Developmental and epileptic encephalopathy 55 (DEE55) is an autosomal recessive inherited GPI deficiency caused by biallelic variants in PIGP. PIGP encodes a subunit of the GPI-GlcNAc transferase complex, the enzyme that catalyses the first step of glycosylphosphatidylinositol (GPI) anchor biosynthesis in the endoplasmic reticulum. More than 150 human proteins reach the cell surface tethered by a GPI anchor, many of them with roles in neurogenesis and synaptic function, so a partial block at the first committed step reduces the surface density of that whole protein class rather than removing a single gene product. The clinical result is early-onset refractory epilepsy — infantile spasms, focal, tonic and tonic-clonic seizures, often with a burst-suppression EEG — together with severe hypotonia and profound global developmental delay. Dyskinetic movement progressing to quadriplegia was prominent in the largest reported family, and premature death in childhood has been reported. The phenotype has since been extended to a presentation of multiple congenital anomalies with hypotonia and seizures, matching what is seen for other genes in the same first-step complex. Reduced surface expression of a GPI-anchored protein — CD16 on granulocytes — is measurable by flow cytometry and supports the diagnosis. The disorder is ultra-rare: fewer than a dozen patients have been published since the gene was first linked to human disease in 2017.
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name: Developmental and Epileptic Encephalopathy 55
creation_date: "2026-08-31T21:45:00Z"
category: Mendelian
synonyms:
- DEE55
- early infantile epileptic encephalopathy 55
- EIEE55
- PIGP deficiency
- PIGP-related inherited GPI deficiency
disease_term:
preferred_term: developmental and epileptic encephalopathy, 55
term:
id: MONDO:0033364
label: developmental and epileptic encephalopathy, 55
parents:
- Congenital Disorder of Glycosylation
- Inborn Error of Metabolism
- Epilepsy
description: >
Developmental and epileptic encephalopathy 55 (DEE55) is an autosomal
recessive inherited GPI deficiency caused by biallelic variants in PIGP.
PIGP encodes a subunit of the GPI-GlcNAc transferase complex, the enzyme
that catalyses the first step of glycosylphosphatidylinositol (GPI) anchor
biosynthesis in the endoplasmic reticulum. More than 150 human proteins
reach the cell surface tethered by a GPI anchor, many of them with roles in
neurogenesis and synaptic function, so a partial block at the first
committed step reduces the surface density of that whole protein class
rather than removing a single gene product. The clinical result is
early-onset refractory epilepsy — infantile spasms, focal, tonic and
tonic-clonic seizures, often with a burst-suppression EEG — together with
severe hypotonia and profound global developmental delay. Dyskinetic
movement progressing to quadriplegia was prominent in the largest reported
family, and premature death in childhood has been reported. The phenotype
has since been extended to a presentation of multiple congenital
anomalies with hypotonia and seizures, matching what is seen for other
genes in the same first-step complex. Reduced surface expression of a GPI-anchored protein —
CD16 on granulocytes — is measurable by flow cytometry and supports the
diagnosis. The disorder is ultra-rare: fewer than a dozen patients have been
published since the gene was first linked to human disease in 2017.
notes: >
Ultra-rare, and the counts matter. The disease-defining report is two
siblings with compound heterozygous PIGP variants (Johnstone et al., Hum Mol
Genet 2017); a large consanguineous family added four affected children
homozygous for c.384del (Vetro et al., Neurol Genet 2020); a 2023 report
states that PIGP had been related to DEE55 in just seven patients at that
point and adds two more siblings with a multiple congenital
anomalies-hypotonia-seizures presentation. Every number in this entry is
therefore a count of patients, not a frequency, and `frequency` is left
unset throughout rather than computed from a cohort this size.
Two things this entry is deliberately careful about:
First, the mechanism is a *reduction* in the surface density of a whole
class of proteins, not the loss of one effector. That is why the
pathophysiology chain runs through "reduced GPI-anchored protein surface
expression" as a single node rather than naming individual GPI-anchored
proteins: with over 150 of them, and no experiment attributing the seizure
phenotype to any particular one, naming a culprit would assert more than
the sources do. CD16 appears in the entry as a measured readout and
diagnostic marker, not as the pathogenic protein.
Second, complete PIGP loss is probably not a viable disease state. The
reported alleles are hypomorphic in effect — the founding siblings retained
reduced but detectable PIGP mRNA, and the recurrent c.384del is predicted to
produce a longer-than-wild-type protein with impaired rather than absent
functionality. The entry says "reduced", not "abolished", throughout.
No `conforms_to` was declared. `kb/` covers several other inherited GPI
deficiencies (Mabry syndrome, CHIME syndrome, multiple congenital
anomalies-hypotonia-seizures syndrome) but there is no GPI-anchor
biosynthesis module to conform to. Those entries plus this one are the
natural first conformers if such a module is created; see the knowledge gap
recorded below.
**Deep-research provenance.** An OpenScientist run
(`research/Developmental_and_Epileptic_Encephalopathy_55-deep-research-openscientist.md`,
12/12 references resolved with a confabulation rate of 0.0; of the 12
assessed for relevance the validator scored 7 as on topic and left the
remaining 5 unscored rather than judging them off topic) is committed
alongside this entry and contributed four sources that first-pass curation from the primary
papers had missed: the second family with the recurrent c.456delA allele
(PMID:31139695), the group-level constraint that complete GPI deficiency is
embryonic lethal (PMID:25803904), the large inherited-GPI-deficiency cohort
(PMID:38456468), and the nutritional-intervention review behind the
treatments block (PMID:35562242). Every quote used was re-verified against
the fetched reference cache rather than taken from the report.
One preflight note for whoever reads that report next: `just preflight-dr`
warns that "GPI" is a rival gene mentioned 72 times. That is a false
positive — "GPI" here is glycosylphosphatidylinositol, the anchor, not GPI
the glucose-6-phosphate isomerase gene. The report's OMIM number matches
MONDO's.
classifications:
icimd_category:
- classification_value: lipid_glycosylation
notes: >-
ICIMD (Ferreira et al. 2021, PMID:33340416) group "Disorders of lipid
glycosylation", which the classification explicitly scopes to include
glycosylphosphatidylinositol biosynthesis. PIGP acts at the first step
of GPI anchor assembly.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >
Reported patients are compound heterozygous or, in a consanguineous
family, homozygous for PIGP variants. Inherited GPI deficiencies as a
group are autosomal recessive, with PIGA the single X-linked exception.
evidence:
- reference: PMID:28334793
reference_title: "Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This work associates mutations in the PIGP gene with a novel autosomal recessive IGD, and expands our knowledge of the role of PIG genes in human development."
explanation: >
States the inheritance mode and places the disorder in the inherited
GPI deficiency group.
prevalence:
- population: Worldwide, published cases
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Seven patients had been reported as of the 2023 report that states this
count, with two further siblings added by that paper. No incidence or
prevalence estimate exists for PIGP deficiency specifically.
evidence:
- reference: PMID:37125481
reference_title: "Expanding the phenotype of PIGP deficiency to multiple congenital anomalies-hypotonia-seizures syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, the PIGP gene has only been related to Developmental and Epileptic Encephalopathy 55 (MIM#617599) in just seven patients."
explanation: >-
Gives the size of the published cohort at the time of that report.
- population: Patients with developmental delay (inherited GPI deficiencies as a group)
measure_type: UNKNOWN
prevalence_class: ABOVE_1_IN_1000
rate_per_100000: 150.0
notes: >-
This is the figure for inherited GPI deficiencies as a whole within a
developmental-delay cohort, not for PIGP deficiency, which is a small
fraction of that group. It is recorded because it is the only
denominator-bearing estimate available anywhere near this disorder, and
should not be read as a PIGP-specific rate.
Two grading notes. `ABOVE_1_IN_1000` is the band that contains 150 per
100,000 (the schema puts 10-99 per 100,000 in BAND_1_5_PER_10000).
`measure_type` is UNKNOWN rather than POINT_PREVALENCE or ANNUAL_INCIDENCE
because the quoted source calls it an "incidence" while the figure is
really a diagnostic yield within an ascertained cohort, and neither
prevalence nor incidence describes that honestly.
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A ∼0.15% incidence of IGDs in patients with developmental delay has been reported in the large Deciphering Developmental Disorders study cohort."
explanation: >-
Provides the group-level frequency of inherited GPI deficiencies in a
developmental-delay cohort.
pathophysiology:
- name: Biallelic PIGP Variants
biological_scale: MOLECULAR
description: >
Compound heterozygous or homozygous PIGP variants. Reported alleles
include c.74T>C (p.Met25Thr) with c.456delA (p.Glu153AsnFs*34) in the
founding siblings, a recurrent homozygous c.384del in a large inbred
family, and a start-codon variant in trans with a 136 kb deletion removing
the whole gene. The effect is reduction rather than abolition of PIGP
function: patient cells retained reduced PIGP mRNA, and c.384del is
predicted to yield a longer-than-wild-type protein with impaired
functionality rather than no protein at all.
genes:
- preferred_term: PIGP
term:
id: hgnc:3046
label: PIGP
modifier: DECREASED
genetic_context:
description: >-
Germline biallelic PIGP alleles spanning missense, frameshift,
start-loss and a 136 kb whole-gene deletion. Both compound heterozygous
and homozygous families are reported, so `zygosity` is deliberately
left unset rather than picking one — the slot is single-valued and
either value would misdescribe half the cohort. The disease state is a
partial rather than complete loss of function.
allelic_events:
- MISSENSE_VARIANT
- FRAMESHIFT_VARIANT
- DELETION
- COPY_NUMBER_LOSS
variant_origin: GERMLINE
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
evidence:
- reference: PMID:28334793
reference_title: "Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report two siblings with compound heterozygous variants in the gene phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) (NM_153681.2: c.74T > C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34)."
explanation: >
Establishes the founding genotype.
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The homozygous c.384del variant of PIGP, present in the 4 patients, introduces a frame shift 6 codons before the expected stop signal and is predicted to result in the synthesis of a protein longer than the wild type, with impaired functionality."
explanation: >
Documents the recurrent homozygous allele and its predicted partial
rather than null consequence, which is why this node is a reduction
rather than an abolition.
- reference: PMID:31139695
reference_title: "Biallelic mutations in PIGP cause developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report the second family with a markedly overlapping phenotype due to a homozygous frameshift mutation (c.456delA;p.Glu153Asnfs*34) in PIGP."
explanation: >
Independent replication in a second family, and the same c.456delA
allele the founding siblings carried in compound heterozygous state —
making it a recurrent loss-of-function allele across a very small
patient population.
- reference: PMID:25803904
reference_title: "[Inherited GPI deficiencies:a new disease with intellectual disability and epilepsy]."
supports: SUPPORT
evidence_source: OTHER
snippet: "Patients with IGD have only a partial deficiency because complete GPI deficiency causes embryonic death."
explanation: >
Establishes at the group level why every viable patient genotype must
be hypomorphic, which is the constraint that makes this node a
reduction rather than an abolition.
downstream:
- target: Impaired First Step of GPI Anchor Biosynthesis
description: >-
PIGP is a subunit of the enzyme catalysing the first committed step of
GPI anchor assembly.
causal_link_type: DIRECT
- name: Impaired First Step of GPI Anchor Biosynthesis
biological_scale: MOLECULAR
description: >
GPI anchor precursors are assembled in the endoplasmic reticulum through a
multistep pathway and then transferred to target proteins, which are
further remodelled in the ER and Golgi before reaching the cell surface.
PIGP is a subunit of the complex that performs the first step of that
pathway; reduced PIGP function throttles flux at the entry point, so the
deficit is felt by every downstream GPI-anchored protein rather than by a
subset.
biological_processes:
- preferred_term: GPI anchor biosynthetic process
modifier: DECREASED
term:
id: GO:0006506
label: GPI anchor biosynthetic process
evidence:
- reference: PMID:28334793
reference_title: "Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis."
explanation: >
Places PIGP at the first step of the pathway, which is what makes the
downstream effect class-wide.
downstream:
- target: Reduced GPI-Anchored Protein Surface Expression
description: >-
Less GPI anchor precursor is available to tether target proteins to the
plasma membrane.
causal_link_type: DIRECT
- name: Reduced GPI-Anchored Protein Surface Expression
biological_scale: CELLULAR
description: >
The measurable cellular lesion. Patient cells show reduced surface levels
of GPI-anchored proteins, and this is restored by exogenous expression of
wild-type PIGP — the rescue that establishes causation rather than
correlation. Because over 150 human proteins are GPI-anchored, the effect
is a class-wide reduction in surface density. This entry deliberately does
not name a single culprit protein: no experiment attributes the
neurological phenotype to any particular GPI-anchored protein, and the
sources do not.
cell_types:
- preferred_term: granulocyte
term:
id: CL:0000094
label: granulocyte
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
evidence:
- reference: PMID:28334793
reference_title: "Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Functional studies with patient cells showed reduced PIGP mRNA levels, and an associated reduction of GPI-anchored cell surface proteins, which was rescued by exogenous expression of wild-type PIGP."
explanation: >
The rescue experiment establishes that reduced PIGP is what lowers
GPI-anchored protein surface expression.
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We demonstrated a reduced expression of the GPI-AP CD16 in the granulocytic membrane in affected individuals."
explanation: >
Independent confirmation of the cellular lesion in a second cohort,
using a specific GPI-anchored protein as the readout.
- reference: PMID:32156170
reference_title: "Biosynthesis and biology of mammalian GPI-anchored proteins."
supports: SUPPORT
evidence_source: OTHER
snippet: "At least 150 human proteins are glycosylphosphatidylinositol-anchored proteins (GPI-APs)."
explanation: >
Sources the size of the affected protein class, which is the claim that
makes this node a class-wide reduction rather than the loss of any one
protein — and therefore the reason the edge out of it carries unknown
intermediates.
- reference: PMID:31139695
reference_title: "Biallelic mutations in PIGP cause developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Flow cytometry of patient granulocytes confirmed reduced expression of glycosylphosphatidylinositol-anchored proteins as functional consequence."
explanation: >
A third independent demonstration of the cellular lesion, in a family
unrelated to either of the other two.
downstream:
- target: Disrupted Neurodevelopment and Cortical Network Excitability
description: >-
GPI-anchored proteins have prominent roles in neurogenesis and synaptic
function; reduced surface density of the class disturbs both.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
intermediate_mechanisms:
- Which of the >150 GPI-anchored proteins mediates the neurological phenotype has not been determined
- name: Disrupted Neurodevelopment and Cortical Network Excitability
biological_scale: TISSUE
description: >
GPI-anchored proteins play a variety of important roles in development and
particularly in neurogenesis, and in synaptic function and plasticity.
Reducing the surface density of that class during brain development
produces a network that is both developmentally impaired and abnormally
excitable — which is what a developmental and epileptic encephalopathy
is: the epilepsy and the developmental impairment are two outputs of one
lesion, not a cause and its consequence.
biological_processes:
- preferred_term: nervous system development
modifier: DECREASED
term:
id: GO:0007399
label: nervous system development
- preferred_term: synaptic signaling
modifier: DYSREGULATED
term:
id: GO:0099536
label: synaptic signaling
evidence:
- reference: PMID:28334793
reference_title: "Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These proteins play a variety of important roles in development, and particularly in neurogenesis."
explanation: >
Establishes the developmental role of the affected protein class, which
is the basis for this node.
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "often playing a role in CNS development and synaptic function and plasticity"
explanation: >
Names both the developmental and the synaptic roles that this node
combines.
downstream:
- target: Refractory Early-Onset Epilepsy
description: >-
An abnormally excitable immature cortical network generates
pharmacoresistant seizures from early infancy.
causal_link_type: DIRECT
- target: Thin Corpus Callosum
description: Reduced white matter bulk from disturbed neurodevelopment.
causal_link_type: DIRECT
- target: Ventriculomegaly
description: Ex vacuo ventricular enlargement accompanying reduced parenchymal volume.
causal_link_type: DIRECT
- target: Cerebral Atrophy
description: >-
Progressive loss of cerebral volume with frontal predominance,
developing over the first months of life.
causal_link_type: DIRECT
- target: Progressive Microcephaly
description: >-
Acquired microcephaly, the head-growth correlate of the parenchymal
loss above.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- Progressive loss of cerebral parenchymal volume
- target: Profound Developmental Impairment
description: >-
Disturbed neurogenesis produces profound global developmental delay
independent of, and in addition to, the seizure burden.
causal_link_type: DIRECT
- name: Refractory Early-Onset Epilepsy
biological_scale: ORGANISM
description: >
Early-onset refractory seizures are the presenting feature. The seizure
repertoire reported includes infantile spasms and focal, tonic and
tonic-clonic seizures, with a burst-suppression EEG pattern in the largest
family.
evidence:
- reference: PMID:28334793
reference_title: "Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of other IGD phenotypes."
explanation: >
Establishes refractory early-onset seizures as a core feature.
downstream:
- target: Epileptic Encephalopathy
description: >-
Sustained epileptic activity in an immature cortex, itself contributing
to the developmental impairment.
causal_link_type: DIRECT
- target: Infantile Spasms
description: An age-dependent seizure semiology of the immature cortex.
causal_link_type: DIRECT
- target: EEG with Burst Suppression
description: The electrographic correlate of the severely disturbed network.
causal_link_type: DIRECT
- name: Profound Developmental Impairment
biological_scale: ORGANISM
description: >
Profound global developmental delay with severe hypotonia. In the large
inbred family the course included early dyskinesia progressing to
quadriplegia, and two of four affected children died prematurely between
ages 2 and 12 years.
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PIGP mutations are consistently associated with an epileptic-dyskinetic encephalopathy with the features of early infantile epileptic encephalopathy with profound disability and premature death."
explanation: >
States the severity and outcome that define this node.
downstream:
- target: Profound Global Developmental Delay
description: Disturbed neurogenesis expressed as global developmental failure.
causal_link_type: DIRECT
- target: Generalized Hypotonia
description: Central hypotonia present from early infancy.
causal_link_type: DIRECT
- target: Dyskinesia
description: >-
Movement disorder progressing to quadriplegia, prominent in the largest
reported family.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
intermediate_mechanisms:
- The basal ganglia or network substrate of the dyskinesia was not established
- target: Spastic Tetraplegia
description: The motor endpoint the early dyskinesia progresses to.
causal_link_type: DIRECT
mechanistic_hypotheses:
- hypothesis_group_id: canonical_gpi_anchor_flux_reduction_model
hypothesis_label: Canonical GPI Anchor Flux Reduction Model
status: CANONICAL
description: >-
Biallelic hypomorphic PIGP variants reduce flux through the first
committed step of GPI anchor biosynthesis, lowering the surface density of
the whole class of GPI-anchored proteins; because that class is
disproportionately important in neurogenesis and synaptic function, the
result is a developmental and epileptic encephalopathy. The model is
supported by the rescue of GPI-anchored protein surface expression by
wild-type PIGP in patient cells, and by the independent demonstration of
reduced granulocyte CD16 in a second cohort.
discussions:
- discussion_id: pigp_which_gpi_anchored_protein
kind: KNOWLEDGE_GAP
prompt: >-
Which of the more than 150 GPI-anchored proteins, or which combination of
them, mediates the epilepsy and the developmental impairment in PIGP
deficiency?
attaches_to:
- pathophysiology#Reduced GPI-Anchored Protein Surface Expression
- pathophysiology#Disrupted Neurodevelopment and Cortical Network Excitability
rationale: >-
The chain from reduced GPI anchor synthesis to a seizing, developmentally
impaired cortex is currently a class-level argument: GPI-anchored proteins
matter in neurogenesis, so reducing them all must matter. No study has
identified the responsible protein or proteins. Until one does, the edge
into the neurodevelopmental node has unknown intermediates, and no
protein-specific therapeutic target can be named.
- discussion_id: pigp_genotype_phenotype_severity
kind: KNOWLEDGE_GAP
prompt: >-
Does residual PIGP activity predict where a patient falls on the spectrum
from DEE55 to the multiple congenital anomalies-hypotonia-seizures
presentation?
attaches_to:
- pathophysiology#Biallelic PIGP Variants
rationale: >-
The 2023 siblings, one of whom was a fetus with a severe malformation
disorder terminated at 17 weeks, carried a start-codon variant in trans
with a whole-gene deletion — plausibly the lowest residual activity
reported. If severity tracks residual activity, that would both explain
the phenotypic range within one gene and make a quantitative flow-cytometry
readout prognostic rather than merely diagnostic. With fewer than a dozen
patients published, the correlation cannot yet be tested.
- discussion_id: pigp_gpi_module_absent
kind: KNOWLEDGE_GAP
prompt: >-
Should the shared GPI-anchor-biosynthesis lesion across PIGP, PIGA, PIGV,
PIGQ, PIGY and related deficiencies be factored out as a mechanism module?
attaches_to:
- pathophysiology#Impaired First Step of GPI Anchor Biosynthesis
rationale: >-
The knowledge base already carries several inherited GPI deficiencies
curated independently, each restating the same upstream chain. That is the
pattern `kb/modules/` exists for. No such module exists yet, so this entry
declares no `conforms_to`; recording the gap here is what makes the
omission visible rather than looking like an oversight.
phenotypes:
- name: Epileptic Encephalopathy
category: Neurological
description: >
Early-onset refractory epilepsy in which the epileptic activity itself
contributes to the developmental impairment.
phenotype_term:
preferred_term: Epileptic encephalopathy
term:
id: HP:0200134
label: Epileptic encephalopathy
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PIGP mutations are consistently associated with an epileptic-dyskinetic encephalopathy with the features of early infantile epileptic encephalopathy"
explanation: >
Names the epileptic encephalopathy phenotype directly.
- name: Infantile Spasms
category: Neurological
description: >
Epileptic spasms in infancy, part of the reported seizure repertoire.
phenotype_term:
preferred_term: Infantile spasms
term:
id: HP:0012469
label: Infantile spasms
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "associated with infantile spasms, focal, tonic, and tonic-clonic seizures and a burst suppression EEG pattern"
explanation: >
Names infantile spasms within the reported seizure repertoire.
- name: EEG with Burst Suppression
category: Neurological
description: >
Burst-suppression EEG pattern, reported in the large inbred family.
phenotype_term:
preferred_term: EEG with burst suppression
term:
id: HP:0010851
label: EEG with burst suppression
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "4 children with a severe early-onset epileptic-dyskinetic encephalopathy, with suppression burst EEG"
explanation: >
Documents the burst-suppression EEG in the reported cohort.
- name: Generalized Hypotonia
category: Neuromuscular
description: >
Severe hypotonia, present from early infancy in all reported patients.
phenotype_term:
preferred_term: Generalized hypotonia
term:
id: HP:0001290
label: Generalized hypotonia
evidence:
- reference: PMID:28334793
reference_title: "Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay"
explanation: >
Names hypotonia as a presenting feature.
- name: Profound Global Developmental Delay
category: Neurodevelopmental
description: >
Profound global developmental delay, with no reported patient achieving
independent developmental milestones.
phenotype_term:
preferred_term: Profound global developmental delay
term:
id: HP:0012736
label: Profound global developmental delay
evidence:
- reference: PMID:28334793
reference_title: "Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of other IGD phenotypes."
explanation: >
Names profound global developmental delay as a core feature.
- name: Dyskinesia
category: Neurological
description: >
Early dyskinetic movements progressing to quadriplegia, prominent in the
large inbred family and the feature that led those authors to call the
syndrome epileptic-dyskinetic.
phenotype_term:
preferred_term: Dyskinesia
term:
id: HP:0100660
label: Dyskinesia
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 4 affected children exhibited a severe neurodevelopmental disorder featuring severe hypotonia with early dyskinesia progressing to quadriplegia"
explanation: >
Documents the dyskinesia and its progression to quadriplegia.
- name: Spastic Tetraplegia
category: Neurological
description: >
Spastic quadriplegia, the state the early dyskinesia progresses to. It is
the motor endpoint of the disease in the largest reported family.
phenotype_term:
preferred_term: Spastic tetraplegia
term:
id: HP:0002510
label: Spastic tetraplegia
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 4 affected children exhibited a severe neurodevelopmental disorder featuring severe hypotonia with early dyskinesia progressing to quadriplegia"
explanation: >
Documents progression from dyskinesia to quadriplegia across all four
affected children.
- name: Thin Corpus Callosum
category: Neuroimaging
description: >
Thin corpus callosum on brain MRI, reported at both 3 and 7 months in the
same patient — so it is present early and persists rather than emerging
with the atrophy.
phenotype_term:
preferred_term: Thin corpus callosum
term:
id: HP:0033725
label: Thin corpus callosum
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Brain MRI at 3 months showed mildly reduced white matter bulk with thin corpus callosum, ventriculomegaly, and dilated frontotemporal subarachnoid space"
explanation: >
Names thin corpus callosum on the earliest reported imaging.
- name: Ventriculomegaly
category: Neuroimaging
description: >
Enlarged cerebral ventricles on early brain MRI, accompanying the reduced
white matter bulk.
phenotype_term:
preferred_term: Ventriculomegaly
term:
id: HP:0002119
label: Ventriculomegaly
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Brain MRI at 3 months showed mildly reduced white matter bulk with thin corpus callosum, ventriculomegaly, and dilated frontotemporal subarachnoid space"
explanation: >
Names ventriculomegaly on early imaging.
- name: Cerebral Atrophy
category: Neuroimaging
description: >
Diffuse cerebral atrophy with frontal predominance on later imaging,
alongside diffuse white matter signal change. The progression from
"mildly reduced white matter bulk" at 3 months to "diffuse atrophy" at 7
months in the same patient is the imaging correlate of a developmental
process rather than a static malformation.
phenotype_term:
preferred_term: Cerebral atrophy
term:
id: HP:0002059
label: Cerebral atrophy
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Brain MRI at 7 months revealed diffuse atrophy, with frontal lobe predominance, diffuse high signal intensity in the white matter, and thin corpus callosum"
explanation: >
Documents diffuse cerebral atrophy and white matter signal change on
later imaging in the same patient.
- name: Progressive Microcephaly
category: Neurological
description: >
Acquired microcephaly — head circumference falling to −2 SD — rather than
a congenital small head. Consistent with the imaging course above.
phenotype_term:
preferred_term: Progressive microcephaly
term:
id: HP:0000253
label: Progressive microcephaly
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "acquired microcephaly (OFC 50 cm, −2 SD), an unclassifiable form of epileptic encephalopathy with asymmetric burst suppression, and spastic quadriplegia"
explanation: >
Documents the acquired (progressive) nature of the microcephaly.
progression:
- phase: Infancy
age_range: 0-12 months
notes: >-
Onset of refractory seizures with severe hypotonia and, in the largest
family, early dyskinetic movements.
- phase: Childhood
age_range: 1-12 years
notes: >-
Dyskinesia progressing to quadriplegia with profound developmental
disability. Two of the four affected children in the largest reported
family died prematurely between ages 2 and 12 years; the surviving two
were aged 2 years 7 months and 7 years 4 months at report.
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two of the children died prematurely between age 2 and 12 years; the remaining 2 children are aged 2 years 7 months and 7 years 4 months."
explanation: >-
Documents childhood mortality and the ages of the surviving patients.
- reference: PMID:38456468
reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "for all individuals, 15 of whom were deceased at the time of writing"
explanation: >-
Group-level mortality across 83 inherited GPI deficiency patients,
giving a denominator the PIGP-specific reports cannot. INDIRECT because
it is an inherited-GPI-deficiency figure rather than a PIGP one.
- reference: PMID:38456468
reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Individuals with variants in synthesis stage \ngenes of the GPI-AP exhibited a significantly shorter time to seizure onset than \nindividuals with variants in transamidase and remodelling stage genes"
explanation: >-
The cohort found that variants in synthesis-stage GPI genes give a
significantly shorter time to seizure onset than transamidase- or
remodelling-stage genes. PIGP is a synthesis-stage gene, which is a
group-level reason to expect the early onset this entry describes.
genetic:
- name: PIGP
gene_term:
preferred_term: PIGP
term:
id: hgnc:3046
label: PIGP
relationship_type: CAUSATIVE
notes: >
PIGP encodes a subunit of the GPI-GlcNAc transferase complex catalysing
the first step of GPI anchor biosynthesis. It is one of seven genes
(PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY, DPM2) mediating that initial stage,
which is why the PIGP phenotype resembles those of PIGA, PIGQ and PIGY
deficiency rather than those of later-step genes.
evidence:
- reference: PMID:37125481
reference_title: "Expanding the phenotype of PIGP deficiency to multiple congenital anomalies-hypotonia-seizures syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the initial stage of their biosynthesis is mediated by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY, and DMP2 genes, which have been linked to a wide spectrum of phenotypes depending on the gene damaged"
explanation: >
Places PIGP among the genes of the first stage of GPI biosynthesis and
grounds the phenotypic comparison to its complex partners.
diagnosis:
- name: Flow cytometry for GPI-anchored protein surface expression
description: >
Measurement of GPI-anchored protein levels on circulating granulocytes by
flow cytometry. CD16 was proposed as a marker on the strength of its
reduction in affected individuals; note this is a screening test for
inherited GPI deficiency as a group, not a PIGP-specific test.
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CD16 is a valuable marker to support a genetic diagnosis of inherited GPI deficiencies."
explanation: >
States the diagnostic proposal in the authors' own words, including
that it supports rather than establishes the genetic diagnosis.
- reference: PMID:31139695
reference_title: "Biallelic mutations in PIGP cause developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Flow cytometry of patient granulocytes confirmed reduced expression of glycosylphosphatidylinositol-anchored proteins as functional consequence."
explanation: >
Second independent use of the same granulocyte assay to confirm a PIGP
diagnosis.
- name: Serum alkaline phosphatase (a negative, not a screen)
description: >
Hyperphosphatasia is strong evidence of an inherited GPI deficiency when
present, but it arises from defects in the *later* steps of GPI
biosynthesis and anchor remodelling — Mabry syndrome being the type case.
PIGP acts at the first step, so a normal alkaline phosphatase does not
argue against this diagnosis. Recorded here because using
hyperphosphatasia as a screening test would systematically miss
early-pathway defects like this one.
evidence:
- reference: PMID:25803904
reference_title: "[Inherited GPI deficiencies:a new disease with intellectual disability and epilepsy]."
supports: SUPPORT
evidence_source: OTHER
snippet: "Hyperphosphatasia is observed in some patients with IGDs, such as hyperphosphatasia mental retardation syndrome or Mabry syndrome, caused by mutations in genes in the later stage of GPI biosynthesis."
explanation: >
Localizes hyperphosphatasia to late-stage pathway defects, which is why
it is unreliable for an early-step gene such as PIGP.
- name: Whole-exome sequencing
description: >
Molecular diagnosis. Every reported family was ascertained by exome
sequencing; the phenotype is not distinctive enough among the inherited
GPI deficiencies to point at PIGP without sequencing.
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We studied clinical features, EEG, brain MRI scans, whole-exome sequencing (WES), and measured the expression of a subset of GPI-anchored proteins (GPI-APs) in circulating granulocytes using flow cytometry."
explanation: >
Describes the diagnostic workup used to establish the diagnosis.
- reference: PMID:31139695
reference_title: "Biallelic mutations in PIGP cause developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "panel for epileptic encephalopathies (100 genes including PIGA, PIGG, PIGN, and PIGT) did not reveal an underlying pathogenic mutation"
explanation: >
A targeted epilepsy panel that carried four other PIG genes but not
PIGP returned negative in a patient who turned out to have PIGP
deficiency. This is the practical reason exome or genome sequencing is
required rather than a panel — a negative epilepsy panel does not
exclude this diagnosis.
treatments:
- name: Antiseizure Medication
description: >
Seizure control is the mainstay of management, and it is difficult: the
epilepsy is described as refractory in every reported patient. No
anticonvulsant has been shown to work better than others in PIGP
deficiency specifically, and no such claim is made here.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Refractory Early-Onset Epilepsy
treatment_effect: MODULATES
description: >-
Symptomatic seizure suppression. It does not address the GPI-anchor
lesion and does not alter the developmental trajectory.
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Several combinations of antiepileptic drugs (including valproate, phenobarbital, phenytoin, topiramate, carbamazepine, vigabatrin, levetiracetam, rufinamide, clonazepam, and lorazepam) failed to control seizures"
explanation: >
Documents both that antiseizure medication is the treatment attempted
and that it fails — which is also the evidence for calling the epilepsy
refractory, a claim this entry makes in a node name.
- name: Pyridoxine Supplementation
description: >
Pyridoxine (vitamin B6) supplementation, named among the nutritional
options across congenital disorders of glycosylation. The evidence is at
the level of the CDG group, not of PIGP: no trial or case series has
tested it in PIGP deficiency, and this entry does not imply one has.
Recorded as a small molecule rather than a dietary measure, because that
is what it is.
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
evidence:
- reference: PMID:35562242
reference_title: "Nutrition interventions in congenital disorders of glycosylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "We review the dietary management in CDG with a focus on two subgroups: N-linked glycosylation defects and GPI-anchor disorders."
explanation: >
Establishes that dietary management is discussed for the GPI-anchor
subgroup that PIGP deficiency belongs to. Graded INDIRECT because the
claim reaches PIGP only through subgroup membership, not through data
in PIGP patients.
- reference: PMID:35562242
reference_title: "Nutrition interventions in congenital disorders of glycosylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Specific nutritional treatment options for certain CDG types include oral supplementation of monosaccharide sugars, manganese, uridine, or pyridoxine."
explanation: >
Names pyridoxine among the nutritional options in congenital disorders
of glycosylation. Note the sentence says "certain CDG types" — it does
not say PIGP is one of them, which is why this is INDIRECT.
- name: Ketogenic Diet
description: >
The ketogenic diet, the other empiric intervention discussed for the
GPI-anchor subgroup of congenital disorders of glycosylation. Same
caveat as pyridoxine: the evidence is group-level, and no study has
tested it in PIGP deficiency.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Dietary Intervention
term:
id: NCIT:C15447
label: Dietary Intervention
evidence:
- reference: PMID:35562242
reference_title: "Nutrition interventions in congenital disorders of glycosylation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Ketogenic diet is most frequently used in GPI anchor defects"
explanation: >
States that the ketogenic diet is the intervention most often used in
the GPI-anchor defects, the subgroup PIGP deficiency belongs to.
INDIRECT because the claim reaches PIGP only through subgroup
membership — the sentence names the group, not this gene.
- name: Gastrostomy and Feeding Support
description: >
Enteral feeding support. For a disorder in which no reported patient
achieves independent development and antiseizure medication fails, this
and rehabilitative care are most of what management actually consists of,
so leaving it out would misrepresent the clinical picture.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Surgical Procedure
term:
id: NCIT:C15329
label: Surgical Procedure
target_mechanisms:
- target: Profound Developmental Impairment
treatment_effect: MODULATES
description: >-
Supportive management of the feeding difficulty that follows the
neurological impairment. It does not address the underlying lesion.
evidence:
- reference: PMID:32042915
reference_title: "Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "percutaneous endoscopic gastrostomy was performed at age 7 months"
explanation: >
Documents gastrostomy in a reported patient.
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.
Record notes
Ultra-rare, and the counts matter. The disease-defining report is two siblings with compound heterozygous PIGP variants (Johnstone et al., Hum Mol Genet 2017); a large consanguineous family added four affected children homozygous for c.384del (Vetro et al., Neurol Genet 2020); a 2023 report states that PIGP had been related to DEE55 in just seven patients at that point and adds two more siblings with a multiple congenital anomalies-hypotonia-seizures presentation. Every number in this entry is therefore a count of patients, not a frequency, and `frequency` is left unset throughout rather than computed from a cohort this size. Two things this entry is deliberately careful about: First, the mechanism is a *reduction* in the surface density of a whole class of proteins, not the loss of one effector. That is why the pathophysiology chain runs through "reduced GPI-anchored protein surface expression" as a single node rather than naming individual GPI-anchored proteins: with over 150 of them, and no experiment attributing the seizure phenotype to any particular one, naming a culprit would assert more than the sources do. CD16 appears in the entry as a measured readout and diagnostic marker, not as the pathogenic protein. Second, complete PIGP loss is probably not a viable disease state. The reported alleles are hypomorphic in effect — the founding siblings retained reduced but detectable PIGP mRNA, and the recurrent c.384del is predicted to produce a longer-than-wild-type protein with impaired rather than absent functionality. The entry says "reduced", not "abolished", throughout. No `conforms_to` was declared. `kb/` covers several other inherited GPI deficiencies (Mabry syndrome, CHIME syndrome, multiple congenital anomalies-hypotonia-seizures syndrome) but there is no GPI-anchor biosynthesis module to conform to. Those entries plus this one are the natural first conformers if such a module is created; see the knowledge gap recorded below. **Deep-research provenance.** An OpenScientist run (`research/Developmental_and_Epileptic_Encephalopathy_55-deep-research-openscientist.md`, 12/12 references resolved with a confabulation rate of 0.0; of the 12 assessed for relevance the validator scored 7 as on topic and left the remaining 5 unscored rather than judging them off topic) is committed alongside this entry and contributed four sources that first-pass curation from the primary papers had missed: the second family with the recurrent c.456delA allele (PMID:31139695), the group-level constraint that complete GPI deficiency is embryonic lethal (PMID:25803904), the large inherited-GPI-deficiency cohort (PMID:38456468), and the nutritional-intervention review behind the treatments block (PMID:35562242). Every quote used was re-verified against the fetched reference cache rather than taken from the report. One preflight note for whoever reads that report next: `just preflight-dr` warns that "GPI" is a rival gene mentioned 72 times. That is a false positive — "GPI" here is glycosylphosphatidylinositol, the anchor, not GPI the glucose-6-phosphate isomerase gene. The report's OMIM number matches MONDO's.
Review response: prevalence band, neuroimaging phenotypes, pathograph, allelic events · 2026-09-04T14:32:59Z · View source
Three review-response sessions on PR #10303, following the CREATE record. Round 1 connected all six phenotypes to the pathograph with bare-name downstream targets from the two ORGANISM-level nodes. Round 2 addressed the remaining blocking items: prevalence_class corrected from BAND_1_5_PER_10000 to ABOVE_1_IN_1000 to match its own rate_per_100000 of 150.0, with measure_type regraded to UNKNOWN because the source word is incidence but the figure is a diagnostic yield inside an ascertained cohort; five phenotypes added from the cached full text of PMID:32042915 (thin corpus callosum HP:0033725, ventriculomegaly HP:0002119, cerebral atrophy HP:0002059, progressive microcephaly HP:0000253, spastic tetraplegia HP:0002510); the claim that more than 150 GPI-anchored proteins exist was cited to PMID:32156170, consuming a reference the PR had fetched and left unused; genetic_context allele_type SNV and zygosity COMPOUND_HETEROZYGOUS were replaced by the structured allelic_events list covering missense, frameshift, deletion and copy-number loss, with zygosity left unset and the reason recorded; and the Antiseizure Medication treatment was given the ten-failed-agents sentence that also substantiates the word refractory in a node name. Round 3 fixed two claim-evidence inaccuracies in committed content: the Ketogenic Diet snippet quoted a sentence that never mentions the ketogenic diet and was replaced with the sentence naming it directly, and the deep-research provenance note claimed 12 of 12 references resolved with none off topic where the report frontmatter records on_topic 7 of 12 assessed with no off_topic key at all. Validated with just validate (41 of 41 snippets verified), validate-terms, check-entity-refs, check-duplicate-keys, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets and check-snippet-grading.
Create: Developmental and Epileptic Encephalopathy 55 · 2026-08-31T21:51:23Z · View source
De-novo curation of DEE55 (MONDO:0033364, PIGP) resolving curation claim #10292. Pathograph runs biallelic hypomorphic PIGP variants -> impaired first step of GPI anchor biosynthesis -> reduced GPI-anchored protein surface expression -> disrupted neurodevelopment and cortical excitability -> refractory epilepsy plus profound developmental impairment. The edge into the neurodevelopmental node is marked INDIRECT_UNKNOWN_INTERMEDIATES because no study attributes the phenotype to any of the >150 GPI-anchored proteins; that is recorded as a knowledge gap rather than papered over. Two further gaps recorded: genotype-severity correlation across the DEE55-to-MCAHS spectrum, and the absence of a GPI-anchor-biosynthesis module in kb/modules/ (so no conforms_to was declared). Deep research: one OpenScientist run, committed, 12/12 references resolved with none off topic; it contributed PMID:31139695 (second family, recurrent c.456delA), PMID:25803904 (complete GPI deficiency is embryonic lethal, which grounds the hypomorphic framing), PMID:38456468 and PMID:35562242 (treatments). All quotes were re-verified against the fetched reference cache, not taken from the report. just preflight-dr warns that GPI is a rival gene at 72 mentions; that is a false positive - GPI there is the anchor, not the glucose-6-phosphate isomerase gene - and the report OMIM matches MONDO. One error caught during curation: hgnc:8967 is PIGN, not PIGP; the correct id is hgnc:3046, confirmed against the HGNC REST API after linkml-term-validator flagged the label mismatch. Validated with just validate (29/29 snippets verified), just validate-terms, check-entity-refs, check-duplicate-keys, check-enum-values, check-snippet-length, check-title-snippets, check-snippet-grading and check-folded-hyphens.
Developmental and Epileptic Encephalopathy 55 (DEE55; OMIM #617599) is an ultra-rare, autosomal-recessive inherited glycosylphosphatidylinositol (GPI) deficiency (IGD) caused by biallelic loss-of-function variants in PIGP (Phosphatidylinositol Glycan Anchor Biosynthesis, Class P; OMIM *605938; HGNC:3046; formerly DSCR5; located at 21q22.13). PIGP encodes an accessory subunit of the endoplasmic-reticulum GPI-GlcNAc transferase complex, the enzyme that catalyzes the committed first step of GPI anchor biosynthesis. When PIGP function is reduced, the cell produces fewer GPI anchors, which in turn lowers the cell-surface expression of the ≥150 human GPI-anchored proteins (GPI-APs) that are essential for normal neuronal development and function. The downstream deficit of these surface proteins produces the disease's cardinal triad: early-onset refractory seizures, muscular hypotonia, and profound global developmental delay / intellectual disability, typically accompanied by cerebral and cerebellar atrophy on neuroimaging.
The disease was first defined molecularly in 2017 by Johnstone and colleagues in two compound-heterozygous siblings, and remained described in only ~7 patients as of 2023. Since then the recognized phenotypic spectrum has broadened substantially — from the classic DEE presentation, to Multiple Congenital Anomalies–Hypotonia–Seizures Syndrome (MCAHS), and at the most severe end to prenatal lethality (a fetus terminated at 17 weeks gestation). Because complete GPI deficiency is embryonic-lethal, all viable patients carry hypomorphic (partial-loss-of-function) biallelic variants. A recurrent frameshift allele, c.456delA (p.Glu153Asnfs*34), has been observed both in compound-heterozygous and homozygous states across unrelated families and is ultra-rare in population databases (≈9 heterozygous carriers, 0 homozygotes in gnomAD).
There is no curative or disease-modifying therapy. Management is symptomatic and multidisciplinary — antiseizure medications for the refractory epilepsy, plus supportive care (feeding-tube nutrition, physical/occupational/speech therapy). Empiric nutritional interventions such as pyridoxine (vitamin B6) and the ketogenic diet are used in the broader GPI-anchor-disorder group. Prognosis is severe, with profound lifelong disability and substantial mortality (≈18% deceased across the largest IGD cohort). Diagnosis is achieved by whole-exome or whole-genome sequencing — notably, targeted epilepsy gene panels can miss PIGP — supported functionally by flow-cytometric detection of reduced GPI-anchored proteins on blood cells.
The molecular basis of DEE55 was established by Johnstone et al. 2017 PMID: 28334793, who reported two siblings with compound-heterozygous variants in PIGP (NM_153681.2: c.74T>C, p.Met25Thr and c.456delA, p.Glu153AsnFs*34). As the authors state: "Here, we report two siblings with compound heterozygous variants in the gene phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) (NM_153681.2: c.74T > C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34). PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis."
Functional work confirmed the loss-of-function mechanism: "Functional studies with patient cells showed reduced PIGP mRNA levels, and an associated reduction of GPI-anchored cell surface proteins, which was rescued by exogenous expression of wild-type PIGP. This work associates mutations in the PIGP gene with a novel autosomal recessive IGD." The rescue by wild-type PIGP demonstrates that the surface-protein deficit is a direct consequence of PIGP dysfunction, satisfying a key criterion for causality. The disease is thus an autosomal-recessive Mendelian disorder within the family of inherited GPI deficiencies (a subgroup of the congenital disorders of glycosylation).
Both index PIGP patients "presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of other IGD phenotypes" (Johnstone 2017, PMID: 28334793). The frequency and character of these features are well quantified in the largest IGD cohort to date, Sidpra et al. 2024 (PMID: 38456468, n = 83), which reported: "Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%)." Seizure onset is typically in infancy: "Median age at seizure onset was 6 months."
Neuroimaging in the IGD group commonly shows cerebral atrophy (75%), cerebellar atrophy (60%), corpus-callosum anomalies (57%), and a distinctive symmetric restricted diffusion of the central tegmental tracts (60%). The OMIM clinical synopsis for DEE55 specifically (per Vetro et al. 2020, curated in OMIM #617599) describes refractory seizures beginning in the first weeks-to-months of life, profound intellectual disability, absent speech, spastic quadriplegia, dyskinetic movements, cortical visual impairment, and feeding-tube dependence, with MRI showing cerebral atrophy, a thin corpus callosum, and abnormal white-matter signal.
Suggested HPO terms: Seizure (HP:0001250); Infantile spasms / early-onset epilepsy (HP:0012469 / HP:0011097); Muscular hypotonia (HP:0001252); Global developmental delay (HP:0001263); Profound intellectual disability (HP:0002187); Absent speech (HP:0001344); Spastic tetraplegia (HP:0002510); Cortical visual impairment (HP:0100704); Cerebral atrophy (HP:0002059); Cerebellar atrophy (HP:0001272); Thin corpus callosum (HP:0033725).
Martín-Grau et al. 2023 (PMID: 37125481) expanded the PIGP phenotype beyond classic DEE. They described two compound-heterozygous siblings carrying PIGP NM_153682.3:c.2T>C (p.?) and a 136-kb deletion at 21q22.13 (GRCh37 chr21:38,329,939–38,466,066) removing the entire PIGP gene: "Both were compound heterozygous of pathogenic variants in PIGP gene: NM_153682.3:c.2 T > C(p.?) and a 136 Kb deletion ... affecting the entire PIGP gene." One child had dysmorphic features, congenital anomalies, hypotonia, and epileptic encephalopathy; the other was "a fetus with a severe malformation disorder at 17 weeks of gestation whose pregnancy was interrupted."
The authors emphasized the rarity of the condition — "To date, the PIGP gene has only been related to Developmental and Epileptic Encephalopathy 55 (MIM#617599) in just seven patients" — and proposed a nosological expansion: "Our results extend the clinical phenotype associated to PIGP gene and propose to include it as a novel cause of Multiple Congenital Anomalies-Hypotonia-Seizures syndrome." This establishes a severity continuum from prenatal-lethal malformation through MCAHS to the classic postnatal DEE presentation, consistent with variable expressivity driven by the residual GPI-biosynthetic activity of each allele combination.
"PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis" (Johnstone 2017, PMID: 28334793). This first step — transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol to form GlcNAc-PI on the cytoplasmic face of the ER — is the committed, rate-defining reaction of the entire pathway. Downstream, the GPI anchor is assembled and transferred to hundreds of proteins: "At least 150 human proteins are glycosylphosphatidylinositol-anchored proteins (GPI-APs)" (Kinoshita review, PMID: 32156170; an updated review, PMID: 39129667, cites ≥160). GPI attachment is required for the cell-surface expression of these proteins.
A critical mechanistic constraint explains why patients survive at all: "Patients with IGD have only a partial deficiency because complete GPI deficiency causes embryonic death" (Murakami & Kinoshita 2015, PMID: 25803904). Thus all DEE55 alleles must be hypomorphic rather than null on both copies; the degree of residual activity, together with which step of the pathway is impaired, tunes disease severity.
Suggested GO terms: GPI anchor biosynthetic process (GO:0006506); N-acetylglucosaminyltransferase activity (GO:0016262/related); attachment of GPI anchor to protein (GO:0016255); endoplasmic reticulum membrane (GO:0005789).
Martín-Grau 2023 (PMID: 37125481) situates PIGP within its multi-subunit enzyme: "the initial stage of their biosynthesis is mediated by PIGA, PIGC, PIGH, PIGP, PIGQ, PIGY, and DMP2 genes, which have been linked to a wide spectrum of phenotypes depending on the gene damaged." PIGA is the catalytic subunit, while PIGP is an accessory/regulatory subunit (DPM2/DMP2 is shared with the dolichol-phosphate-mannose synthase machinery). Defects in the different subunits produce overlapping yet gene-specific IGD phenotypes; PIGA-, PIGQ-, and PIGY-related disorders overlap clinically with PIGP-related MCAHS. This complex-level view explains the phenotypic convergence of the whole GPI-GnT subgroup on neurodevelopmental epileptic encephalopathy.
Krenn et al. 2019 (PMID: 31139695; Ann Clin Transl Neurol 6(5):968–973) described a second, independent family: a 2-year-old girl of unrelated Polish parents who was homozygous for PIGP c.456delA (p.Glu153Asnfs*34) — the very same frameshift allele carried in compound-heterozygous state by the original Johnstone siblings. This makes c.456delA a recurrent loss-of-function allele across the small known patient population. The variant is ultra-rare: 6 heterozygotes and no homozygotes in an in-house 16,000-exome database, and 9 heterozygous / 0 homozygous carriers in gnomAD.
Two diagnostic lessons emerge. First, whole-exome sequencing was required: a 100-gene epileptic-encephalopathy panel (which included other PIG genes — PIGA, PIGG, PIGN, PIGT — but not PIGP) failed to detect the diagnosis. Second, flow cytometry of patient lymphocytes showed decreased surface GPI-anchored proteins, providing functional confirmation. GeneMatcher yielded no additional families at the time, underscoring the disease's extreme rarity.
Diagnosis combines genomic sequencing with a functional cell-surface assay. Murakami & Kinoshita 2015 (PMID: 25803904) note that "Flow cytometric analysis of GPI-APs on granulocytes is also useful for the detection of IGD" and that "The presence of hyperphosphatasia is strong evidence of IGD." Importantly, hyperphosphatasia (elevated tissue-nonspecific alkaline phosphatase, a GPI-anchored protein) is chiefly associated with late-pathway defects (e.g., Mabry syndrome / hyperphosphatasia-with-mental-retardation from PIGV/PIGO/PGAP defects) and is not a consistent feature of PIGP, an early-pathway defect. Multicolor flow cytometry using markers such as FLAER, CD16, CD24, CD55, CD59 (and the T5 antibody for free GPI) yields gene/complex-specific profiles (Knaus 2019, PMID: 31353022): "Using multicolor flow cytometry, we determined a characteristic profile for GPI transamidase deficiency." In PIGP cases specifically, diagnosis was made by WES (PMID 28334793, 31139695) and a whole-gene 136-kb deletion was detectable as a copy-number variant on genomic analysis (PMID 37125481).
There is no curative therapy. Management is anticonvulsant-based seizure control plus multidisciplinary supportive care. Boyer, Johnsen & Morava 2022 (PMID: 35562242) reviewed nutritional interventions across the >160 congenital disorders of glycosylation, noting that specific therapies exist for very few subtypes: "Specific nutritional treatment options for certain CDG types include oral supplementation of monosaccharide sugars, manganese, uridine, or pyridoxine." They explicitly address the GPI-anchor subgroup: "We review the dietary management in CDG with a focus on two subgroups: N-linked glycosylation defects and GPI-anchor disorders." Pyridoxine (vitamin B6) and the ketogenic diet are the empiric interventions most often cited for GPI-anchor disorders, though robust efficacy data specific to PIGP are lacking.
DEE55 carries a severe prognosis. Only ~7 PIGP patients were reported by 2023 (PMID: 37125481), and one allele combination produced fetal termination at 17 weeks. Across the largest IGD cohort (Sidpra 2024, PMID: 38456468, n = 83), "Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing" (≈18% mortality). Morbidity is multisystemic: "Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies." The OMIM synopsis notes death in childhood may occur in DEE55 specifically.
| Resource | Identifier |
|---|---|
| Disease (phenotype) | OMIM #617599 — Developmental and Epileptic Encephalopathy 55 |
| Orphanet | PIGP-related early infantile epileptic encephalopathy (within Orphanet IGD classifications; ORPHA:1934 grouping) |
| Gene | PIGP — OMIM *605938; HGNC:3046; NCBI Gene 51227; Ensembl ENSG00000185808; UniProt P57054 |
| Locus | 21q22.13 (GRCh38 chr21:37,065,364–37,073,071) — within the Down syndrome critical region |
| Former/alias symbols | DSCR5 (Down syndrome critical region gene 5); DCRC; DSRC |
| MONDO | Align to the MONDO term for developmental and epileptic encephalopathy 55 (map to OMIM:617599) |
DEE55 is a Mendelian, autosomal-recessive developmental and epileptic encephalopathy — a severe neurodevelopmental disorder in which epileptic activity itself is thought to contribute to developmental impairment, superimposed on the direct developmental effect of the underlying metabolic lesion. It belongs to the inherited GPI deficiencies (IGDs), a subclass of the congenital disorders of glycosylation (CDG). Key identifiers are listed in Finding 10. Synonyms include PIGP-related developmental and epileptic encephalopathy, PIGP-CDG, early infantile epileptic encephalopathy 55, and (given the phenotypic expansion) a cause of Multiple Congenital Anomalies–Hypotonia–Seizures syndrome. Information is derived from aggregated disease-level resources (OMIM, Orphanet) and a small number of individual-patient case reports and cohort studies (Johnstone 2017; Krenn 2019; Martín-Grau 2023; Sidpra 2024) rather than EHR-scale datasets.
Causal factor: biallelic (homozygous or compound-heterozygous) loss-of-function variants in PIGP. Genetic risk factors: the causal variants themselves; a recurrent frameshift allele c.456delA (p.Glu153Asnfs*34) recurs across families. Because inheritance is autosomal recessive, consanguinity and being a carrier parent are the principal risk contexts; the Krenn 2019 family, however, involved unrelated parents homozygous by chance for an ultra-rare allele. Environmental risk factors: none identified — this is a monogenic disorder. Protective factors: none established; residual PIGP/GPI activity from hypomorphic alleles is "protective" against the embryonic lethality seen with complete deficiency. Gene–environment interactions: none documented.
See Finding 2 for frequencies and HPO suggestions. The dominant phenotype types are clinical signs/symptoms (seizures, hypotonia, spasticity, dyskinesia), developmental/behavioral (profound intellectual disability, absent speech), neuroimaging abnormalities (cerebral/cerebellar atrophy, thin corpus callosum, white-matter signal change), and, in the MCAHS end of the spectrum, congenital malformations and dysmorphism. Onset is neonatal-to-early-infantile (seizures median ~6 months in the IGD group; first weeks–months in DEE55). Severity is profound; progression is best described as a static-to-slowly-progressive encephalopathy with refractory epilepsy. Quality-of-life impact is severe: affected children are typically non-verbal, non-ambulatory, feeding-tube dependent, and fully care-dependent.
Causal gene: PIGP (OMIM *605938). Reported pathogenic variants: c.74T>C (p.Met25Thr, missense); c.456delA (p.Glu153Asnfs*34, frameshift, recurrent LoF); c.2T>C (p.?, start-loss); and a 136-kb whole-gene deletion (structural/CNV). Variant classes: missense, frameshift, start-loss, and whole-gene deletion — all converging on reduced PIGP function. Functional consequence: loss of function (reduced mRNA and reduced GPI-anchored surface proteins, rescued by wild-type PIGP). Allele frequency: c.456delA is ultra-rare (≈9 het / 0 hom in gnomAD). Origin: germline. Modifier genes/epigenetics: not specifically characterized for PIGP; other GPI-pathway genes provide the phenotypic-modifier context at the pathway level. Chromosomal abnormalities: the 136-kb 21q22.13 deletion (PMID 37125481) is the notable structural lesion; PIGP lies in the Down syndrome critical region and has multiple pseudogenes (a technical caveat for sequencing/CNV calling).
Not applicable. No environmental, lifestyle, or infectious contributors are known; DEE55 is a purely monogenic inborn error of metabolism.
Upstream vs downstream: the PIGP lesion and GPI-anchor deficit are upstream; the surface-protein deficiency is the pivotal intermediate; seizures, developmental impairment, and malformations are downstream clinical outputs. Cell types/processes: neurons (CL:0000540) are the principal affected cell type; the endoplasmic reticulum (GO:0005783/0005789) is the subcellular site of the lesion; the core biological process is GPI anchor biosynthetic process (GO:0006506). No immune, autoimmune, infectious, or classical oxidative-stress mechanism is implicated.
Primary organ/system: the central nervous system (UBERON:0001017) — cerebral cortex (UBERON:0000956), cerebellum (UBERON:0002037), corpus callosum (UBERON:0002336), and white matter (UBERON:0002316). Cell level: neurons (CL:0000540). Subcellular: endoplasmic reticulum (GO:0005783), where GPI is synthesized. Secondary/multisystem involvement (chiefly in the broader IGD/MCAHS spectrum): gastrointestinal tract, heart, and kidney. Lateralization: brain involvement is bilateral and symmetric (e.g., symmetric restricted diffusion of central tegmental tracts in the IGD group).
Onset: neonatal to early infancy (seizures typically within the first weeks–months; median ~6 months in IGDs). Onset pattern: early and progressive within infancy. Course: chronic, lifelong, with refractory epilepsy and static-to-slowly-progressive encephalopathy; imaging often shows progressive atrophy. Critical period: the prenatal/early-infantile window is both the period of greatest vulnerability (malformation, lethality at the severe end) and the practical window for any future intervention. Remission: seizures are characteristically refractory; sustained remission is uncommon.
Inheritance: autosomal recessive. Penetrance: effectively complete for biallelic hypomorphic genotypes, with highly variable expressivity (prenatal-lethal ↔ MCAHS ↔ classic DEE). Epidemiology: ultra-rare — only ~7 patients reported by 2023; prevalence/incidence not formally estimated. Carrier frequency: the recurrent c.456delA allele is present at ≈9 heterozygotes / 0 homozygotes in gnomAD, indicating a very low carrier frequency. Founder effects/geography: none established; reported families are geographically dispersed (including Polish ancestry in Krenn 2019). Sex ratio: no sex bias expected or reported (autosomal). Consanguinity: relevant for AR disorders generally, though homozygosity has also arisen between unrelated parents by chance.
See Findings 6–7. First-line: trio whole-exome (WES) or whole-genome sequencing (WGS); WGS/CMA also captures the whole-gene deletion. Caveat: targeted epilepsy gene panels may omit PIGP and yield false negatives. Functional confirmation: flow cytometry for reduced surface GPI-anchored proteins (FLAER, CD16, CD24, CD55, CD59) on granulocytes/lymphocytes. Biomarker: serum alkaline phosphatase may be checked, but hyperphosphatasia is typically absent in PIGP (early-pathway defect), distinguishing it from late-pathway IGDs like Mabry syndrome. Imaging: brain MRI (cerebral/cerebellar atrophy, thin corpus callosum, white-matter change, symmetric tegmental-tract diffusion changes). EEG: epileptiform/encephalopathic patterns. Differential diagnosis: other IGDs (PIGA, PIGQ, PIGY, PIGN, PIGT, PIGO, PIGV, PIGB, PIGL) and other genetic DEEs.
See Finding 9. Severe: profound lifelong disability; substantial mortality (≈18% across IGDs; death in childhood possible in DEE55; prenatal lethality at the severe end). Prognostic factors relate to the residual GPI-biosynthetic activity of the allele combination — more severe (near-null) genotypes trend toward malformation and early death. Quality-of-life outcomes are poor (non-verbal, non-ambulatory, feeding-tube dependent).
See Finding 8. Pharmacotherapy: antiseizure medications (empirically chosen; the epilepsy is often refractory) — NCIT concept "Anticonvulsant Agent." Nutritional/metabolic: empiric pyridoxine (vitamin B6) (given the pyridoxine-responsive differentials in early epileptic encephalopathy) and the ketogenic diet. Supportive/rehabilitative: feeding support (gastrostomy), physical/occupational/speech therapy, management of spasticity and dyskinesia, vision support for cortical visual impairment. Advanced/experimental: no gene, cell, or RNA therapy exists; no PIGP-specific clinical trials identified. Care is coordinated by pediatric neurology and metabolic genetics.
No primary prevention exists for this monogenic disorder. Genetic counseling is central: 25% recurrence risk per pregnancy for carrier couples. Carrier and cascade testing, prenatal diagnosis, and preimplantation genetic testing (PGT-M) are available once the familial variants are known. No population newborn-screening test currently detects PIGP deficiency.
No naturally occurring animal disease specific to PIGP has been catalogued (no OMIA entry noted). PIGP is evolutionarily conserved; orthologs exist across mammals (mouse Pigp) and the GPI pathway is conserved throughout eukaryotes (yeast, trypanosomes). The GPI pathway's conservation is illustrated by the trypanosome GPI-biosynthesis literature (PMID: 19724691), though that work concerns parasite biology rather than a PIGP-disease model. Neuronal GPI-anchored proteins (e.g., Thy-1, CD24) show developmentally regulated expression in the mouse CNS (PMID: 10813783; PMID: 8783272), supporting the biological plausibility that GPI-anchor deficiency disrupts neurodevelopment — but these are not disease models of PIGP deficiency per se.
No published PIGP-specific animal model (knockout/knock-in) recapitulating DEE55 was identified in this investigation. Relevant to interpretation: complete GPI deficiency is embryonic-lethal in mammals (Murakami & Kinoshita 2015, PMID 25803904), which constrains constitutive-knockout modeling and argues for hypomorphic or conditional (e.g., neuron-specific) models to study the disease. Patient-derived cells (fibroblasts/lymphocytes) with a flow-cytometric GPI-AP readout serve as the principal functional in-vitro system, and wild-type-PIGP rescue in patient cells (PMID 28334793) is the validated cellular assay. Patient-derived iPSC-neurons and organoids are logical future models but were not reported.
Biallelic hypomorphic PIGP variants
(missense p.Met25Thr / frameshift p.Glu153Asnfs*34 /
start-loss p.? / 136-kb whole-gene deletion)
│ (reduced PIGP mRNA & protein — demonstrated)
▼
Impaired ER GPI-GlcNAc transferase complex
(PIGA–PIGC–PIGH–PIGP–PIGQ–PIGY–DPM2)
│ ↓ committed 1st step: PI + UDP-GlcNAc → GlcNAc-PI
▼
Reduced GPI-anchor biosynthesis (partial, never complete —
complete deficiency = embryonic lethal)
│
▼
↓ Cell-surface expression of ≥150 GPI-anchored proteins
(rescued by WT PIGP — demonstrated by flow cytometry)
│
┌───────────┼─────────────────────────┐
▼ ▼ ▼
Epileptogenesis Impaired brain Impaired embryonic
→ refractory growth/maturation morphogenesis
early-onset → DD/ID, absent → congenital anomalies,
seizures speech, spasticity, MCAHS, prenatal
cerebral/cerebellar lethality (severe end)
atrophy, thin CC
The unifying interpretation is a dosage/threshold model: DEE55 severity is set by the residual GPI-biosynthetic output of a patient's specific two-allele combination. Above the embryonic-lethal threshold but well below normal, the surface-protein deficit compromises neuronal migration, connectivity, and excitability — yielding the DEE triad. As residual activity falls toward the lethal threshold, the phenotype broadens to congenital malformation (MCAHS) and, at the extreme, fetal loss. This single axis parsimoniously accounts for the striking intra-gene phenotypic variability documented across the ~7–9 reported patients.
| PMID | Study | Type | Contribution |
|---|---|---|---|
| 28334793 | Johnstone et al. 2017 | Human case report + in-vitro functional | Defining paper: biallelic PIGP variants; reduced mRNA & surface GPI-APs; WT rescue; AR IGD. Supports Findings 1, 2, 4, 6. |
| 31139695 | Krenn et al. 2019 | Human case report + flow cytometry | Second family; homozygous recurrent c.456delA; gnomAD rarity; panel miss; functional confirmation. Supports Finding 6. |
| 37125481 | Martín-Grau et al. 2023 | Human case report | Phenotype expansion to MCAHS & prenatal lethality; 136-kb deletion; "only 7 patients"; seven-gene complex context. Supports Findings 3, 5, 7, 10. |
| 38456468 | Sidpra et al. 2024 | Human cohort (n=83, IGDs) | Frequencies of DD/ID, seizures, hypotonia; seizure onset; imaging; mortality; multisystem involvement. Supports Findings 2, 9. |
| 25803904 | Murakami & Kinoshita 2015 | Review | Partial-deficiency principle (complete = embryonic lethal); flow cytometry & hyperphosphatasia as diagnostics. Supports Findings 4, 7. |
| 32156170 | Kinoshita 2020 | Review | ≥150 human GPI-APs; GPI-AP biology. Supports Finding 4. |
| 39129667 | Kinoshita 2024 | Review | ≥160 GPI-APs; updated biosynthesis mechanism. Supports Finding 4. |
| 31353022 | Knaus et al. 2019 | Human + flow cytometry | Multicolor flow-cytometry profiling distinguishes GPI-biosynthesis defects. Supports Finding 7. |
| 35562242 | Boyer, Johnsen & Morava 2022 | Review | Nutritional therapy in CDG incl. GPI-anchor disorders (pyridoxine, diet). Supports Finding 8. |
| 10813783, 8783272 | Thy-1 / CD24 expression studies | Model organism (mouse) | Developmental expression of neuronal GPI-APs — biological plausibility for neurodevelopmental impact. Contextual support for mechanism. |
Note on non-relevant hits: Several PubMed results referencing "PigP" concern the Serratia marcescens pigment/quorum-sensing regulator PigP — an unrelated bacterial gene — and were excluded from disease inference.
Report compiled from a five-iteration autonomous investigation: 10 confirmed findings across 27 reviewed papers. Evidence types are human clinical (case reports, cohort), in-vitro functional (patient-cell flow cytometry, WT-rescue), and review/computational. All mechanistic and clinical claims are cited to primary literature by PMID with verbatim supporting quotes drawn from the underlying knowledge state.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 12 |
| Resolved | 12 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 12 |
| On topic | 7 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 26 |
| Resolved | 23 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 3 |
| Terms whose name was checked | 3 |
| Terms named correctly | 3 |
| Terms named as a different term | 0 |
Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM.
23 of 26 terms resolved to a current term; the rest could not be looked up either way.