypomyelination), peripheral axons. Subcellular: the initiating defect is in the endoplasmic reticulum (GPI assembly) and plasma membrane (GPI-AP presentation).

UBERON terms: UBERON:0000955 (brain); UBERON:0000956 (cerebral cortex); UBERON:0002037 (cerebellum); UBERON:0002316 (white matter); UBERON:0002298 (brainstem tegmentum, central tegmental tract region); UBERON:0000044 (peripheral nerve / dorsal root ganglion). Lateralization: bilateral/symmetric (e.g., symmetric central tegmental tract diffusion restriction; bilateral foot deformity).

8. Temporal Development

Onset. Congenital to early-infantile. In IGDs the median age at seizure onset is 6 months (PMID: 38456468); developmental delay is apparent from infancy. Onset pattern is chronic/insidious for developmental features and can be acute for seizures.

Progression. The disorder is progressive after birth — "the disease progresses even after birth" (PMID: 26165085) — arguing for early diagnosis and treatment. Course ranges from rapidly fatal (8 children dead before age 4 in the founding cohort; 15/83 deceased in the IGD cohort) to a more static but severely disabled trajectory in milder cases.

Patterns. Seizures are often intractable; no spontaneous remission is described. Critical periods: the prenatal/early-infantile window of corticogenesis and myelination is when the irreversible structural damage occurs, and the early-infantile period is the therapeutic window for seizure control (pyridoxine). Fever/infection are episodic aggravators.

9. Inheritance and Population

Epidemiology. Ultra-rare; exact prevalence/incidence are not established. Fewer than ~20 PIGB-specific patients are reported in the literature; DEE80 sits within the broader IGD group (>200 individuals reported across all GPI-pathway genes). No population-level prevalence figure exists.

Inheritance. Autosomal recessive. Requires two pathogenic PIGB alleles. Penetrance appears complete for biallelic loss-of-function. Expressivity is variable (lethal neonatal to milder childhood phenotypes), likely reflecting residual enzyme activity. Genetic anticipation: not applicable (no repeat expansion). Germline mosaicism: not specifically reported. Consanguinity contributes (homozygous cases in consanguineous families). Carrier frequency: not established; individually rare alleles.

Population demographics. Reported families are geographically and ethnically diverse (no established founder population for PIGB). Sex ratio: autosomal — no sex bias expected. Age distribution: affected individuals are infants and young children; survival beyond childhood occurs in milder cases.

10. Diagnostics

Biochemical clues (Finding F003). Elevated serum alkaline phosphatase (hyperphosphatasia) is a hallmark and a strong pointer to IGD: "The presence of hyperphosphatasia is strong evidence of IGD. Flow cytometric analysis of GPI-APs on granulocytes is also useful for the detection of IGD" (PMID: 25803904). Clinical-clue combinations — "Certain combinations, such as seizures with aplastic/hypoplastic nails or abnormal alkaline phosphatase levels suggest an inherited GPI deficiency" (PMID: 30054924). Note: not all IGDs show hyperphosphatasia; some show normal/low ALP depending on where the biosynthetic block lies.

Flow cytometry. Reduced surface GPI-anchored proteins (e.g., CD16, CD24, FLAER, CD59) on granulocytes/blood cells is a functional confirmatory assay (PMID: 31256876; PMID: 25803904).

Genetic testing (definitive). Diagnosis is confirmed by whole-exome (WES) or whole-genome (WGS) sequencing identifying biallelic PIGB variants; WGS/RNA analysis is valuable for detecting deep-intronic/splice variants (e.g., the exon-skipping intronic allele in AFFND1, PMID: 34400385). Targeted gene panels for epileptic encephalopathy / congenital disorders of glycosylation that include the PIG genes are appropriate first-line. Segregation studies confirm biallelic inheritance.

Imaging. Brain MRI may show polymicrogyria, hypomyelination, cerebral/cerebellar atrophy, callosal anomalies, and symmetric restricted diffusion of the central tegmental tracts (PMID: 38456468).

Electrophysiology. EEG documents epileptiform activity; nerve conduction studies confirm axonal peripheral neuropathy.

Metabolic. Urine organic acids may reveal 2-oxoglutaric aciduria in severe cases (PMID: 31256876).

Differential diagnosis. Other IGDs (PIGA, PIGV, PIGN, PIGO, PIGT, PIGS, PIGW, PIGG, etc.), DOORS syndrome, hyperphosphatasia-mental retardation syndrome (Mabry syndrome, PIGV/PIGO), pyridoxine-dependent epilepsy (ALDH7A1), and other early-infantile epileptic encephalopathies. Two DEE80 patients were initially diagnosed clinically as DOORS syndrome.

11. Outcome / Prognosis

Survival / mortality. Guarded, particularly in severe forms: eight of ~16 affected children in the founding cohort died before age four (PMID: 31256876); 15 of 83 individuals in the broad IGD cohort were deceased at reporting (PMID: 38456468). Milder patients survive into later childhood.

Morbidity / function. Severe lifelong disability — intellectual disability, absent/minimal speech, motor impairment, epilepsy, neuropathy, orthopedic complications (scoliosis, foot deformity). Full caregiver dependence is typical.

Prognostic factors. Severity of the underlying allele (null vs hypomorphic), presence of cortical malformation, seizure intractability, and neuroimaging burden (cerebral/cerebellar atrophy and central tegmental tract diffusion restriction are described as prognostically significant, PMID: 38456468). 2-oxoglutaric aciduria marks the most severe metabolic end.

12. Treatment

There is no cure; management is symptomatic and supportive, with one mechanism-based pharmacologic lever.

Vitamin B6 (pyridoxine / pyridoxal-5′-phosphate) — mechanism-based, partial (Finding F004). In a cohort of 7 GPI-deficiency patients treated with high-dose pyridoxine (20–30 mg/kg/day) or pyridoxal-5′-phosphate: "We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom" (PMID: 35080266); no significant EEG change was seen in 6/7. Murakami & Kinoshita emphasize early treatment: "Early diagnosis and treatment are desirable because the disease progresses even after birth and vitamin B6(pyridoxine) is very effective for some patients with intractable seizures" (PMID: 26165085). The biochemical rationale is the TNAP–PLP link (Findings F006, F007). NCIT: Pyridoxine (C793); Pyridoxal Phosphate (C88250).

Antiseizure medications. Standard antiepileptic drugs are used for seizure control, though seizures are frequently intractable. Choice is empirical/supportive; no genotype-specific ASM is validated.

Supportive / rehabilitative care. Physical, occupational and speech therapy; nutritional support; orthopedic management of scoliosis/foot deformity; management of intercurrent infections that provoke seizures; multidisciplinary developmental support. NCIT: Supportive Care (C15277); Physical Therapy (C15359).

Advanced / experimental therapeutics. No approved gene, cell, or RNA therapy exists for DEE80. Gene replacement is a conceptually attractive future avenue (recessive loss-of-function of a single enzyme), but none is in clinical trials for PIGB. Pharmacogenomics: not established.

13. Prevention

Primary prevention. Not possible for a spontaneously arising recessive disorder except through reproductive genetic counseling. Genetic counseling for at-risk families (25% recurrence risk for carrier couples) is central. Carrier screening and, where an affected proband's variants are known, prenatal diagnosis or preimplantation genetic testing (PGT-M) can prevent recurrence.

Secondary prevention. Early molecular diagnosis (rapid WES/WGS in neonates with epileptic encephalopathy plus hyperphosphatasia) enables early initiation of pyridoxine and multidisciplinary support during the progressive early period. There is no population newborn-screening test for PIGB deficiency, though hyperphosphatasia on routine chemistry can be an incidental flag.

Tertiary prevention. Prevention of complications — aspiration, infection-triggered status epilepticus, orthopedic deterioration — through proactive management.

14. Other Species / Natural Disease

PIGB is evolutionarily conserved; orthologs and GPI-pathway homologs exist across eukaryotes (mammals, fungi, protozoa). Functional studies of PIG-B localization/activity have been performed in fungal systems (PMID: 30266758; PMID: 32051283), and the shared BindGPILA membrane domain is conserved across PIG-B/M/V/W/U/Z (PMID: 29764287). Orthologs: mouse Pigb (NCBI Gene 55981). No naturally occurring PIGB-deficiency disease in companion animals or wildlife is catalogued (no OMIA entry identified). GPI biosynthesis is essential and broadly conserved, so complete loss is generally embryonic-lethal in model organisms. No zoonotic relevance.

15. Model Organisms

Cellular models (principal experimental system). PIGB-deficient Chinese hamster ovary (CHO) cells are the workhorse for GPI biology and were pivotal in establishing DEE80 mechanism: they show loss of surface GPI-anchored proteins and the diagnostic secretion of ALP (PMID: 22228761); transfection rescue confirms variant pathogenicity (PMID: 33216889). PIGB-knockout human cell lines were used to show altered EthN-P bridge usage on GPI anchors (PMID: 35603428). Patient fibroblasts and blood cells serve as primary-cell models for flow-cytometric GPI-AP quantitation (PMID: 31256876).

Genetic model types. Knockout/knock-down cell lines are the primary genetic models. A dedicated mouse model of PIGB deficiency recapitulating DEE80 is not prominently reported (complete GPI-pathway knockouts are typically embryonic lethal; conditional/hypomorphic strategies would be required). MGI lists Pigb (mouse), enabling future targeted or conditional models.

Phenotype recapitulation & limitations. Cellular models faithfully reproduce the biochemical phenotype (reduced surface GPI-APs; ALP shedding) and are excellent for variant functional testing, but cannot recapitulate the neurodevelopmental phenotype (cortical migration, epilepsy, neuropathy). Patient-derived iPSC neurons/organoids would be the logical next step to model corticogenesis defects.

Mechanistic Model / Interpretation

   PIGB biallelic loss-of-function (15q21.3)
 │  (loss of GPI mannosyltransferase-III; no 3rd mannose)
 ▼
   Incomplete, mannose-bearing GPI accumulates in ER
 │
   ┌─────────────┼───────────────────────────────┐
   ▼             ▼                                 ▼
 Global loss   Transamidase still attaches      Reduced surface
 of surface    TNAP to incomplete anchor        TNAP pool
 GPI-APs       → TNAP SECRETED (shed)                │
   │                │                                 ▼
   ▼                ▼                     Impaired PLP (vit B6)
 Loss of        Serum hyperphosphatasia   dephosphorylation
 glypicans,     (diagnostic clue)              │
 contactins,                                    ▼
 RGMa, etc.                          Contributes to seizures →
   │                                 partial response to pyridoxine/PLP
   ▼
 Impaired cortical progenitor proliferation,
 neuronal migration, axon guidance, myelination
   │
   ├──► Polymicrogyria, hypomyelination, cerebral/cerebellar atrophy
   ├──► Axonal peripheral neuropathy
   └──► Cortical hyperexcitability ──► early-onset intractable epilepsy
                 │
                 ▼
DEVELOPMENTAL & EPILEPTIC ENCEPHALOPATHY 80
(DD/ID, seizures, hypotonia, high early mortality)

The unifying concept is that one enzymatic lesion removes an entire class of ~150 cell-surface proteins, producing a pleiotropic, multi-branch phenotype. Two branches are biochemically demonstrated (GPI-AP loss by flow cytometry; TNAP shedding in CHO cells); the neurodevelopmental branch is inferred from the well-established individual functions of GPI-anchored guidance/adhesion molecules; and the vitamin-B6 branch is a biochemically grounded therapeutic hypothesis supported by partial clinical efficacy.

Evidence Base

PMID Title (abbrev.) Evidence type Role
31256876 Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect... Human clinical + in vitro Founding paper; defines gene, phenotype, mortality, flow-cytometry defect (F001, F002)
34161862 Further delineation of PIGB-related early infantile EE Human case Milder-end phenotype (F002)
22228761 Mechanism for release of alkaline phosphatase in GPI deficiency In vitro (CHO) Explains hyperphosphatasia (F006)
23860646 Multisystemic functions of alkaline phosphatases Review TNAP–PLP–seizure link (F007)
39728440 Structural/functional integration of TNAP Review Confirms TNAP dephosphorylates PLP (F007)
35080266 Pyridoxine or PLP for seizures in GPI deficiency Human cohort (n=7) Partial efficacy of B6 (F004)
26165085 [Inherited GPI deficiency...] Review B6 effective in some; progressive disease (F004)
25803904 [Inherited GPI deficiencies...] Review Hyperphosphatasia + flow cytometry diagnostics (F003)
30054924 Clinical variability in IGDs Human cohort (n=202) Diagnostic clues (F003)
38456468 Clinical and genetic spectrum of IGDs Human cohort (n=83) Natural history, imaging signature (F008)
42275470 Glypican core proteins in corticogenesis Model/in vitro GPC4/GPC2 in migration (F005)
36240740 GPC3-Unc5 receptor complex in migration Model/structural GPC3 guides cortical neurons (F005)
40580015, 38745463, 30629639 Contactins CNTN2/CNTN4/CNTN1 Model Migrating-neuron / neurite roles (F005)
36089003 RGMa... Model GPI-anchored guidance/survival molecule (F005)
34400385 Intronic PIGB variant in AFFND1 Human + in vitro Allelic spectrum; null via exon skipping
33216889 PNH from CN-LOH of constitutional PIGB Human + in vitro Rescue assay; distinct PNH mechanism
29764287, 31569500, 30266758, 32051283 PIG-B structure/topology/localization Computational/model Enzyme biology context
35603428 EthN-P on second mannose... In vitro PIGB-KO GPI biology
30269814, 32198969, 38055078 PIGS/PIGW IGDs Human Related IGDs; differential diagnosis, B6-responsive seizures

Limitations and Knowledge Gaps

  1. Small n. Fewer than ~20 molecularly confirmed PIGB/DEE80 patients are reported; frequency estimates and genotype–phenotype correlations are provisional. Many cohort-level statistics (imaging, seizure onset, mortality) derive from cross-gene IGD cohorts, not PIGB-specific data — an extrapolation caveat.
  2. Neurodevelopmental branch is inferred. The link from GPI-AP loss to cortical malformation and epilepsy rests on the established biology of individual GPI-APs (glypicans, contactins, RGMa) rather than direct demonstration in PIGB-deficient neurons.
  3. No faithful whole-animal or iPSC-neuronal model of DEE80 is established; the neurodevelopmental phenotype has not been experimentally reconstituted.
  4. Vitamin B6 mechanism is partly hypothetical. The TNAP–PLP rationale is biochemically sound, but efficacy is partial and no participant achieved seizure freedom; the precise contribution of disturbed B6 metabolism to PIGB-related seizures is not fully proven.
  5. No prevalence/incidence, QoL, or long-term natural-history data specific to DEE80.
  6. Epigenetic, metabolomic, and multi-omic profiling of DEE80 tissues is essentially absent (2-oxoglutaric aciduria in severe cases is unexplained mechanistically).

Proposed Follow-up Experiments / Actions

  1. Patient-derived iPSC cortical organoids / neurons carrying PIGB variants to directly test whether reduced surface glypicans/contactins/RGMa cause migration and myelination defects — closing the inference gap in the neurodevelopmental branch.
  2. PIGB conditional/hypomorphic mouse model (neural-specific) to recapitulate cortical malformation, epilepsy and neuropathy, and to test pyridoxine/PLP and GPI-pathway-directed therapies in vivo.
  3. Quantitative PLP/pyridoxal metabolomics (serum and, where possible, CSF) in PIGB patients before/after high-dose B6, correlated with surface TNAP activity, to test the F007 mechanism directly and identify B6 responders.
  4. Genotype–phenotype registry aggregating all PIGB cases with standardized phenotyping, MRI (including central tegmental tract diffusion), ALP levels, and residual enzyme activity to build predictive prognostic models.
  5. Systematic ClinVar/gnomAD curation of PIGB variants with functional (CHO rescue / flow-cytometry) classification to improve ACMG interpretation and diagnostic yield.
  6. Explore GPI-pathway or substrate-supplementation therapeutics (e.g., strategies used in other CDGs) as candidate disease-modifying approaches, given the recessive single-enzyme etiology.

Report compiled from 8 confirmed findings and 29 reviewed papers across 5 investigation iterations. Evidence types are labeled human clinical, model organism, in vitro, computational, or review throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 26
Resolved 26
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 15
Quoted claims found in source 15
Quoted claims not found in source 0
References weighed for topical relevance 26
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 36
Resolved 35
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 12
Terms named correctly 4
Terms named as a different term 6
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0001252 (1 mention) - the report calls it "72% (IGD cohort)"; HP calls it Hypotonia
  • HP:0100022 (1 mention) - the report calls it "64% (IGD cohort)"; HP calls it Abnormality of movement
  • HP:0002126 (1 mention) - the report calls it "2/~16 (PIGB)"; HP calls it Polymicrogyria
  • HP:0003155 (1 mention) - the report calls it "Most"; HP calls it Elevated circulating alkaline phosphatase concentration
  • HP:0001999 (1 mention) - the report calls it "82% (IGD cohort), variable"; HP calls it Abnormal facial shape
  • UBERON:0002298 (1 mention) - the report calls it "brainstem tegmentum, central tegmental tract region"; UBERON calls it brainstem

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0003355 (1 mention) - the report calls it "Organic aciduria"; HP calls it Aminoaciduria
  • UBERON:0000044 (1 mention) - the report calls it "peripheral nerve / dorsal root ganglion"; UBERON calls it dorsal root ganglion