Glycosylphosphatidylinositol Biosynthesis Defect 15

Mendelian MONDO:0060627 Pathograph 27 Show in embeddings browser Disorder of GPI Anchor Biosynthesis Congenital Disorder of Glycosylation Inborn Error of Metabolism Epilepsy

Glycosylphosphatidylinositol biosynthesis defect 15 (GPIBD15) is an autosomal recessive inherited GPI deficiency caused by biallelic variants in GPAA1. GPAA1 is one of five subunits of the GPI transamidase complex (with PIGK, PIGS, PIGT and PIGU), which in the endoplasmic reticulum cleaves the C-terminal attachment signal of precursor proteins and joins the completed GPI anchor to the new C terminus. When the complex fails, precursor proteins are not anchored and the surface density of the whole GPI-anchored protein class falls: reduced FLAER, CD16 and CD59 on leukocytes and reduced CD73 and CD109 on fibroblasts were shown in the founding report, and re-expressing wild-type GPAA1 partly restored them. No patient carries two null alleles, which suggests some residual GPAA1 function is needed for survival. The clinical picture is global developmental delay and hypotonia in essentially every patient, early-onset and often drug-resistant epilepsy (most often generalized tonic-clonic and myoclonic seizures, frequently fever-sensitive), cerebellar atrophy that appears to be acquired rather than congenital, cerebellar signs such as ataxia, nystagmus, dysarthria and dysmetria, and osteopenia. Unlike the late-pathway GPI defects, serum alkaline phosphatase is normal or low, not raised. About two dozen patients have been published, the oldest followed into adulthood.

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1
Inheritance
6
Pathophys.
20
Phenotypes
2
Hypotheses
2
Gaps
27
Pathograph
1
Genes
4
Medical Actions
1
Deep Research
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Classifications

ICIMD (Inherited Metabolic Disorders)
lipid glycosylation
👪

Inheritance

1
Autosomal recessive HP:0000007
Reported patients are compound heterozygous or homozygous for GPAA1 variants. A heterozygous carrier father had normal leukocyte GPI-anchored protein expression.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:37510348 SUPPORT Human Clinical
"Glycosylphosphatidylinositol biosynthesis defect 15 is a rare autosomal recessive disorder due to biallelic loss of function of GPAA1."
States the recessive inheritance and biallelic basis directly.
PMID:34703884 SUPPORT Human Clinical
"The father of an affected parent, who carries a frameshift variant in GPAA1, did not have abnormalities on flow cytometry"
A heterozygous carrier has normal GPI-anchored protein expression, consistent with recessive inheritance.
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Mechanistic Hypotheses

2
Canonical GPI Transamidase Deficiency Model
canonical_gpi_transamidase_deficiency_model CANONICAL
Biallelic hypomorphic GPAA1 variants lower GPI transamidase activity, so fewer proteins receive a GPI anchor and the surface density of the GPI-anchored protein class falls. Because that class is important in neural and cerebellar development, the result is developmental delay, epilepsy and cerebellar atrophy. Supported by reduced GPI-anchored proteins on patient leukocytes and fibroblasts and by partial rescue with wild-type GPAA1.
Osteoblast Alkaline Phosphatase Hypothesis for Osteopenia
osteoblast_alkaline_phosphatase_hypothesis EMERGING
Reduced GPI-anchored alkaline phosphatase on the osteoblast surface lowers bone formation and so bone mineral density. Proposed by analogy across GPI deficiencies; not measured in GPAA1 patients, and confounded by epilepsy, antiseizure drugs and immobility.
Pathograph links
Reduced Cell-Surface GPI-Anchored Proteins -> Impaired Osteoblast Bone Formation INDIRECT UNKNOWN INTERMEDIATES
Impaired Osteoblast Bone Formation -> Osteopenia
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Discussions and Knowledge Gaps

2
How does partial loss of GPAA1 produce acquired cerebellar atrophy, given that no mammalian GPAA1 model has been described?
KNOWLEDGE GAP gpaa1_no_mammalian_model
Attached to
pathophysiology#Acquired Cerebellar Degeneration
The cerebellar mechanism currently rests on patient imaging and on background work with reduced transamidase activity in general. The only GPAA1-deficient animal reported is a zebrafish made to study vascular anomalies, whose neurological phenotype was not described. A hypomorphic mammalian model would test whether the atrophy is Purkinje-cell loss and when it begins.
Which GPI-anchored proteins, or which combination, mediate the epilepsy and developmental impairment in GPAA1 deficiency?
KNOWLEDGE GAP gpaa1_which_gpi_anchored_protein
Attached to
pathophysiology#Reduced Cell-Surface GPI-Anchored Proteins pathophysiology#Impaired Neural GPI-Anchored Protein Function
The chain from reduced GPI anchoring to epilepsy is a class-level argument. No study has identified the responsible proteins, so the edge into the neural node has unknown intermediates and no protein-specific treatment target can be named.
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Pathophysiology

6
Biallelic Hypomorphic GPAA1 Variants
Biallelic GPAA1 variants. The founding cohort carried two frameshift alleles, one intronic splice-region allele that lowered GPAA1 mRNA, and six missense alleles; the pooled 2026 review counts 28 variants, mostly missense, with frameshift, splicing and one nonsense allele. No patient has two null alleles, so the disease state is read as partial rather than complete loss of GPAA1 function. GPAA1 is a non-catalytic subunit, so the activity it loses is that of the whole transamidase complex.
GPAA1 hgnc:4446 ↓ DECREASED HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased GPAA1 (hgnc:4446). hgnc:4446 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE allelic_event: MISSENSE_VARIANT allelic_event: FRAMESHIFT_VARIANT allelic_event: SPLICE_SITE_VARIANT allelic_event: NONSENSE_VARIANT functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Germline biallelic GPAA1 alleles; both compound heterozygous and homozygous patients are reported, so zygosity is left unset. At least one allele in every reported patient is a missense or splice allele.
GPI-anchor transamidase activity GO:0003923 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased GPI-anchor transamidase activity (GO:0003923). GO:0003923 is a molecular function from the Gene Ontology.
Downstream
Impaired GPI Anchor Attachment to Precursor Proteins
Show evidence (4 references)
PMID:29100095 SUPPORT Human Clinical
"Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families."
Founding report establishing biallelic GPAA1 variants as the cause.
PMID:29100095 SUPPORT In Vitro
"The splicing mutation was found to decrease GPAA1 mRNA."
Shows a loss-of-expression effect for one of the founding alleles.
PMID:42001530 SUPPORT Human Clinical
"When combining data from this study and published studies, 28 variants were identified, including 19 missense variants, 5 frameshift variants, 3 intronic splicing variants, and one nonsense variant."
Gives the allelic spectrum across all published patients.
+ 1 more reference
Impaired GPI Anchor Attachment to Precursor Proteins
The GPI transamidase complex in the endoplasmic reticulum cleaves the C-terminal GPI attachment signal of precursor proteins and transfers the GPI anchor to the new C terminus. PIGK carries the catalytic residues; structural work indicates GPAA1 is not itself catalytic but is required for the complex to work.
attachment of GPI anchor to protein GO:0016255 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased attachment of GPI anchor to protein (GO:0016255). GO:0016255 is a biological process from the Gene Ontology.
Downstream
Reduced Cell-Surface GPI-Anchored Proteins
Show evidence (3 references)
PMID:29100095 SUPPORT BACKGROUND Other
"This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum."
Defines the step GPAA1 participates in.
PMID:38963495 SUPPORT REVIEW SYNTHESIS In Vitro
"While the structural data confirm the catalytic role of PIGK, which likely uses a caspase-like mechanism to cleave the proproteins, they suggest that unlike previously proposed, GPAA1 is not a catalytic subunit."
Clarifies GPAA1's role in the complex; supports describing it as essential but non-catalytic.
PMID:38963495 SUPPORT REVIEW SYNTHESIS In Vitro
"Consistent with the assembly mechanisms and the active site architecture, most of the disease mutations occur near the active site or the subunit interfaces."
Places disease variants where they would be expected to impair assembly or catalysis of the complex.
Reduced Cell-Surface GPI-Anchored Proteins
Precursor proteins that are not anchored do not reach the cell surface as GPI-anchored proteins, so the surface density of the whole class falls. Patient leukocytes showed reduced FLAER (total GPI-anchored proteins), CD16 and CD59; patient fibroblasts showed reduced CD73 and CD109. Lentiviral re-expression of wild-type GPAA1 partly rescued the fibroblast deficit. With over 150 GPI-anchored proteins, no single one has been shown to account for any clinical feature.
Osteoblast Alkaline Phosphatase Hypothesis for Osteopenia
granulocyte CL:0000094 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulocyte (CL:0000094). CL:0000094 is a cell type from the Cell Ontology. fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
Downstream
Impaired Neural GPI-Anchored Protein Function
Acquired Cerebellar Degeneration
Impaired Osteoblast Bone Formation Osteoblast Alkaline Phosphatase Hypothesis for Osteopenia
Show evidence (3 references)
PMID:29100095 SUPPORT Human Clinical
"flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109)"
Direct measurement of reduced surface GPI-anchored proteins in patient cells.
PMID:29100095 SUPPORT In Vitro
"Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins."
Rescue experiment tying the surface deficit to GPAA1 loss.
PMID:34703884 SUPPORT Human Clinical
"However, flow cytometry assays support the pathogenicity of the variants by demonstrating reduction in CD16 in granulocytes."
Independent cohort confirming reduced granulocyte CD16.
Impaired Neural GPI-Anchored Protein Function
GPI-anchored proteins in the nervous system take part in axon growth, regeneration, synapse formation and synaptic plasticity. Their reduction is the proposed route to the developmental delay, hypotonia and epilepsy, but no study has attributed these features to a particular GPI-anchored protein in GPAA1 deficiency.
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
Global developmental delay
Intellectual disability
Hypotonia
Spasticity
Seizure
Bilateral tonic-clonic seizure with generalized onset
Myoclonic seizure
Seizure precipitated by febrile infection
Generalized non-motor (absence) seizure
Epileptic spasm
Delayed myelination
Thin corpus callosum
Show evidence (1 reference)
PMID:34703884 SUPPORT INDIRECT BACKGROUND Other
"In the nervous system, GPI-APs play an vital role in axon growth, axon regeneration, synapse formation, and synaptic plasticity."
Background statement of neural GPI-anchored protein functions. It is a general claim, not a measurement in GPAA1-deficient neurons, so the link to this disorder is indirect.
Acquired Cerebellar Degeneration
Cerebellar atrophy, often with vermian involvement, that appears to develop after birth: a patient with a normal cerebellum at 15 months had atrophy at 33 months, and another had atrophy on follow-up imaging at age 2 years that was not reported initially. Its absence on an early scan therefore does not exclude the diagnosis. In the oldest patient the atrophy was stable between ages 21 and 29.
cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellum (UBERON:0002037). UBERON:0002037 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cerebellar atrophy
Ataxia
Nystagmus
Dysarthria
Dysmetria
Show evidence (5 references)
PMID:37510348 SUPPORT Human Clinical
"When he was 15 months, the cerebellum was normal. When he was 33 months old, after the molecular diagnosis, magnetic resonance imaging was repeated, showing cerebellar atrophy."
Serial imaging documenting acquired cerebellar atrophy.
PMID:34703884 SUPPORT Human Clinical
"Acquired, rather than congenital, cerebellar abnormalities may prove to be a common feature of the disorder, not yet fully appreciated as most children have MRI scans after onset of clinical manifestations caused by the presence of cerebellar atrophy."
Authors' interpretation that the cerebellar lesion is acquired.
PMID:34703884 SUPPORT Human Clinical
"The second patient did not have neuroimaging until age 21 years; this demonstrated cerebellar atrophy, which has been stable on repeat imaging at ages 25 and 29 years."
Shows the atrophy need not progress in adulthood.
+ 2 more references
Impaired Osteoblast Bone Formation
Hypothesized mechanism for osteopenia: reduced surface alkaline phosphatase on osteoblasts lowers bone formation. This is the authors' hypothesis, not a measured result, and epilepsy, antiseizure drugs and reduced mobility independently lower bone density in these patients.
Osteoblast Alkaline Phosphatase Hypothesis for Osteopenia
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
Downstream
Osteopenia Osteoblast Alkaline Phosphatase Hypothesis for Osteopenia
Show evidence (1 reference)
PMID:34703884 SUPPORT INDIRECT BACKGROUND Other
"Osteopenia and osteoporosis are hypothesized to be secondary to decreased alkaline phosphatase (ALP) expression on the surface of osteoblasts, impairing their function and leading to decreased bone formation and therefore bone mineral density."
States the mechanism as a hypothesis; recorded as indirect support only.
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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 Glycosylphosphatidylinositol Biosynthesis Defect 15 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

20
Eye 1
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"Associated features included nystagmus in 2 patients, dysarthria in 1 patient (not assessed in 4 patients given their age or language capacity), dysmetria in 1 patient, and ataxia in 3 patients."
Nystagmus in two of seven patients.
Head and Neck 2
Prominent forehead HP:0011220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent forehead (HP:0011220). HP:0011220 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"Variable dysmorphic features were described, with common descriptions including prominent forehead and a tented upper lip."
Names the most common facial findings.
Tented upper lip vermilion HP:0010804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tented upper lip, annotated with Tented upper lip vermilion (HP:0010804). HP:0010804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"Variable dysmorphic features were described, with common descriptions including prominent forehead and a tented upper lip."
Names the most common facial findings.
Musculoskeletal 3
Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42001530 SUPPORT Human Clinical
"The clinical manifestations included global developmental delay (100%), hypotonia (95.8%), and epilepsy (83.3%)."
Pooled frequency of hypotonia.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"Six of 7 patients were described as hypotonic and 2 demonstrated spasticity."
Spasticity in two of seven patients.
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29100095 SUPPORT Human Clinical
"Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia."
Osteopenia in the founding cohort.
PMID:34703884 SUPPORT Human Clinical
"Osteopenia was a universal finding in the first cohort of patients identified by Nguyen et al. in 2017."
States that every founding-cohort patient had osteopenia.
PMID:34703884 SUPPORT Human Clinical
"Only 2 patients in this series have been assessed with dual-energy X-ray absorptiometry scans, with osteopenia present in 1."
Shows how sparsely bone density has been measured outside the founding cohort.
Nervous System 14
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 (2 references)
PMID:42001530 SUPPORT Human Clinical
"The clinical manifestations included global developmental delay (100%), hypotonia (95.8%), and epilepsy (83.3%)."
Pooled frequency of developmental delay across 24 patients.
PMID:29100095 SUPPORT Human Clinical
"Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia."
Founding cohort.
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:37510348 SUPPORT Human Clinical
"The main clinical features are intellectual disability, hypotonia, seizures, and cerebellar atrophy."
Lists intellectual disability among the main features.
Seizure 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 (2 references)
PMID:42001530 SUPPORT Human Clinical
"The clinical manifestations included global developmental delay (100%), hypotonia (95.8%), and epilepsy (83.3%). 60% of patients experienced seizure onset before the age of one."
Pooled frequency and age at onset of epilepsy.
PMID:42001530 SUPPORT Human Clinical
"All patients had drug-resistant epilepsy."
Drug resistance in the five newly reported patients.
Bilateral tonic-clonic seizure with generalized onset VERY_FREQUENT HP:0025190 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized tonic-clonic seizure, annotated with Bilateral tonic-clonic seizure with generalized onset (HP:0025190). HP:0025190 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42001530 SUPPORT Human Clinical
"The main seizure types were generalized tonic-clonic seizures (GTCS) (82.4%) and myoclonic seizures (70.6%)."
Pooled frequency of GTCS; the denominator (patients with seizure-type data) is not stated in the abstract.
Myoclonic seizure FREQUENT HP:0032794 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonic seizure (HP:0032794). HP:0032794 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42001530 SUPPORT Human Clinical
"The main seizure types were generalized tonic-clonic seizures (GTCS) (82.4%) and myoclonic seizures (70.6%)."
Pooled frequency of myoclonic seizures; denominator not stated in the abstract.
Seizure precipitated by febrile infection FREQUENT HP:0032894 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever-sensitive seizures, annotated with Seizure precipitated by febrile infection (HP:0032894). HP:0032894 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42001530 SUPPORT Human Clinical
"Febrile sensitivity was presented in 66.7% of patients."
Pooled frequency of fever sensitivity.
PMID:34703884 SUPPORT Human Clinical
"Numerous seizure types were observed, with 4 patients experiencing febrile seizures, 2 patients with absence seizures, 3 patients with bilateral tonic-clonic seizures, 2 patients with myoclonic jerks, and 1 patient experiencing epileptic spasms."
Febrile seizures in four of seven patients in an independent cohort.
Cerebellar atrophy FREQUENT HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42001530 SUPPORT Human Clinical
"60.9% of patients had cerebellar atrophy."
Pooled frequency of cerebellar atrophy.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"Associated features included nystagmus in 2 patients, dysarthria in 1 patient (not assessed in 4 patients given their age or language capacity), dysmetria in 1 patient, and ataxia in 3 patients."
Ataxia in three of seven patients.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"Associated features included nystagmus in 2 patients, dysarthria in 1 patient (not assessed in 4 patients given their age or language capacity), dysmetria in 1 patient, and ataxia in 3 patients."
Dysarthria in one patient; most were too young or nonverbal to assess.
Dysmetria HP:0001310 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysmetria (HP:0001310). HP:0001310 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"Associated features included nystagmus in 2 patients, dysarthria in 1 patient (not assessed in 4 patients given their age or language capacity), dysmetria in 1 patient, and ataxia in 3 patients."
Dysmetria in one patient.
Delayed myelination OCCASIONAL HP:0012448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed myelination (HP:0012448). HP:0012448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"In 2 of these individuals, additional abnormalities were noted, including slightly delayed myelination and mild thinning or hypoplasia of the corpus callosum."
Delayed myelination in two of seven patients.
Thin corpus callosum OCCASIONAL HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin or hypoplastic corpus callosum, annotated with Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"In 2 of these individuals, additional abnormalities were noted, including slightly delayed myelination and mild thinning or hypoplasia of the corpus callosum."
Thin or hypoplastic corpus callosum in two of seven patients.
Generalized non-motor (absence) seizure OCCASIONAL HP:0002121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absence seizure, annotated with Generalized non-motor (absence) seizure (HP:0002121). HP:0002121 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"Numerous seizure types were observed, with 4 patients experiencing febrile seizures, 2 patients with absence seizures, 3 patients with bilateral tonic-clonic seizures, 2 patients with myoclonic jerks, and 1 patient experiencing epileptic spasms."
Absence seizures in two of seven patients.
Epileptic spasm HP:0011097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic spasms, annotated with Epileptic spasm (HP:0011097). HP:0011097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"Numerous seizure types were observed, with 4 patients experiencing febrile seizures, 2 patients with absence seizures, 3 patients with bilateral tonic-clonic seizures, 2 patients with myoclonic jerks, and 1 patient experiencing epileptic spasms."
Epileptic spasms in one of seven patients.
🧬

Genetic Associations

1
GPAA1
Gene: GPAA1 hgnc:4446 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GPAA1 (hgnc:4446). hgnc:4446 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:29100095 SUPPORT Human Clinical
"Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families."
Founding gene-disease report.
PMID:34703884 SUPPORT Human Clinical
"Ten novel variants were identified in 7 patients."
Independent replication in a second cohort.
💊

Medical Actions

4
Antiseizure Medication
Action: anticonvulsant therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticonvulsant therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticonvulsant Therapy NCIT:C64172
Platform: Small molecule
Symptomatic seizure control is the main treatment and is often unsuccessful. No anticonvulsant has been shown to work better than another in GPAA1 deficiency.
Mechanism Target:
MODULATES Seizure — Symptomatic; does not address the GPI anchoring defect.
Show evidence (2 references)
PMID:34703884 SUPPORT Human Clinical
"At present, treatments for GPI-related disorders are limited and primarily focused on seizure control."
Establishes seizure control as the main treatment.
PMID:42001530 SUPPORT Human Clinical
"All patients had drug-resistant epilepsy."
Shows the limits of antiseizure medication in this disorder.
Pyridoxine Supplementation
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.
Platform: Small molecule
Used by three of seven patients in one series. Pyridoxine has helped seizures in the hyperphosphatasia GPI disorders, but in this series it was not felt to have contributed significantly to seizure control.
Show evidence (2 references)
PMID:34703884 SUPPORT Human Clinical
"Three of 7 patients in this report are using B6 as a part of their treatment regimen for seizure control."
Documents use of pyridoxine in GPAA1 deficiency.
PMID:34703884 REFUTE Human Clinical
"B6 is not felt to have contributed significantly to seizure control."
The same series did not find a clear benefit, so the treatment is recorded without a claim of efficacy.
Ketogenic Diet
Action: ketogenic dietNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is ketogenic diet (NCIT:C173168). NCIT:C173168 is a clinical intervention from the NCI Thesaurus. Ontology label: Ketogenic Diet NCIT:C173168
Platform: Behavioral / lifestyle
Two patients in one series were managed with the ketogenic diet, and at least one had a partial but significant reduction in seizure frequency.
Mechanism Target:
MODULATES Seizure — Symptomatic seizure reduction.
Show evidence (2 references)
PMID:34703884 SUPPORT Human Clinical
"Two patients in this cohort are currently or were previously managed on the ketogenic diet."
Documents use of the ketogenic diet in GPAA1 deficiency.
PMID:34703884 SUPPORT Human Clinical
"In at least one of the patients, a partial but significant reduction in seizure frequency was observed."
Reports a partial response in a patient on the ketogenic diet.
Bone Health Monitoring
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. NCIT:C15747
Bone density should be monitored because osteopenia is reported and epilepsy, antiseizure medication and immobility add fracture risk.
Show evidence (1 reference)
PMID:34703884 SUPPORT Human Clinical
"Given the independent association of osteopenia and osteoporosis with epilepsy, antiepileptic use, and decreased mobility, one may anticipate patients with GPAA1 deficiency are at risk of fractures, and bone health should be promoted and monitored."
Recommends bone-health monitoring in GPAA1 deficiency.
🔬

Biochemical Markers

1
Serum alkaline phosphatase (Normal or decreased)
Show evidence (2 references)
PMID:34703884 SUPPORT Human Clinical
"Alkaline phosphatase was within the normal range in 5 individuals and low in 1 individual, as has been noted in other transamidase defects."
Alkaline phosphatase results in the cohort.
PMID:34703884 SUPPORT Human Clinical
"None of the patients described in the literature with pathogenic variants in GPI-transamidase complex genes have elevated ALP."
Generalizes the absence of hyperphosphatasia to transamidase defects.
🔬

Diagnosis

2
Flow cytometry for GPI-anchored protein surface expression
CD16 on granulocytes is the most consistently reduced marker. FLAER and CD59 on leukocytes, and CD73 and CD109 on fibroblasts, were reduced in the founding cohort, but in a later series CD55, CD59 and FLAER were only slightly reduced or unchanged. There is no GPAA1-specific profile; the assay supports the pathogenicity of variants found by sequencing.
flow cytometry NCIT:C16585 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:34703884 SUPPORT Human Clinical
"GPAA1 deficiency does not demonstrate a characteristic pattern; however, measuring GPI-APs through flow cytometry remains a mechanism by which functional consequences of GPAA1 variants can be investigated."
States both the use and the limit of the assay.
PMID:34703884 SUPPORT Human Clinical
"CD55, CD59, and total GPI-AP levels in these individuals showed slightly decreased or no change in the levels compared with healthy controls."
Shows that markers other than CD16 may be normal.
Exome sequencing
The founding patients were diagnosed by exome sequencing; the phenotype is not specific enough among inherited GPI deficiencies to suggest GPAA1 without it.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29100095 SUPPORT Human Clinical
"Using whole-exome sequencing, we identified two frameshift mutations"
Diagnostic method used in the founding cohort.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Ultra Rare
Fewer than twenty patients by 2023; 24 in the 2026 pooled review (five new and nineteen previously published).
Show evidence (2 references)
PMID:37510348 SUPPORT Human Clinical
"At the moment, less than twenty patients have been reported, usually compound heterozygous for GPAA1 variants."
Gives the published case count as of 2023.
PMID:42001530 SUPPORT Human Clinical
"Clinical data of five patients with GPAA1 variants from our study and 19 patients from published studies were collected and analyzed."
Gives the pooled published case count as of 2026.
{ }

Source YAML

click to show 
name: Glycosylphosphatidylinositol Biosynthesis Defect 15
creation_date: "2026-10-14T16:00:00Z"
category: Mendelian
synonyms:
- GPIBD15
- GPAA1 deficiency
- GPAA1-related GPI deficiency
disease_term:
  preferred_term: glycosylphosphatidylinositol biosynthesis defect 15
  term:
    id: MONDO:0060627
    label: glycosylphosphatidylinositol biosynthesis defect 15
parents:
- Disorder of GPI Anchor Biosynthesis
- Congenital Disorder of Glycosylation
- Inborn Error of Metabolism
- Epilepsy
description: >-
  Glycosylphosphatidylinositol biosynthesis defect 15 (GPIBD15) is an
  autosomal recessive inherited GPI deficiency caused by biallelic variants in
  GPAA1. GPAA1 is one of five subunits of the GPI transamidase complex (with
  PIGK, PIGS, PIGT and PIGU), which in the endoplasmic reticulum cleaves the
  C-terminal attachment signal of precursor proteins and joins the completed
  GPI anchor to the new C terminus. When the complex fails, precursor proteins
  are not anchored and the surface density of the whole GPI-anchored protein
  class falls: reduced FLAER, CD16 and CD59 on leukocytes and reduced CD73 and
  CD109 on fibroblasts were shown in the founding report, and re-expressing
  wild-type GPAA1 partly restored them. No patient carries two null alleles,
  which suggests some residual GPAA1 function is needed for survival. The
  clinical picture is global developmental delay and hypotonia in essentially
  every patient, early-onset and often drug-resistant epilepsy (most often
  generalized tonic-clonic and myoclonic seizures, frequently fever-sensitive),
  cerebellar atrophy that appears to be acquired rather than congenital,
  cerebellar signs such as ataxia, nystagmus, dysarthria and dysmetria, and
  osteopenia. Unlike the late-pathway GPI defects, serum alkaline phosphatase
  is normal or low, not raised. About two dozen patients have been published,
  the oldest followed into adulthood.
notes: >-
  Case counts, not cohort frequencies. The founding report (Nguyen et al. 2017)
  described ten individuals from five families; Castle et al. 2021 added seven;
  a 2026 Seizure review pooled five new and nineteen published patients. The
  frequencies for developmental delay, hypotonia and epilepsy are over all 24;
  the seizure-type, fever-sensitivity and cerebellar-atrophy percentages are
  over the subset with data, whose size the abstract does not state. All
  carry the uncertainty of a series this small.

  Two reports are deliberately kept out of the phenotype list. A single Chinese
  patient with GPIBD15 also had periodic fever with raised inflammatory markers
  that responded to glucocorticoids (PMID:38112147); one case does not
  establish the fever as part of the disease. Separately, a heterozygous GPAA1
  missense variant (c.968A>G) segregated with familial vascular anomalies in
  one large pedigree (PMID:32533362). That is a dominant, vascular claim about
  a single family, not the recessive neurodevelopmental disorder curated here,
  and it is not merged into this entry.

  No GeneReviews chapter covers GPAA1 or the inherited GPI deficiencies as a
  group.
classifications:
  icimd_category:
  - classification_value: lipid_glycosylation
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416) group "Disorders of lipid
      glycosylation", which the classification scopes to include
      glycosylphosphatidylinositol biosynthesis. GPAA1 acts at the transamidase
      step that attaches the completed anchor to protein.
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 homozygous for GPAA1
    variants. A heterozygous carrier father had normal leukocyte GPI-anchored
    protein expression.
  evidence:
  - reference: PMID:37510348
    reference_title: "A Novel Homozygous GPAA1 Variant in a Patient with a Glycosylphosphatidylinositol Biosynthesis Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glycosylphosphatidylinositol biosynthesis defect 15 is a rare autosomal recessive disorder due to biallelic loss of function of GPAA1."
    explanation: States the recessive inheritance and biallelic basis directly.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The father of an affected parent, who carries a frameshift variant in GPAA1, did not have abnormalities on flow cytometry"
    explanation: A heterozygous carrier has normal GPI-anchored protein expression, consistent with recessive inheritance.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than twenty patients by 2023; 24 in the 2026 pooled review (five
    new and nineteen previously published).
  evidence:
  - reference: PMID:37510348
    reference_title: "A Novel Homozygous GPAA1 Variant in a Patient with a Glycosylphosphatidylinositol Biosynthesis Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the moment, less than twenty patients have been reported, usually compound heterozygous for GPAA1 variants."
    explanation: Gives the published case count as of 2023.
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical data of five patients with GPAA1 variants from our study and 19 patients from published studies were collected and analyzed."
    explanation: Gives the pooled published case count as of 2026.
pathophysiology:
- name: Biallelic Hypomorphic GPAA1 Variants
  biological_scale: MOLECULAR
  description: >-
    Biallelic GPAA1 variants. The founding cohort carried two frameshift
    alleles, one intronic splice-region allele that lowered GPAA1 mRNA, and
    six missense alleles; the pooled 2026 review counts 28 variants, mostly
    missense, with frameshift, splicing and one nonsense allele. No patient
    has two null alleles, so the disease state is read as partial rather than
    complete loss of GPAA1 function. GPAA1 is a non-catalytic subunit, so the
    activity it loses is that of the whole transamidase complex.
  molecular_functions:
  - preferred_term: GPI-anchor transamidase activity
    modifier: DECREASED
    term:
      id: GO:0003923
      label: GPI-anchor transamidase activity
  genes:
  - preferred_term: GPAA1
    term:
      id: hgnc:4446
      label: GPAA1
    modifier: DECREASED
  genetic_context:
    description: >-
      Germline biallelic GPAA1 alleles; both compound heterozygous and
      homozygous patients are reported, so zygosity is left unset. At least
      one allele in every reported patient is a missense or splice allele.
    allelic_events:
    - MISSENSE_VARIANT
    - FRAMESHIFT_VARIANT
    - SPLICE_SITE_VARIANT
    - NONSENSE_VARIANT
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  downstream:
  - target: Impaired GPI Anchor Attachment to Precursor Proteins
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34576938
      reference_title: "Functional Analysis of the GPI Transamidase Complex by Screening for Amino Acid Mutations in Each Subunit."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "GPI-TA consists of five subunits: PIGK, GPAA1, PIGT, PIGS, and PIGU, and the absence of any subunit leads to the loss of activity."
      explanation: Losing GPAA1 removes transamidase activity, which is the step this edge asserts.
    - reference: PMID:34576938
      reference_title: "Functional Analysis of the GPI Transamidase Complex by Screening for Amino Acid Mutations in Each Subunit."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The D250A construct reduced GPI-TA activity without changing the protein stability"
      explanation: A single GPAA1 amino acid change lowers transamidase activity in GPAA1-knockout cells, showing that a missense lesion in GPAA1 can impair the complex.
  evidence:
  - reference: PMID:29100095
    reference_title: "Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families."
    explanation: Founding report establishing biallelic GPAA1 variants as the cause.
  - reference: PMID:29100095
    reference_title: "Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The splicing mutation was found to decrease GPAA1 mRNA."
    explanation: Shows a loss-of-expression effect for one of the founding alleles.
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When combining data from this study and published studies, 28 variants were identified, including 19 missense variants, 5 frameshift variants, 3 intronic splicing variants, and one nonsense variant."
    explanation: Gives the allelic spectrum across all published patients.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similar to the previous cohort, no homozygous loss-of-function variants were identified in this series of patients."
    explanation: Basis for reading the alleles as hypomorphic rather than null.
- name: Impaired GPI Anchor Attachment to Precursor Proteins
  biological_scale: MOLECULAR
  description: >-
    The GPI transamidase complex in the endoplasmic reticulum cleaves the
    C-terminal GPI attachment signal of precursor proteins and transfers the
    GPI anchor to the new C terminus. PIGK carries the catalytic residues;
    structural work indicates GPAA1 is not itself catalytic but is required
    for the complex to work.
  biological_processes:
  - preferred_term: attachment of GPI anchor to protein
    term:
      id: GO:0016255
      label: attachment of GPI anchor to protein
    modifier: DECREASED
  downstream:
  - target: Reduced Cell-Surface GPI-Anchored Proteins
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29100095
    reference_title: "Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum."
    explanation: Defines the step GPAA1 participates in.
  - reference: PMID:38963495
    reference_title: "Structure and Function of the Glycosylphosphatidylinositol Transamidase, a Transmembrane Complex Catalyzing GPI Anchoring of Proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "While the structural data confirm the catalytic role of PIGK, which likely uses a caspase-like mechanism to cleave the proproteins, they suggest that unlike previously proposed, GPAA1 is not a catalytic subunit."
    explanation: Clarifies GPAA1's role in the complex; supports describing it as essential but non-catalytic.
  - reference: PMID:38963495
    reference_title: "Structure and Function of the Glycosylphosphatidylinositol Transamidase, a Transmembrane Complex Catalyzing GPI Anchoring of Proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Consistent with the assembly mechanisms and the active site architecture, most of the disease mutations occur near the active site or the subunit interfaces."
    explanation: Places disease variants where they would be expected to impair assembly or catalysis of the complex.
- name: Reduced Cell-Surface GPI-Anchored Proteins
  biological_scale: CELLULAR
  description: >-
    Precursor proteins that are not anchored do not reach the cell surface as
    GPI-anchored proteins, so the surface density of the whole class falls.
    Patient leukocytes showed reduced FLAER (total GPI-anchored proteins), CD16
    and CD59; patient fibroblasts showed reduced CD73 and CD109. Lentiviral
    re-expression of wild-type GPAA1 partly rescued the fibroblast deficit.
    With over 150 GPI-anchored proteins, no single one has been shown to
    account for any clinical feature.
  cell_types:
  - preferred_term: granulocyte
    term:
      id: CL:0000094
      label: granulocyte
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Impaired Neural GPI-Anchored Protein Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Acquired Cerebellar Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Osteoblast Bone Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - osteoblast_alkaline_phosphatase_hypothesis
  evidence:
  - reference: PMID:29100095
    reference_title: "Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109)"
    explanation: Direct measurement of reduced surface GPI-anchored proteins in patient cells.
  - reference: PMID:29100095
    reference_title: "Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins."
    explanation: Rescue experiment tying the surface deficit to GPAA1 loss.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, flow cytometry assays support the pathogenicity of the variants by demonstrating reduction in CD16 in granulocytes."
    explanation: Independent cohort confirming reduced granulocyte CD16.
- name: Impaired Neural GPI-Anchored Protein Function
  biological_scale: CELLULAR
  description: >-
    GPI-anchored proteins in the nervous system take part in axon growth,
    regeneration, synapse formation and synaptic plasticity. Their reduction
    is the proposed route to the developmental delay, hypotonia and epilepsy,
    but no study has attributed these features to a particular GPI-anchored
    protein in GPAA1 deficiency.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Global developmental delay
  - target: Intellectual disability
  - target: Hypotonia
  - target: Spasticity
  - target: Seizure
  - target: Bilateral tonic-clonic seizure with generalized onset
  - target: Myoclonic seizure
  - target: Seizure precipitated by febrile infection
  - target: Generalized non-motor (absence) seizure
  - target: Epileptic spasm
  - target: Delayed myelination
  - target: Thin corpus callosum
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: "In the nervous system, GPI-APs play an vital role in axon growth, axon regeneration, synapse formation, and synaptic plasticity."
    explanation: >-
      Background statement of neural GPI-anchored protein functions. It is a
      general claim, not a measurement in GPAA1-deficient neurons, so the link
      to this disorder is indirect.
- name: Acquired Cerebellar Degeneration
  biological_scale: TISSUE
  description: >-
    Cerebellar atrophy, often with vermian involvement, that appears to
    develop after birth: a patient with a normal cerebellum at 15 months had
    atrophy at 33 months, and another had atrophy on follow-up imaging at age
    2 years that was not reported initially. Its absence on an early scan
    therefore does not exclude the diagnosis. In the oldest patient the
    atrophy was stable between ages 21 and 29.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  downstream:
  - target: Cerebellar atrophy
  - target: Ataxia
  - target: Nystagmus
  - target: Dysarthria
  - target: Dysmetria
  evidence:
  - reference: PMID:37510348
    reference_title: "A Novel Homozygous GPAA1 Variant in a Patient with a Glycosylphosphatidylinositol Biosynthesis Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When he was 15 months, the cerebellum was normal. When he was 33 months old, after the molecular diagnosis, magnetic resonance imaging was repeated, showing cerebellar atrophy."
    explanation: Serial imaging documenting acquired cerebellar atrophy.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acquired, rather than congenital, cerebellar abnormalities may prove to be a common feature of the disorder, not yet fully appreciated as most children have MRI scans after onset of clinical manifestations caused by the presence of cerebellar atrophy."
    explanation: Authors' interpretation that the cerebellar lesion is acquired.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The second patient did not have neuroimaging until age 21 years; this demonstrated cerebellar atrophy, which has been stable on repeat imaging at ages 25 and 29 years."
    explanation: Shows the atrophy need not progress in adulthood.
  - reference: PMID:37510348
    reference_title: "A Novel Homozygous GPAA1 Variant in a Patient with a Glycosylphosphatidylinositol Biosynthesis Defect."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: "Reduced activity of the complex does not grossly affect the structure of the brain, but it impairs cerebellum micro-organization and Purkinje cell dendritic arborization"
    explanation: >-
      Background citation of mouse work on reduced GPI biosynthesis in the
      developing cerebellum. It is not about GPAA1, so the link to this
      disorder is indirect.
  - reference: PMID:32179897
    reference_title: "CNS glycosylphosphatidylinositol deficiency results in delayed white matter development, ataxia and premature death in a novel mouse model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "The mutants show progressive decline with severe ataxia consistent with defects in cerebellar development. We show that the mutants have reduced myelination and defective Purkinje cell development."
    explanation: >-
      CNS-specific Piga knockout mice develop ataxia with Purkinje-cell and
      myelination defects. Piga acts at a different step of the same pathway,
      so this supports GPI deficiency in general, not GPAA1 specifically, as a
      cause of the cerebellar lesion.
- name: Impaired Osteoblast Bone Formation
  biological_scale: CELLULAR
  description: >-
    Hypothesized mechanism for osteopenia: reduced surface alkaline
    phosphatase on osteoblasts lowers bone formation. This is the authors'
    hypothesis, not a measured result, and epilepsy, antiseizure drugs and
    reduced mobility independently lower bone density in these patients.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  downstream:
  - target: Osteopenia
    hypothesis_groups:
    - osteoblast_alkaline_phosphatase_hypothesis
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: "Osteopenia and osteoporosis are hypothesized to be secondary to decreased alkaline phosphatase (ALP) expression on the surface of osteoblasts, impairing their function and leading to decreased bone formation and therefore bone mineral density."
    explanation: States the mechanism as a hypothesis; recorded as indirect support only.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_gpi_transamidase_deficiency_model
  hypothesis_label: Canonical GPI Transamidase Deficiency Model
  status: CANONICAL
  description: >-
    Biallelic hypomorphic GPAA1 variants lower GPI transamidase activity, so
    fewer proteins receive a GPI anchor and the surface density of the
    GPI-anchored protein class falls. Because that class is important in
    neural and cerebellar development, the result is developmental delay,
    epilepsy and cerebellar atrophy. Supported by reduced GPI-anchored
    proteins on patient leukocytes and fibroblasts and by partial rescue with
    wild-type GPAA1.
- hypothesis_group_id: osteoblast_alkaline_phosphatase_hypothesis
  hypothesis_label: Osteoblast Alkaline Phosphatase Hypothesis for Osteopenia
  status: EMERGING
  description: >-
    Reduced GPI-anchored alkaline phosphatase on the osteoblast surface lowers
    bone formation and so bone mineral density. Proposed by analogy across GPI
    deficiencies; not measured in GPAA1 patients, and confounded by epilepsy,
    antiseizure drugs and immobility.
discussions:
- discussion_id: gpaa1_no_mammalian_model
  kind: KNOWLEDGE_GAP
  prompt: >-
    How does partial loss of GPAA1 produce acquired cerebellar atrophy, given
    that no mammalian GPAA1 model has been described?
  attaches_to:
  - pathophysiology#Acquired Cerebellar Degeneration
  rationale: >-
    The cerebellar mechanism currently rests on patient imaging and on
    background work with reduced transamidase activity in general. The only
    GPAA1-deficient animal reported is a zebrafish made to study vascular
    anomalies, whose neurological phenotype was not described. A hypomorphic
    mammalian model would test whether the atrophy is Purkinje-cell loss and
    when it begins.
- discussion_id: gpaa1_which_gpi_anchored_protein
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which GPI-anchored proteins, or which combination, mediate the epilepsy
    and developmental impairment in GPAA1 deficiency?
  attaches_to:
  - pathophysiology#Reduced Cell-Surface GPI-Anchored Proteins
  - pathophysiology#Impaired Neural GPI-Anchored Protein Function
  rationale: >-
    The chain from reduced GPI anchoring to epilepsy is a class-level argument.
    No study has identified the responsible proteins, so the edge into the
    neural node has unknown intermediates and no protein-specific treatment
    target can be named.
phenotypes:
- category: Neurological
  name: Global developmental delay
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestations included global developmental delay (100%), hypotonia (95.8%), and epilepsy (83.3%)."
    explanation: Pooled frequency of developmental delay across 24 patients.
  - reference: PMID:29100095
    reference_title: "Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia."
    explanation: Founding cohort.
- category: Neurological
  name: Intellectual disability
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:37510348
    reference_title: "A Novel Homozygous GPAA1 Variant in a Patient with a Glycosylphosphatidylinositol Biosynthesis Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical features are intellectual disability, hypotonia, seizures, and cerebellar atrophy."
    explanation: Lists intellectual disability among the main features.
- category: Neurological
  name: Hypotonia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestations included global developmental delay (100%), hypotonia (95.8%), and epilepsy (83.3%)."
    explanation: Pooled frequency of hypotonia.
- category: Neurological
  name: Seizure
  description: >-
    Epilepsy with onset usually in infancy (60% before age one) and multiple
    seizure types. All five patients in the 2026 series were drug-resistant,
    while seizures were well controlled in some patients of other series. HPO
    has no drug-resistant epilepsy term, so that is recorded here.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestations included global developmental delay (100%), hypotonia (95.8%), and epilepsy (83.3%). 60% of patients experienced seizure onset before the age of one."
    explanation: Pooled frequency and age at onset of epilepsy.
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had drug-resistant epilepsy."
    explanation: Drug resistance in the five newly reported patients.
- category: Neurological
  name: Bilateral tonic-clonic seizure with generalized onset
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Generalized tonic-clonic seizure
    term:
      id: HP:0025190
      label: Bilateral tonic-clonic seizure with generalized onset
  evidence:
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main seizure types were generalized tonic-clonic seizures (GTCS) (82.4%) and myoclonic seizures (70.6%)."
    explanation: Pooled frequency of GTCS; the denominator (patients with seizure-type data) is not stated in the abstract.
- category: Neurological
  name: Myoclonic seizure
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main seizure types were generalized tonic-clonic seizures (GTCS) (82.4%) and myoclonic seizures (70.6%)."
    explanation: Pooled frequency of myoclonic seizures; denominator not stated in the abstract.
- category: Neurological
  name: Seizure precipitated by febrile infection
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fever-sensitive seizures
    term:
      id: HP:0032894
      label: Seizure precipitated by febrile infection
  evidence:
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Febrile sensitivity was presented in 66.7% of patients."
    explanation: Pooled frequency of fever sensitivity.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Numerous seizure types were observed, with 4 patients experiencing febrile seizures, 2 patients with absence seizures, 3 patients with bilateral tonic-clonic seizures, 2 patients with myoclonic jerks, and 1 patient experiencing epileptic spasms."
    explanation: Febrile seizures in four of seven patients in an independent cohort.
- category: Neurological
  name: Cerebellar atrophy
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "60.9% of patients had cerebellar atrophy."
    explanation: Pooled frequency of cerebellar atrophy.
- category: Neurological
  name: Ataxia
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Associated features included nystagmus in 2 patients, dysarthria in 1 patient (not assessed in 4 patients given their age or language capacity), dysmetria in 1 patient, and ataxia in 3 patients."
    explanation: Ataxia in three of seven patients.
- category: Neurological
  name: Nystagmus
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Associated features included nystagmus in 2 patients, dysarthria in 1 patient (not assessed in 4 patients given their age or language capacity), dysmetria in 1 patient, and ataxia in 3 patients."
    explanation: Nystagmus in two of seven patients.
- category: Neurological
  name: Dysarthria
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Associated features included nystagmus in 2 patients, dysarthria in 1 patient (not assessed in 4 patients given their age or language capacity), dysmetria in 1 patient, and ataxia in 3 patients."
    explanation: Dysarthria in one patient; most were too young or nonverbal to assess.
- category: Neurological
  name: Dysmetria
  phenotype_term:
    preferred_term: Dysmetria
    term:
      id: HP:0001310
      label: Dysmetria
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Associated features included nystagmus in 2 patients, dysarthria in 1 patient (not assessed in 4 patients given their age or language capacity), dysmetria in 1 patient, and ataxia in 3 patients."
    explanation: Dysmetria in one patient.
- category: Neurological
  name: Spasticity
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six of 7 patients were described as hypotonic and 2 demonstrated spasticity."
    explanation: Spasticity in two of seven patients.
- category: Neurological
  name: Delayed myelination
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Delayed myelination
    term:
      id: HP:0012448
      label: Delayed myelination
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2 of these individuals, additional abnormalities were noted, including slightly delayed myelination and mild thinning or hypoplasia of the corpus callosum."
    explanation: Delayed myelination in two of seven patients.
- category: Neurological
  name: Thin corpus callosum
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Thin or hypoplastic corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2 of these individuals, additional abnormalities were noted, including slightly delayed myelination and mild thinning or hypoplasia of the corpus callosum."
    explanation: Thin or hypoplastic corpus callosum in two of seven patients.
- category: Neurological
  name: Generalized non-motor (absence) seizure
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Absence seizure
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Numerous seizure types were observed, with 4 patients experiencing febrile seizures, 2 patients with absence seizures, 3 patients with bilateral tonic-clonic seizures, 2 patients with myoclonic jerks, and 1 patient experiencing epileptic spasms."
    explanation: Absence seizures in two of seven patients.
- category: Neurological
  name: Epileptic spasm
  phenotype_term:
    preferred_term: Epileptic spasms
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Numerous seizure types were observed, with 4 patients experiencing febrile seizures, 2 patients with absence seizures, 3 patients with bilateral tonic-clonic seizures, 2 patients with myoclonic jerks, and 1 patient experiencing epileptic spasms."
    explanation: Epileptic spasms in one of seven patients.
- category: Skeletal
  name: Osteopenia
  description: >-
    Universal in the founding cohort; in the later series only two patients
    had bone densitometry and one had osteopenia (Z score -2.3).
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:29100095
    reference_title: "Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia."
    explanation: Osteopenia in the founding cohort.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Osteopenia was a universal finding in the first cohort of patients identified by Nguyen et al. in 2017."
    explanation: States that every founding-cohort patient had osteopenia.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 2 patients in this series have been assessed with dual-energy X-ray absorptiometry scans, with osteopenia present in 1."
    explanation: Shows how sparsely bone density has been measured outside the founding cohort.
- category: Craniofacial
  name: Prominent forehead
  description: >-
    Dysmorphic features are inconsistent; prominent forehead and a tented
    upper lip were the most common descriptions, and three of seven patients
    in one series were not dysmorphic.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variable dysmorphic features were described, with common descriptions including prominent forehead and a tented upper lip."
    explanation: Names the most common facial findings.
- category: Craniofacial
  name: Tented upper lip vermilion
  phenotype_term:
    preferred_term: Tented upper lip
    term:
      id: HP:0010804
      label: Tented upper lip vermilion
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variable dysmorphic features were described, with common descriptions including prominent forehead and a tented upper lip."
    explanation: Names the most common facial findings.
biochemical:
- name: Serum alkaline phosphatase
  presence: Normal or decreased
  notes: >-
    Normal in five and low in one of six tested patients. No patient with a
    GPI transamidase defect has had raised alkaline phosphatase, which
    separates this group from the hyperphosphatasia GPI disorders.
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alkaline phosphatase was within the normal range in 5 individuals and low in 1 individual, as has been noted in other transamidase defects."
    explanation: Alkaline phosphatase results in the cohort.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the patients described in the literature with pathogenic variants in GPI-transamidase complex genes have elevated ALP."
    explanation: Generalizes the absence of hyperphosphatasia to transamidase defects.
genetic:
- name: GPAA1
  gene_term:
    preferred_term: GPAA1
    term:
      id: hgnc:4446
      label: GPAA1
  relationship_type: CAUSATIVE
  notes: >-
    GPAA1 encodes a non-catalytic subunit of the GPI transamidase complex
    (PIGK, PIGS, PIGT, PIGU, GPAA1). Defects in the other subunits cause
    related inherited GPI deficiencies with overlapping neurological
    phenotypes.
  evidence:
  - reference: PMID:29100095
    reference_title: "Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families."
    explanation: Founding gene-disease report.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten novel variants were identified in 7 patients."
    explanation: Independent replication in a second cohort.
diagnosis:
- name: Flow cytometry for GPI-anchored protein surface expression
  description: >-
    CD16 on granulocytes is the most consistently reduced marker. FLAER and
    CD59 on leukocytes, and CD73 and CD109 on fibroblasts, were reduced in the
    founding cohort, but in a later series CD55, CD59 and FLAER were only
    slightly reduced or unchanged. There is no GPAA1-specific profile; the
    assay supports the pathogenicity of variants found by sequencing.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GPAA1 deficiency does not demonstrate a characteristic pattern; however, measuring GPI-APs through flow cytometry remains a mechanism by which functional consequences of GPAA1 variants can be investigated."
    explanation: States both the use and the limit of the assay.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD55, CD59, and total GPI-AP levels in these individuals showed slightly decreased or no change in the levels compared with healthy controls."
    explanation: Shows that markers other than CD16 may be normal.
- name: Exome sequencing
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    The founding patients were diagnosed by exome sequencing; the phenotype is
    not specific enough among inherited GPI deficiencies to suggest GPAA1
    without it.
  evidence:
  - reference: PMID:29100095
    reference_title: "Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using whole-exome sequencing, we identified two frameshift mutations"
    explanation: Diagnostic method used in the founding cohort.
treatments:
- name: Antiseizure Medication
  description: >-
    Symptomatic seizure control is the main treatment and is often
    unsuccessful. No anticonvulsant has been shown to work better than
    another in GPAA1 deficiency.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: anticonvulsant therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  target_mechanisms:
  - target: Seizure
    treatment_effect: MODULATES
    description: Symptomatic; does not address the GPI anchoring defect.
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At present, treatments for GPI-related disorders are limited and primarily focused on seizure control."
    explanation: Establishes seizure control as the main treatment.
  - reference: PMID:42001530
    reference_title: "Genotype and phenotype spectrum of epilepsy patients with congenital disorders of glycosylation associated with GPAA1 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had drug-resistant epilepsy."
    explanation: Shows the limits of antiseizure medication in this disorder.
- name: Pyridoxine Supplementation
  description: >-
    Used by three of seven patients in one series. Pyridoxine has helped
    seizures in the hyperphosphatasia GPI disorders, but in this series it was
    not felt to have contributed significantly to seizure control.
  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:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of 7 patients in this report are using B6 as a part of their treatment regimen for seizure control."
    explanation: Documents use of pyridoxine in GPAA1 deficiency.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "B6 is not felt to have contributed significantly to seizure control."
    explanation: The same series did not find a clear benefit, so the treatment is recorded without a claim of efficacy.
- name: Ketogenic Diet
  description: >-
    Two patients in one series were managed with the ketogenic diet, and at
    least one had a partial but significant reduction in seizure frequency.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: ketogenic diet
    term:
      id: NCIT:C173168
      label: Ketogenic Diet
  target_mechanisms:
  - target: Seizure
    treatment_effect: MODULATES
    description: Symptomatic seizure reduction.
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients in this cohort are currently or were previously managed on the ketogenic diet."
    explanation: Documents use of the ketogenic diet in GPAA1 deficiency.
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In at least one of the patients, a partial but significant reduction in seizure frequency was observed."
    explanation: Reports a partial response in a patient on the ketogenic diet.
- name: Bone Health Monitoring
  description: >-
    Bone density should be monitored because osteopenia is reported and
    epilepsy, antiseizure medication and immobility add fracture risk.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:34703884
    reference_title: "Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given the independent association of osteopenia and osteoporosis with epilepsy, antiepileptic use, and decreased mobility, one may anticipate patients with GPAA1 deficiency are at risk of fractures, and bone health should be promoted and monitored."
    explanation: Recommends bone-health monitoring in GPAA1 deficiency.
📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (1)

Create: Glycosylphosphatidylinositol_Biosynthesis_Defect_15 · 2026-10-14T17:33:46Z · View source

New entry for GPIBD15 (MONDO:0060627, GPAA1). Deep research: falcon was requested but failed with an Edison authentication error (503 Failed to authenticate) on two attempts; the justfile in this checkout has no dr_fallback option, so the claude_code provider was run explicitly instead. Its report resolved all 14 references but 3 of 6 quoted sentences did not match the cited source, so no quote was taken from the report; every snippet was copied from the cached abstract or full text. Two of the report's claims were confirmed against source before use: no patient carries two null alleles (PMID:34703884, basis for PARTIAL_LOSS_OF_FUNCTION) and the GPAA1 D250A result (PMID:34576938). Primary sources: Nguyen 2017 (PMID:29100095), Castle 2021 full text (PMID:34703884), Fontana 2023 (PMID:37510348), Ouyang 2026 pooled 24-patient review (PMID:42001530), plus transamidase biochemistry (PMID:34576938, 38963495). Kept out of phenotypes and recorded in notes: single-case periodic fever (PMID:38112147) and the heterozygous familial vascular-anomaly pedigree (PMID:32533362). No GeneReviews chapter exists. Also added the entry to the Disorders_of_GPI_Anchor_Biosynthesis grouping, widening its NECESSARY criterion from GO:0006506 to its parent GO:0180046 (GPI anchored protein biosynthesis), because the GPAA1 lesion is in the attachment step (GO:0016255), a sibling of GO:0006506; all seven existing members still satisfy it, and the closure cache was rebuilt. A fresh-context self-review before the PR led to: reference_title on every evidence item; delayed myelination, thin corpus callosum, absence seizures and epileptic spasms added from Castle 2021; osteopenia Z score corrected to -2.3; flow-cytometry description narrowed to CD16 as the consistent marker; cerebellar node renamed from Progressive to Acquired Cerebellar Degeneration (atrophy was stable from 21 to 29 years in one patient); the Piga Nestin-Cre mouse (PMID:32179897) added as indirect model-organism evidence; an EMERGING osteoblast alkaline phosphatase hypothesis group tagged on the bone branch; seizure-type frequency denominators stated as not given in the abstract. Validation: just validate-disorders, 62/62 snippets verified, check-reference-titles, check-entity-refs, check-causal-targets, check-groupings (8/8 satisfied), validate-grouping-batch. After the PR opened, CI's gene-activity grounding gate failed because the GPAA1 node named no molecular function; GO:0003923 GPI-anchor transamidase activity (DECREASED) was bound there, following the PIGQ entry's treatment of a non-catalytic complex subunit, and the grouping's MONDO note was corrected to list the six members that descend from MONDO:0024321. All 26 CI whole-repo gates then passed locally.

Claude Code ▸
Glycosylphosphatidylinositol Biosynthesis Defect 15 (GPIBD15; GPAA1 deficiency): research report
claude-haiku-5-5, claude-opus-5-5 10 citations 2026-10-14T13:22:29.156688

I've gathered the main sources. Now I'm writing the report.

Glycosylphosphatidylinositol Biosynthesis Defect 15 (GPIBD15; GPAA1 deficiency): research report

Source basis. Most claims below come from ten references cached in this worktree (references_cache/PMID_*.md), with quotes copied verbatim from those files. Identifiers and the structural literature were added from web searches. Where a claim rests only on a search result, an unread abstract, or my own inference, it is marked [unverified] or [inference].

1. Disease information

Overview. GPIBD15 is an autosomal recessive inherited GPI deficiency (IGD) caused by biallelic variants in GPAA1. GPAA1 is a non-catalytic subunit of the ER-resident GPI transamidase (GPI-T). GPI-T attaches the GPI anchor to the C-terminus of precursor proteins. The core picture is: - global developmental delay or intellectual disability - hypotonia - early-onset epilepsy, often fever-sensitive - cerebellar atrophy, frequently acquired or progressive - osteopenia in some patients

"we report bi-allelic mutations in GPAA1 in ten individuals from five families… Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia." — PMID:29100095 (Nguyen et al., Am J Hum Genet 2017)

"Glycosylphosphatidylinositol biosynthesis defect 15 is a rare autosomal recessive disorder due to biallelic loss of function of GPAA1." — PMID:37510348 (Fontana et al., Genes 2023)

Identifiers

System ID
MONDO MONDO:0060627, "glycosylphosphatidylinositol biosynthesis defect 15" (verified in cache/mondo/terms.csv)
OMIM (phenotype) 617810
OMIM (gene) GPAA1 *603048
Orphanet ORPHA:529665 [web search; no local ORPHA cache file exists, so fetch it with just fetch-reference ORPHA:529665 before citing]
MedGen C4540520
Gene GPAA1, chromosome 8q24.3; HGNC ID not looked up here, so resolve it with OAK before binding
ICD-10/ICD-11, MeSH No disease-specific code. It falls under the congenital disorders of glycosylation (CDG) / GPI-deficiency parent concepts.

Synonyms: GPIBD15; GPAA1 deficiency; GPAA1-related GPI deficiency; GPAA1-CDG; "GPI anchoring deficiency due to biallelic variants in GPAA1" (PMID:34703884).

Data source type. Everything is aggregated case-level literature: about 30 patients in case series and case reports. There are no registries or EHR cohorts.

2. Etiology

  • Cause. Biallelic (homozygous or compound heterozygous) germline hypomorphic variants in GPAA1. These reduce GPI-T activity, which lowers the amount of GPI-anchored protein (GPI-AP) on the cell surface.
  • Genetic risk factors.
  • Consanguinity and genetic isolates explain the homozygous cases (PMID:37510348; PMID:39152716 in consanguineous Pakistani families).
  • No susceptibility loci or modifier genes are known.
  • Environmental risk factors. None cause the disease. Fever is a seizure trigger: febrile sensitivity was present in 66.7% of the pooled cohort (PMID:42001530), and in 4 of 7 patients in PMID:34703884.
  • Protective factors and gene–environment interactions. None reported.
  • Disputed heterozygous phenotype. One study (PMID:32533362) proposed that a heterozygous GPAA1 c.968A>G variant causes familial vascular anomalies. Castle et al. (PMID:34703884) found no vascular anomalies in biallelic patients or in carrier parents. Fontana et al. state the association "has not been confirmed by other authors." This should be treated as unconfirmed and kept out of the GPIBD15 entity.

3. Phenotypes

Pooled frequencies are from Ouyang et al. 2026 (PMID:42001530), covering 24 patients: 5 new plus 19 published.

"The clinical manifestations included global developmental delay (100%), hypotonia (95.8%), and epilepsy (83.3%). 60% of patients experienced seizure onset before the age of one. The main seizure types were generalized tonic-clonic seizures (GTCS) (82.4%) and myoclonic seizures (70.6%). Febrile sensitivity was presented in 66.7% of patients. 60.9% of patients had cerebellar atrophy."

Phenotype Suggested HPO term (verify every ID with OAK) Frequency / features Key source
Global developmental delay HP:0001263 Global developmental delay (in the YAML) 100%; onset around 3 months 42001530, 34703884
Intellectual disability HP:0001249 Usually moderate to severe; can be mild 37510348
Hypotonia (neonatal or infantile) HP:0001252 Hypotonia 95.8%; noted by 4 months 34703884
Seizures / epilepsy HP:0001250 Seizure 83.3%; onset 3 months to 3 years 42001530
Generalized tonic-clonic seizures HP:0002069 Bilateral tonic-clonic seizure 82.4% of those with epilepsy 42001530
Myoclonic seizures HP:0032794 [unverified] 70.6% 42001530
Febrile seizures / fever sensitivity HP:0002373 Febrile seizure 66.7% 42001530
Drug-resistant epilepsy HP:0033052 [unverified] 5/5 in the Chinese cohort; elsewhere often controlled 42001530, 37510348
Cerebellar atrophy HP:0001272 Cerebellar atrophy 60.9%; acquired or progressive 42001530, 34703884, 37510348
Ataxia / gait ataxia HP:0001251 / HP:0002066 Common 29100095
Dysarthria HP:0001260 Variable 34703884
Dysmetria HP:0001310 Variable 34703884
Nystagmus HP:0000639 About half 37510348 table
Spasticity HP:0001257 2/7 34703884
Osteopenia HP:0000938 Universal in the first cohort; 1/2 assessed in the second; absent in Fontana's patient 29100095, 34703884
Low serum alkaline phosphatase HP:0003282 Low alkaline phosphatase Occasional (1/6); ALP is never elevated 34703884
Delayed myelination; thin or hypoplastic corpus callosum HP:0012448; HP:0033725 / HP:0002079 Occasional 34703884
Strabismus HP:0000486 Occasional 37510348
Dysmorphism: prominent forehead, tented upper lip, broad nose HP:0011220, HP:0010804 Variable and nonspecific 34703884, 37510348
Microcephaly / relative macrocephaly HP:0000252 / HP:0004482 Both reported 37510348
Preauricular and cheek skin tags HP:0000384 1 case 37510348
Periodic fever with raised CRP/ESR; aphthae; tonsillitis HP:0001954 Recurrent fever 1 case; responded to glucocorticoids 38112147
Reduced GPI-APs on granulocytes or fibroblasts (FLAER, CD16, CD59, CD73, CD109) Lab finding; no specific HPO term Variable; CD16 is the most sensitive marker 29100095, 34703884

Course and impact on daily life. - Most patients are non-ambulant or walk late. One patient walked at 6 years. - Many are nonverbal or have severely limited speech. - The oldest reported patient (38 years) cannot stand, read or write, but eats and undresses independently (PMID:34703884). - No formal quality-of-life (QoL) instruments have been used.

4. Genetic and molecular information

  • Gene. GPAA1 (glycosylphosphatidylinositol anchor attachment 1), RefSeq NM_003801.3, 8q24.3.
  • Variant spectrum. Ouyang 2026 counts 28 variants: 19 missense, 5 frameshift, 3 intronic splicing and 1 nonsense.
Source Variants reported
PMID:29100095 (Nguyen 2017) p.Ser51Leu, p.Ala54Asn (c.160_161delinsAA), p.Trp176Ser, p.Leu290Pro, p.Leu291Pro, p.Ala389Pro, p.Gln327Hisfs*102, p.Gly307Alafs*11, c.1164+5C>T (splice; lowers mRNA)
PMID:34703884 (Castle 2021) p.Met50Lys, p.Met55Thr, p.His306Arg, p.Ala316Val (recurrent: Kurdish-Turkish and Israeli patients), p.Leu350Arg, p.Leu520Arg, p.Trp611Arg, p.Pro412Tyrfs*19, p.Arg493Glyfs*152, p.Met207Cysfs*21
PMID:37510348 (Fontana 2023) Homozygous c.424G>A p.Glu142Lys. ACMG classification VUS (PP4, PP3, PM2, BP1). Absent from gnomAD; CADD 26.8.
  • Genotype. No patient carries two null alleles:

    "Similar to the previous cohort, no homozygous loss-of-function variants were identified… suggestive of the importance of having residual functional gene product" (PMID:34703884)

The functional class is hypomorphic, i.e. partial loss of function. Complete GPAA1 knockout is presumed embryonic lethal [inference, by analogy with null GPI-pathway genes]. - Variant origin. All germline. Missense variants cluster in the luminal domain (residues 66–348) (PMID:34703884, 37510348). - Variant interpretation. Flow cytometry is recommended to support variant classification (PMID:34703884). - Gene curation. Genomics England PanelApp rates GPAA1 Green for early-onset or syndromic epilepsy. ClinGen gene-disease validity: not found in the local cache (no CGGV file). - Not reported: modifier genes, epigenetic findings, chromosomal abnormalities. A SNP microarray was normal in the Fontana case.

5. Environmental information

There are no environmental, lifestyle or infectious causes. Fever, including infection-driven fever, precipitates seizures. One patient had a recurrent sterile periodic-fever syndrome (PMID:38112147).

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic hypomorphic GPAA1 variants (missense in the luminal domain, frameshift, splice) lead to reduced GPAA1 mRNA or protein, or a destabilized subunit. Splice c.1164+5C>T lowers mRNA (demonstrated, PMID:29100095). Missense variants are predicted to disrupt the luminal domain (PMID:37510348, computational).
  2. A deficient GPAA1 subunit impairs assembly and activity of the heteropentameric GPI transamidase (PIGK–GPAA1–PIGT–PIGS–PIGU) in the ER membrane.

  3. "GPI-TA consists of five subunits: PIGK, GPAA1, PIGT, PIGS, and PIGU, and the absence of any subunit leads to the loss of activity." (PMID:34576938, in vitro)

  4. Cryo-EM structures (Zhang 2022, PMID:35165458; Xu 2022, Nat Commun, PMID:35551457 [PMID from search, not cached]) place catalysis in PIGK (C206-H164-N58). GPAA1 is structural, not catalytic: "they suggest that unlike previously proposed, GPAA1 is not a catalytic subunit… most of the disease mutations occur near the active site or the subunit interfaces" (PMID:38963495, review). GPAA1 Asp250 is required for activity (PMID:34576938).
  5. Reduced GPI-T activity results in failed replacement of the C-terminal GPI-attachment signal with a GPI anchor on proproteins. This reduces the delivery of GPI-APs to the cell surface:

    "several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency" (PMID:29100095; human ex vivo / in vitro)

Because the defect sits at the attachment step, the GPI precursor and the unanchored protein are not released as soluble protein, which is why ALP is not raised. Instead, ALP is normal or low, unlike defects of the post-attachment / remodeling steps that cause hyperphosphatasia (PMID:34703884). 4. Branch A: nervous system. Loss of neural GPI-APs, which act in axon growth, synapse formation and synaptic plasticity (PMID:34703884), leads to: - impaired neurodevelopment, giving developmental delay and intellectual disability - neuronal hyperexcitability, giving epilepsy with fever sensitivity. The specific GPI-APs responsible are not demonstrated. - cerebellar micro-organization and Purkinje-cell dendritic defects, giving progressive cerebellar atrophy and ataxia. Fontana cites a transamidase model showing "it impairs cerebellum micro-organization and Purkinje cell dendritic arborization." That is model-organism evidence from a related subunit; GPAA1 itself has no mouse model. A Purkinje-specific Pigk knockout mouse shows cerebellar atrophy, ataxia and Purkinje-cell loss with apoptosis and neuroinflammation [web search, PMID not retrieved]. - Atrophy is often acquired: the cerebellum was normal at 7 months and atrophic at 2 years (PMID:34703884), and normal at 15 months and atrophic at 33 months (PMID:37510348). 5. Branch B: bone. Reduced osteoblast-surface tissue-nonspecific ALP is hypothesized to reduce bone formation, giving osteopenia (PMID:34703884; stated as a hypothesis). Immobility and antiseizure drugs may contribute. 6. Branch C: immune system [speculative]. Reduced complement regulators (CD59, CD55) and loss of CD16 on granulocytes could contribute to the inflammatory or periodic-fever phenotype in one patient (PMID:38112147). This parallels autoinflammation in PIGT-PNH (PMID:34576938 background) but is not demonstrated for GPAA1.

Ontology suggestions (all unverified; look up before binding)

Category Suggested terms
GO biological process GO:0016255 attachment of GPI anchor to protein; GO:0006506 GPI anchor biosynthetic process; GO:0021680 cerebellar Purkinje cell layer development; GO:0001503 ossification
GO cellular component GO:0042765 GPI-anchor transamidase complex; GO:0005789 endoplasmic reticulum membrane
CL cell types CL:0000121 Purkinje cell; CL:0000062 osteoblast; CL:0000775 neutrophil (CD16 readout); CL:0000057 fibroblast
Biomarkers CD16 (FCGR3B), CD59, CD55, FLAER, CD73 (NT5E), CD109, ALP (ALPL)

No transcriptomic, proteomic, metabolomic, single-cell or CRISPR-screen data specific to this disease exist. HEK293 GPAA1-KO cells exist as a complementation system (PMID:34576938).

7. Anatomical structures

Level Structures Suggested terms (unverified)
Primary Brain, especially the cerebellum (vermis and hemispheres); dentate nuclei T2 hyperintensity in one case (PMID:37510348) UBERON:0002037 cerebellum; UBERON:0004720 cerebellar vermis
Secondary Corpus callosum; cerebral white matter (myelination); skeleton (bone mineral density); granulocytes / immune system UBERON:0002336; UBERON:0001474 bone element
Subcellular ER membrane (site of GPI-T); plasma membrane / lipid rafts (where GPI-APs act) GO cellular component
Lateralization Bilateral and symmetric —

8. Temporal development

  • Onset. Hypotonia from birth to 4 months. Delay is evident by about 3 months. Seizures start at 3 months to 3 years, before 1 year in 60%.
  • Course.
  • Chronic and lifelong.
  • Cerebellar atrophy can progress in early childhood and then remain stable into adulthood: stable at 21, 25 and 29 years in the oldest patient (PMID:34703884).
  • Developmental skills are acquired slowly, not lost.
  • Formal staging and remission. None. Seizures may be controlled or drug-resistant.
  • Critical window [inference]. Neuroimaging should be repeated after infancy, because a normal early MRI does not exclude later atrophy.

9. Inheritance and population

  • Inheritance. Autosomal recessive (HP:0000007).
  • Penetrance and expressivity. Penetrance appears complete for biallelic pathogenic variants. Expressivity is markedly variable: one 22-month-old with p.Leu350Arg had only mild delay and no seizures (PMID:34703884).
  • Carriers. Heterozygous parents are unaffected and have normal flow cytometry (PMID:34703884).
  • Prevalence. Unknown. Count of reported patients over time:
Year Patients reported Source
2017 10 (5 families) PMID:29100095
2021 17 PMID:34703884
2023 18 PMID:37510348
2026 about 24 pooled PMID:42001530

Plus further cases in Pakistani (PMID:39152716) and Chinese (PMID:38112147) families. Suggested prevalence_class: CASES_IN_LITERATURE / ULTRA_RARE. - Populations. Reported from European, North American, Egyptian, Finnish, Israeli, Kurdish-Turkish, Italian (genetic isolate in Benevento), Pakistani and Chinese families. - Founder effects and anticipation. No founder variant is established. p.Ala316Val recurred in two unrelated families. No anticipation (not a repeat disorder). Sex ratio is about 1:1.

10. Diagnostics

  • Genetic testing. Exome or genome sequencing is the main route, used in essentially all cases. GPAA1 is also on CDG and epilepsy panels (PanelApp Green).
  • Functional confirmation.
  • Flow cytometry of granulocytes for FLAER, CD16, CD59 and CD55. CD16 is the most sensitive marker, with reductions of 12–47% (PMID:34703884).
  • Fibroblast CD73/CD109 and lentiviral rescue (PMID:29100095).
  • GPAA1 has no characteristic flow profile, unlike PIGT and PIGU.
  • Biochemistry.
  • Serum ALP is normal or low, never high. This separates the transamidase disorders from the HPMRS (hyperphosphatasia) group.
  • Inflammatory markers (CRP, ESR) rise only during febrile episodes in the periodic-fever case.
  • Suggested LOINC for ALP: 6768-6 [unverified; seed with just loinc-seed-cache].
  • Imaging. Brain MRI shows cerebellar (vermian) atrophy, delayed myelination and a thin corpus callosum. DXA can detect osteopenia.
  • EEG. No consistent pattern: findings include normal, multifocal spike-and-wave, polyspike and slow discharges.
  • Differential diagnosis.
  • Other transamidase IGDs: PIGT (intractable seizures, nephrocalcinosis, dental and skeletal findings); PIGS (coarse face, gingival hypertrophy, pontine hypoplasia); PIGK (microcephaly); PIGU (thin corpus callosum).
  • Other IGDs: PIGA, PIGN, PIGG, PGAP1.
  • Hyperphosphatasia–intellectual disability syndromes (HPMRS: PIGV, PIGO, PGAP2/3), which have high ALP.
  • Other CDGs, e.g. PMM2-CDG with cerebellar atrophy.
  • Pontocerebellar hypoplasias and early-onset spinocerebellar ataxias. GPIBD15 spares the brainstem (PMID:37510348).
  • Screening. No newborn screening. Carrier and prenatal or preimplantation testing are possible once familial variants are known.

11. Outcome and prognosis

  • Survival. No survival data. Patients have been reported up to 38 years, so survival into adulthood is documented.
  • Morbidity.
  • Severe neurodevelopmental disability: most are non-ambulant and many nonverbal.
  • Drug-resistant epilepsy in a subset.
  • Fracture risk from osteopenia is inferred, not documented for GPAA1, though fractures occur in PIGT deficiency (PMID:34703884).
  • Prognostic factors. None validated. Milder cases may carry higher residual activity, but no genotype–phenotype correlation is established.

12. Treatment

No disease-modifying therapy exists. Management is symptomatic. Suggested NCIT terms below are unverified; look them up before binding.

Intervention Evidence Suggested NCIT
Antiseizure medication: levetiracetam and others Seizures controlled in some patients (PMID:37510348); drug-resistant in others (PMID:42001530) NCIT:C15986 Pharmacotherapy plus therapeutic_agent CHEBI levetiracetam
Ketogenic diet Partial but significant seizure reduction in 1 of 2 patients (PMID:34703884) NCIT:C15447 Dietary Intervention
Pyridoxine (vitamin B6) Tried in 3/7 patients; "not felt to have contributed significantly" (PMID:34703884) Pharmacotherapy plus CHEBI pyridoxine
Glucocorticoids for periodic fever Fever controlled in 1 case (PMID:38112147) Pharmacotherapy plus a corticosteroid agent (CHEBI:50858)
PT / OT / speech therapy, bone-health monitoring Recommended (PMID:34703884) NCIT:C15302, C121351, C159273
  • Experimental therapy. No trials. Lentiviral GPAA1 gene transfer rescued GPI-APs in patient fibroblasts in vitro (PMID:29100095). That is a proof of concept only.
  • Butyrate. Effective only in PIGM promoter disease, so not applicable here.
  • Pharmacogenomics. None known.

13. Prevention

  • Primary: genetic counseling, which carries a 25% recurrence risk; carrier testing; prenatal or preimplantation diagnosis.
  • Tertiary:
  • Fever control or avoidance to reduce fever-triggered seizures [inference from the febrile-sensitivity data].
  • Bone-density surveillance.
  • Serial MRI.
  • Not applicable: vaccines, public-health measures.

14. Other species

No naturally occurring GPAA1 disease is known in animals. A query of OMIA was not performed. GPAA1 is conserved across eukaryotes; the yeast ortholog is GAA1 (S. cerevisiae). Zoonotic potential: not applicable.

15. Model organisms

Model Findings Evidence / limits
Zebrafish gpaa1 knockout / crispant (PMID:32533362) "displayed several types of developmental defects as well as vascular dysplasia"; shortened length, back hyperextension, small eyes MODEL_ORGANISM. Made for the disputed vascular-anomaly claim, and neurological or cerebellar phenotypes were not characterized, so fidelity to GPIBD15 is low or unknown.
HEK293 GPAA1-KO cells (PMID:34576938) Loss of CD55/CD59; rescue by wild-type but not D250A GPAA1 IN_VITRO complementation assay. Useful for testing variant function.
Patient fibroblasts and leukocytes (PMID:29100095, 34703884) Reduced GPI-APs; partial lentiviral rescue IN_VITRO / ex vivo
Mouse No Gpaa1 mutant published (MGI not checked). The nearest analogues are Purkinje-specific Pigk knockout (cerebellar atrophy, ataxia) and Nestin-Cre Piga (Purkinje and myelination defects). Candidate HUMAN_MODEL_MISMATCH / KNOWLEDGE_GAP: no GPAA1-specific mammalian model exists.
Yeast gaa1Δ GAA1 is essential in S. cerevisiae [known biology; no cached citation] Shows the subunit is essential and conserved.

Curation notes for the dismech entry

  1. Disease-specific evidence anchors are PMIDs 29100095, 34703884, 37510348, 42001530 and 38112147. Their abstracts are cached and the quotes above are verbatim.
  2. Mechanism and structure are covered by 34576938 (full text), 35165458 and 38963495. Xu 2022 (PMID:35551457) still needs just fetch-reference.
  3. Keep the vascular-anomaly paper (32533362) out of the GPIBD15 phenotypes. It concerns a heterozygous, disputed claim. At most, record it as a REFUTE/discussion item quoting Castle's rebuttal.
  4. Pathophysiology node to conform to. The current node should conform to an existing GPI-anchor-deficiency module if there is one; check with just list-modules gpi.
  5. Do not use PMID:20301507. The retired GeneReviews N-linked CDG chapter is not GPIBD15-specific.
  6. GeneReviews baseline. Run just check-genereviews to confirm that no GPIBD15 chapter exists.

Sources

Cached abstracts and full texts (all in references_cache/): - PMID:29100095 (Nguyen 2017) - PMID:34703884 (Castle 2021) - PMID:37510348 (Fontana 2023) - PMID:42001530 (Ouyang 2026) - PMID:38112147 (Chen 2023) - PMID:39152716 (Bibi 2024) - PMID:32533362 (Li 2020) - PMID:34576938 (Liu 2021) - PMID:35165458 (Zhang 2022) - PMID:38963495 (Li 2024)

Web: - MedGen C4540520 - LOVD GPIBD15 - PanelApp GPAA1 (Genomics England) - PanelApp Australia CDG - Xu et al. 2022 Nat Commun (PMC) - RCSB 7WLD - Zhang et al. 2022 NSMB - Liu et al. 2021 Molecules - PMC7206848 (GPI mouse model review) - bioRxiv Pigk Purkinje model

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 6
Quoted claims found in source 3
Quoted claims not found in source 3
References weighed for topical relevance 14
On topic 7
Off topic 2

Quotes not found in the cited source

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

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

  • PMID:34703884: "GPI anchoring deficiency due to biallelic variants in GPAA1"
  • closest text in source: "There is a case report of an individual with GPI deficiency due to variants in PIGM whose severe seizures were treated successfully with the histone deacetylase inhibitor sodium butyrate.30,31 However, this is likely not a feasible treatment for all GPI-related disorders, as the patient's specific pathogenic variant was in the PIGM promotor and led to decreased acetylation and therefore decreased gene expression"
  • PMID:34703884: "Similar to the previous cohort, no homozygous loss-of-function variants were identified… suggestive of the importance of having residual functional gene product"
  • closest text in source: "Similar to the previous cohort, no homozygous loss-of-function variants were identified in this series of patients"
  • PMID:38963495 (abstract only): "they suggest that unlike previously proposed, GPAA1 is not a catalytic subunit… most of the disease mutations occur near the active site or the subunit interfaces"
  • closest text in source: "Consistent with the assembly mechanisms and the active site architecture, most of the disease mutations occur near the active site or the subunit interfaces"

References that may not be about this subject

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

  • PMID:35551457 (2 mentions) - Molecular insights into biogenesis of glycosylphosphatidylinositol anchor proteins.
  • shared terms: gpi-ap, anchor
  • PMID:20301507 (1 mention) - Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
  • shared terms: anchor

Weighed against this report's own most characteristic terms: gpaa1, patient, seizure, cerebellar, variant, gpibd15, phenotype, atrophy, fever, epilepsy, gpi-ap, fibroblast, fontana, unverified, disease, year, delay, developmental, normal, anchor.

Term Validation

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

Outcome Count
Terms checked 48
Resolved 47
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 11
Terms named correctly 7
Terms named as a different term 2
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:0032794 (1 mention) - the report calls it "unverified"; HP calls it Myoclonic seizure
  • HP:0033052 (1 mention) - the report calls it "unverified"; HP calls it Non-epileptic seizure

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:0000384 (1 mention) - the report calls it "Preauricular and cheek skin tags"; HP calls it Preauricular skin tag, and lists "Preauricular skin tags" among its other names
  • CHEBI:50858 (1 mention) - the report calls it "Pharmacotherapy plus a corticosteroid agent"; CHEBI calls it corticosteroid, and lists "corticosteroides" among its other names

Prefixes with no resolver

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.