Mabry Syndrome - dismech

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Classifications

ISDS Skeletal Nosology

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Inheritance

1

Autosomal recessive HP:0000007

All six HPMRS subtypes are inherited in an autosomal recessive manner from biallelic hypomorphic (partial loss-of-function) variants; recurrence risk is 25% per pregnancy. Expressivity is highly variable both within and between the six genes. Complete null alleles are not compatible with life in this pathway, so at least one hypomorphic allele is always retained.

Autosomal recessive inheritance Penetrance: COMPLETE Expressivity: VARIABLE

Show evidence (1 reference)

PMID:20802478 SUPPORT Human Clinical

"Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase."

Establishes the autosomal recessive inheritance and the defining triad of HPMRS.

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Subtypes

6

HPMRS1 (PIGV) MONDO:0009398

PIGV hgnc:26031

Most common subtype; caused by biallelic PIGV variants. PIGV encodes GPI mannosyltransferase II, which adds the second mannose to the GPI glycan in the endoplasmic reticulum. The recurrent European founder allele c.1022C>A (p.Ala341Glu) is present in ~80% of PIGV-positive families.

HPMRS2 (PIGO) MONDO:0013882

PIGO hgnc:23215

Caused by biallelic PIGO variants. PIGO is the phosphoethanolamine transferase that adds the ethanolamine phosphate bridge to the third mannose in the ER; the second-most-frequently implicated gene after PIGV.

HPMRS3 (PGAP2) MONDO:0013628

PGAP2 hgnc:17893

Caused by biallelic PGAP2 variants. PGAP2 performs Golgi fatty-acid remodeling (stearate reacylation) of the GPI anchor; the 1970 index Mabry family carries a PGAP2 variant. HPMRS3 appears the most pyridoxine-responsive subtype.

HPMRS4 (PGAP3) MONDO:0014318

PGAP3 hgnc:23719

Caused by biallelic PGAP3 variants. PGAP3 is the GPI-anchor maturation deacylase in the Golgi; pathogenic noncoding (intronic/3'UTR) variants are documented and are missed by panel-based testing.

HPMRS5 (PIGW) MONDO:0014457

PIGW hgnc:23213

Caused by biallelic PIGW variants. PIGW is the inositol acyltransferase acting early in ER GPI assembly; reported presentations include West syndrome with hypsarrhythmia.

HPMRS6 (PIGY) MONDO:0014780

PIGY hgnc:28213

Caused by biallelic PIGY variants. PIGY is a subunit of the GPI-GlcNAc transferase complex; severity tracks residual expression, ranging from lethal multisystem disease to moderate developmental delay with microcephaly.

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Discussions and Knowledge Gaps

2

Does HPMRS/Mabry syndrome have a reproducible DNA-methylation episignature or a disease-specific human transcriptomic/proteomic/metabolomic signature that could serve as a diagnostic classifier or severity biomarker?

KNOWLEDGE GAP OPEN gap_mabry_episignature_omics

Attached to

pathophysiology#Reduced Cell-Surface Display of GPI-Anchored Proteins

Unlike several other intellectual-disability syndromes, no DNA-methylation episignature and no human omics dataset specific to HPMRS have been reported; the only omics data are from the Pigv341E mouse. Neither serum ALP nor flow-cytometry GPI-anchored-protein levels correlate with phenotypic severity, so there is currently no validated molecular severity biomarker. Filling this gap would improve diagnosis of ALP-normal cases and enable objective outcome measures.

Proposed experiments

Genome-wide methylation and multi-omics profiling of HPMRS patient cohorts

exp_mabry_episignature

Perform EPIC-array DNA methylation profiling plus RNA-seq on blood and fibroblasts across HPMRS genes to test for a reproducible episignature and genotype/severity-correlated expression signatures.

How faithfully does the Pigv341E knock-in mouse model the human HPMRS phenotype, given that it inverts the social phenotype and leaves the defining biomarker unmeasured?

HUMAN MODEL MISMATCH OPEN hmm_mabry_pigv341e_mouse

Attached to

pathophysiology#Impaired Neuronal GPI-Anchored-Protein-Dependent Synaptic Function

The Pigv341E mouse faithfully recapitulates the neurologic core (motor deficits, seizure susceptibility, memory impairment, hippocampal synaptopathy), but shows ENHANCED rather than reduced sociability - opposite in valence to the human phenotype - and did not quantify alkaline phosphatase, so it does not validate the defining hyperphosphatasia biomarker. Facial dysmorphism, brachytelephalangy, Hirschsprung disease, and progressive cerebral/cerebellar atrophy are also not reproduced. Translational validity of the social-behavior and biomarker domains is therefore the open question.

Proposed experiments

Serum ALP and cross-species behavioral validation in GPI-anchor-deficient mice

exp_mabry_mouse_alp

Quantify serum tissue-nonspecific alkaline phosphatase and re-assess social behavior with standardized assays across Pigv341E and additional HPMRS-gene mouse lines to test whether the biomarker and social-domain mismatches are model-specific.

Show evidence (1 reference)

PMID:33402532 SUPPORT Model Organism

"A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human"

The knock-in mouse mirrors human neurologic phenotypes but diverges on sociability and the ALP biomarker.

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Pathophysiology

9

Hypomorphic GPI-Pathway Enzyme Deficiency

Biallelic hypomorphic variants reduce the abundance or activity of a GPI-anchor biosynthesis enzyme (PIGV, PIGO, PIGW, or PIGY) in the endoplasmic reticulum membrane. The A341E founder change, for example, drastically decreases PIGV protein expression rather than abolishing the catalytic site, leaving partial pathway function intact.

GPI anchor biosynthetic process GO:0006506 ↓ DECREASED

GPI mannosyltransferase activity GO:0004376 ↓ DECREASED

endoplasmic reticulum membrane GO:0005789

Downstream

Accumulation of Incomplete Mannosylated GPI Intermediates

Show evidence (1 reference)

PMID:22228761 SUPPORT In Vitro

"Mutations found in four families caused amino acid substitutions A341E, A341V, Q256K, and H385P, which drastically decreased expression of the PIGV protein."

Demonstrates the hypomorphic (reduced-abundance) nature of HPMRS-causing PIGV variants.

Accumulation of Incomplete Mannosylated GPI Intermediates

With a biosynthetic enzyme partially deficient, GPI assembly stalls mid-pathway and mannose-bearing incomplete GPI intermediates accumulate in the ER. This mannose-bearing (rather than mannose-free) stall is the decisive branch point that determines whether hyperphosphatasia follows.

endoplasmic reticulum membrane GO:0005789

Downstream

Transamidase-Mediated Release of Soluble Alkaline Phosphatase

Reduced Cell-Surface Display of GPI-Anchored Proteins

Impaired Golgi GPI-Anchor Fatty-Acid Remodeling

In the remodeling-arm subtypes (PGAP2, PGAP3), ER GPI assembly completes but Golgi fatty-acid remodeling of the attached anchor fails. The unremodeled lyso-GPI anchor cannot stably partition into membrane lipid rafts and becomes a substrate for phospholipases that release the attached protein. This arm converges on the same downstream nodes as the biosynthesis arm.

Golgi membrane GO:0000139

Downstream

Transamidase-Mediated Release of Soluble Alkaline Phosphatase

Reduced Cell-Surface Display of GPI-Anchored Proteins

Show evidence (1 reference)

PMID:23561847 SUPPORT Other

"PGAP2 is involved in fatty-acid GPI-anchor remodeling, which occurs in the Golgi apparatus"

Cell-biology characterization (from a human genetics report) defining the Golgi remodeling arm as a distinct upstream route to the shared downstream defect.

Transamidase-Mediated Release of Soluble Alkaline Phosphatase

The GPI transamidase recognizes the truncated mannose-bearing intermediate, cleaves the C-terminal signal peptide from tissue-nonspecific alkaline phosphatase anyway, and liberates the enzyme as a soluble, unanchored protein into the serum. This is the direct molecular cause of the hyperphosphatasia biomarker, and it explains why mannose-free GPI defects (e.g. PIGM) show no hyperphosphatasia.

GPI-anchor transamidase activity GO:0003923 alkaline phosphatase activity GO:0004035

Downstream

Circulating Pyridoxal-5-Phosphate Depletion

Show evidence (2 references)

PMID:22228761 SUPPORT In Vitro

"Hyperphosphatasia resulted from secretion of ALP, a GPI-anchored protein normally expressed on the cell surface, into serum due to PIGV deficiency."

Directly demonstrates the transamidase-dependent soluble-ALP-release mechanism.

PMID:22228761 SUPPORT In Vitro

"In contrast, a previously reported PIGM deficiency, in which there is a defect in the transfer of the first mannose, does not result in hyperphosphatasia."

The mannose-dependent branch condition distinguishing HPMRS from GPI defects without hyperphosphatasia.

Reduced Cell-Surface Display of GPI-Anchored Proteins

The failed anchor also leaves a broad guild of GPI-anchored surface proteins (CD55, CD59, contactins, NCAM-120, ephrin-A ligands, glypicans) reduced on the cell surface of patient granulocytes and fibroblasts. This surface deficiency, rather than the ALP release, is the arm that actually causes the disease.

fibroblast CL:0000057 neutrophil CL:0000775

Downstream

Impaired Neuronal GPI-Anchored-Protein-Dependent Synaptic Function

Many GPI-anchored proteins are axon-guidance and synapse-organizing molecules, so their surface loss impairs neuronal connectivity and synaptic transmission. The Pigv341E mouse shows decreased hippocampal synaptic transmission underlying impaired memory formation.

neuron CL:0000540 microglial cell CL:0000129

chemical synaptic transmission GO:0007268 ↓ DECREASED

synapse GO:0045202

Downstream

Abnormal Brain Development and Progressive Neurodegeneration

Show evidence (1 reference)

PMID:33402532 SUPPORT Model Organism

"decreased hippocampal synaptic transmission that could underlie impaired memory formation"

Mouse knock-in of the human PIGV founder allele shows the synaptic-transmission defect.

Abnormal Brain Development and Progressive Neurodegeneration

Disordered GPI-AP-dependent wiring produces structural brain abnormalities (cerebral and cerebellar atrophy, callosal anomalies, delayed myelination). Serial imaging demonstrates progressive cerebral and cerebellar volume loss, indicating a superimposed neurodegenerative process on the neurodevelopmental substrate.

brain UBERON:0000955 cerebellum UBERON:0002037

Downstream

Seizures and Developmental Epileptic Encephalopathy

Circulating Pyridoxal-5-Phosphate Depletion

Free (unanchored) serum alkaline phosphatase dephosphorylates and degrades circulating pyridoxal 5'-phosphate, the active vitamin B6 vitamer and the cofactor for glutamate decarboxylase. CNS pyridoxal-5-phosphate falls, GABA synthesis falls, and a genetically fixed enzyme-trafficking defect thereby creates an acquired, nutritionally correctable cofactor deficiency in the brain.

Downstream

Seizures and Developmental Epileptic Encephalopathy

Show evidence (1 reference)

PMID:36636587 SUPPORT Human Clinical

"Cerebrospinal fluid (CSF) neurotransmitter analysis showed low levels of pyridoxal phosphate and 5-methyltetrahydrofolate and raised homovanillic acid"

HPMRS3 case with documented low CSF pyridoxal-5-phosphate, directly evidencing the cofactor-depletion side branch.

Seizures and Developmental Epileptic Encephalopathy

Two converging inputs drive the epilepsy phenotype: the structural/synaptic substrate from disordered brain development, and the treatable cofactor-depletion substrate (low CNS pyridoxal-5-phosphate). The dual input explains why pyridoxine partially helps a subset while rarely achieving seizure freedom.

chemical synaptic transmission GO:0007268

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"seizures (83%), hypotonia (72%)"

Seizures are a core feature in the largest inherited GPI deficiency cohort.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

18

Cardiovascular 1

Cardiac anomalies OCCASIONAL Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies"

Cardiac anomalies in 19% of the inherited GPI deficiency cohort.

Digestive 1

Gastrointestinal anomalies FREQUENT Abnormality of the gastrointestinal tract HP:0011024

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies"

GI involvement in 66% of the inherited GPI deficiency cohort.

Ear 1

Sensorineural hearing impairment HP:0000407

Eye 1

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:24129430 SUPPORT Human Clinical

"particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in"

Distinctive facial anomalies are consistently found in PIGV-positive individuals.

Genitourinary 1

Renal anomalies OCCASIONAL Abnormality of the kidney HP:0000077

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies"

Renal anomalies in 14% of the inherited GPI deficiency cohort.

Musculoskeletal 1

Hypotonia FREQUENT HP:0001252

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"seizures (83%), hypotonia (72%)"

Hypotonia reported in 72% of the cohort.

Nervous System 8

Intellectual disability VERY_FREQUENT HP:0001249

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"Core clinical features were developmental delay or intellectual disability (DD/ID, 90%)"

DD/ID reported in 90% of the inherited GPI deficiency cohort (broader-than-HPMRS denominator).

Global developmental delay VERY_FREQUENT HP:0001263

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"Core clinical features were developmental delay or intellectual disability (DD/ID, 90%)"

Developmental delay reported in 90% of the inherited GPI deficiency cohort.

Seizures VERY_FREQUENT HP:0001250

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"seizures (83%), hypotonia (72%)"

Seizures reported in 83% of the inherited GPI deficiency cohort.

Delayed speech and language development VERY_FREQUENT HP:0000750

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"delayed or absent speech (95%)"

Delayed or absent speech in 95% of the inherited GPI deficiency cohort.

Cerebral atrophy VERY_FREQUENT HP:0002059

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"cerebral atrophy (75%)"

Cerebral atrophy in 75% of the inherited GPI deficiency cohort.

Cerebellar atrophy FREQUENT HP:0001272

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"cerebellar atrophy (60%)"

Cerebellar atrophy in 60% of the inherited GPI deficiency cohort.

Callosal anomalies FREQUENT Abnormal corpus callosum morphology HP:0001273

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"callosal anomalies (57%)"

Callosal anomalies in 57% of the inherited GPI deficiency cohort.

Severe global developmental delay FREQUENT HP:0011344

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"severe-to-profound DD/ID (59%)"

Severe-to-profound DD/ID in 59% of the inherited GPI deficiency cohort.

Other 4

Elevated serum alkaline phosphatase VERY_FREQUENT Elevated circulating alkaline phosphatase concentration HP:0003155

Show evidence (1 reference)

PMID:24129430 SUPPORT Human Clinical

"Severe developmental delays, particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in"

Hyperphosphatasia is consistently found in PIGV-positive individuals.

Brachytelephalangy Short distal phalanx of finger HP:0009882

Show evidence (1 reference)

PMID:24129430 SUPPORT Human Clinical

"brachytelephalangy, and hyperphosphatasia are consistently found in"

Brachytelephalangy consistently found in PIGV-positive individuals.

Aganglionic megacolon (Hirschsprung disease) HP:0002251

Show evidence (1 reference)

PMID:24129430 SUPPORT Human Clinical

"a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations"

Hirschsprung disease is frequent at the severe end of the PIGV spectrum.

Inability to walk FREQUENT HP:0002540

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"motor delay with non-ambulance (64%)"

Non-ambulance in 64% of the inherited GPI deficiency cohort.

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Genetic Associations

7

PIGV

Gene: PIGV hgnc:26031 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:20802478 SUPPORT Human Clinical

"to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR"

Identifies PIGV as the first HPMRS gene by identity-by-descent exome filtering.

PIGO

Gene: PIGO hgnc:23215 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:22683086 SUPPORT Human Clinical

"Our data identify PIGO as the second gene associated with HPMRS"

Establishes PIGO as the second HPMRS gene.

PGAP2

Gene: PGAP2 hgnc:17893 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:23561847 SUPPORT Human Clinical

"PGAP2 is involved in fatty-acid GPI-anchor remodeling, which occurs in the Golgi apparatus"

Establishes PGAP2 as a remodeling-arm HPMRS gene acting in the Golgi.

PGAP3

Gene: PGAP3 hgnc:23719 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:24439110 SUPPORT Human Clinical

"Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation"

Establishes PGAP3 as the HPMRS4 (remodeling-arm) gene.

PIGW

Gene: PIGW hgnc:23213 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:24367057 SUPPORT Human Clinical

"anchor deficiency caused by mutations in PIGW is associated with West syndrome and hyperphosphatasia with mental retardation"

Establishes PIGW as an HPMRS gene, with a West syndrome presentation.

PIGY

Gene: PIGY hgnc:28213 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:26293662 SUPPORT Human Clinical

"homozygous recessive sequence variants in the GPI biosynthesis gene PIGY"

Establishes PIGY as an HPMRS gene via homozygous recessive variants.

ALPL

Gene: ALPL (tissue-nonspecific alkaline phosphatase) hgnc:438 relationship_type: BIOMARKER

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Medical Actions

6

High-dose pyridoxine / pyridoxal-5-phosphate

Action: pyridoxine supplementation Ontology label: Nutritional Support NCIT:C15433

Agent: pyridoxine CHEBI:16709

High-dose oral pyridoxine (or pyridoxal-5-phosphate) restores the CNS cofactor pool depleted by circulating free alkaline phosphatase. It reduces seizure frequency in roughly a third to a half of patients but rarely achieves seizure freedom, with no established dose-response and occasional paradoxical worsening; chronic high-dose exposure carries a risk of sensory peripheral neuropathy.

Mechanism Target:

MODULATES Circulating Pyridoxal-5-Phosphate Depletion — Supplemental pyridoxine/P5P replenishes the CNS pyridoxal-5-phosphate pool depleted by circulating free alkaline phosphatase, partially relieving the cofactor-deficiency arm that drives seizures.

Show evidence (1 reference)

PMID:35080266 SUPPORT Human Clinical

"reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants"

Prospective cohort found partial seizure reduction in a subset, with no participant reaching seizure freedom.

Folinic acid

Action: Pharmacotherapy NCIT:C15986

Agent: folinic acid CHEBI:15640

Co-administered with pyridoxine when CSF 5-methyltetrahydrofolate is low, as in the documented HPMRS3 case.

Show evidence (1 reference)

PMID:36636587 SUPPORT Human Clinical

"correction with pyridoxine and Folinic acid"

Folinic acid was co-administered with pyridoxine to correct the CSF vitamer deficiencies.

Anticonvulsant therapy

Action: anticonvulsant agent therapy Ontology label: Anticonvulsant Therapy NCIT:C64172

Symptomatic antiseizure medication; levetiracetam is the most-used agent. Epilepsy is drug-resistant in a majority, and no agent is specifically indicated.

Gastrostomy

Action: gastrostomy Ontology label: Gastrostomy NCIT:C52006

Enteral feeding for aspiration risk and feeding difficulty.

Supportive and rehabilitative care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Multidisciplinary supportive care including physical, occupational, and speech therapy, bone-health and scoliosis monitoring, and management of cardiac, renal, and sensory complications.

Genetic counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Recurrence-risk counseling (25% per pregnancy), carrier and cascade testing, and reproductive options including preimplantation and prenatal testing.

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Biochemical Markers

1

Serum tissue-nonspecific alkaline phosphatase

Show evidence (2 references)

PMID:22228761 SUPPORT In Vitro

"Hyperphosphatasia resulted from secretion of ALP, a GPI-anchored protein normally expressed on the cell surface, into serum due to PIGV deficiency."

Mechanistic basis of the elevated serum alkaline phosphatase.

PMID:29310717 SUPPORT Human Clinical

"hyperphosphatasia is a variable feature that is not ideal for a clinical classification"

Hyperphosphatasia is not universal across GPI biosynthesis defects, so a normal or low ALP does not exclude the diagnosis.

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Diagnosis

2

Flow cytometry for GPI-anchored protein surface expression

Functional confirmatory assay: flow cytometry for reduced surface GPI-anchored proteins (FLAER binding the GPI core; CD16/CD24 on granulocytes; CD55/CD59) on blood cells and fibroblasts. Flow confirms a GPI biosynthesis defect but does not identify the specific gene or predict severity.

Markers: FLAER, CD16, CD24, CD55, CD59 on granulocytes and fibroblasts

Show evidence (1 reference)

PMID:29310717 SUPPORT Human Clinical

"flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively"

Flow cytometry of blood cells and fibroblasts is a confirmatory screen for GPI biosynthesis defects.

Molecular genetic testing (exome/genome sequencing)

Whole-exome or whole-genome sequencing (ideally with RNA-seq) is first-line for undiagnosed developmental delay/seizures with high ALP, since targeted panels can miss intronic/3'UTR and promoter variants (documented for PGAP3 and PIGY). Serum transferrin isoelectric focusing is normal, distinguishing HPMRS from classical N-glycosylation CDGs.

clinical whole-exome sequencing NCIT:C101295

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Progression

3

Neonatal-infantile onset

Age: neonatal to first year

Neonatal hypotonia, facial dysmorphism, and incidental hyperphosphatasia, with developmental delay apparent in the first year and median seizure onset around 6 months.

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"Median age at seizure onset was 6 months"

Median seizure onset at 6 months in the largest cohort.

Progressive neurodegeneration

Age: childhood

Long framed as a static encephalopathy, serial imaging instead shows progressive cerebral volume loss (87.5%) and progressive cerebellar atrophy (70.8%), indicating a superimposed neurodegenerative process, with intractable epilepsy and feeding/aspiration difficulty.

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"cerebellar atrophy in 70.8%, indicating a neurodegenerative process"

Serial imaging documents progressive atrophy, establishing a neurodegenerative course.

Outcome

Mortality is substantial (about 18% in the largest cohort), driven by respiratory infection, seizure-related death, and SUDEP; milder genotypes can survive to adulthood.

Show evidence (1 reference)

PMID:38456468 SUPPORT Human Clinical

"15 of whom were deceased at the time of writing"

15 of 83 individuals deceased, the basis for the ~18% mortality figure.

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Prevalence

1

Worldwide

Point Prevalence 0.1 per 100,000 <1 in 1,000,000

Orphanet lists point prevalence <1/1,000,000 (ORPHA:247262). Fewer than ~100 HPMRS patients are reported for the common subtypes; some subtypes have single-digit case counts.

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Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Mabry Syndrome:

Transient hyperphosphatasemia of infancy

Overlapping Features Benign, self-resolving elevation of alkaline phosphatase in infancy without neurologic features; the most common benign mimic to exclude.

Distinguishing Features

Self-limited, resolving over weeks to months, with no developmental or seizure phenotype.

Hypophosphatasia

Overlapping Features The biochemical mirror image: pathogenically LOW alkaline phosphatase from ALPL deficiency, with rickets/osteomalacia rather than the HPMRS neurodevelopmental picture.

Distinguishing Features

Low (not elevated) serum alkaline phosphatase; skeletal mineralization defect.

Other congenital disorders of glycosylation

Overlapping Features Classical N-glycosylation CDGs share multisystem/neurologic features but show an abnormal serum transferrin isoelectric focusing pattern, which is normal in HPMRS.

Distinguishing Features

Abnormal transferrin isoelectric focusing (normal in HPMRS).

GPI biosynthesis defects without hyperphosphatasia

Overlapping Features Multiple congenital anomalies-hypotonia-seizures syndromes (PIGN, PIGT, PIGA) and other GPI defects overlap clinically but lack the mannose-dependent release of soluble ALP and so do not show hyperphosphatasia.

Distinguishing Features

Normal or low alkaline phosphatase despite a GPI-anchor biosynthesis defect.

{ }

Source YAML

click to show

name: Mabry Syndrome
creation_date: "2026-07-27T12:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Mabry syndrome
  term:
    id: MONDO:0016596
    label: hyperphosphatasia-intellectual disability syndrome
synonyms:
- hyperphosphatasia with impaired intellectual development syndrome
- hyperphosphatasia with mental retardation syndrome
- HPMRS
- GPI biosynthesis defect
description: >-
  Mabry syndrome (hyperphosphatasia with intellectual disability syndrome, HPMRS)
  is an autosomal recessive, multisystem neurodevelopmental disorder caused by
  defective biosynthesis or Golgi remodeling of the glycosylphosphatidylinositol
  (GPI) anchor, the lipid moiety that tethers more than 150 proteins to the outer
  face of the plasma membrane. The clinical hallmark is a paradoxical pairing of a
  neurodevelopmental syndrome (developmental delay, intellectual disability,
  seizures, hypotonia, facial dysmorphism, brachytelephalangy) with a bone enzyme
  abnormality on routine chemistry: persistently elevated serum tissue-nonspecific
  alkaline phosphatase (hyperphosphatasia). Six genetically distinct subtypes
  (HPMRS1-6; genes PIGV, PIGO, PGAP2, PGAP3, PIGW, PIGY) sit within the broader
  family of inherited GPI deficiencies. Every viable patient retains partial pathway
  function, because complete GPI loss is embryonic-lethal.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >-
    All six HPMRS subtypes are inherited in an autosomal recessive manner from
    biallelic hypomorphic (partial loss-of-function) variants; recurrence risk is
    25% per pregnancy. Expressivity is highly variable both within and between the
    six genes. Complete null alleles are not compatible with life in this pathway,
    so at least one hypomorphic allele is always retained.
  evidence:
  - reference: PMID:20802478
    reference_title: "Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase."
    explanation: Establishes the autosomal recessive inheritance and the defining triad of HPMRS.

has_subtypes:
- name: HPMRS1
  display_name: HPMRS1 (PIGV)
  description: >-
    Most common subtype; caused by biallelic PIGV variants. PIGV encodes GPI
    mannosyltransferase II, which adds the second mannose to the GPI glycan in the
    endoplasmic reticulum. The recurrent European founder allele c.1022C>A
    (p.Ala341Glu) is present in ~80% of PIGV-positive families.
  subtype_term:
    preferred_term: hyperphosphatasia with intellectual disability syndrome 1
    term:
      id: MONDO:0009398
      label: hyperphosphatasia with intellectual disability syndrome 1
  genes:
  - preferred_term: PIGV
    term:
      id: hgnc:26031
      label: PIGV
- name: HPMRS2
  display_name: HPMRS2 (PIGO)
  description: >-
    Caused by biallelic PIGO variants. PIGO is the phosphoethanolamine transferase
    that adds the ethanolamine phosphate bridge to the third mannose in the ER; the
    second-most-frequently implicated gene after PIGV.
  subtype_term:
    preferred_term: hyperphosphatasia with intellectual disability syndrome 2
    term:
      id: MONDO:0013882
      label: hyperphosphatasia with intellectual disability syndrome 2
  genes:
  - preferred_term: PIGO
    term:
      id: hgnc:23215
      label: PIGO
- name: HPMRS3
  display_name: HPMRS3 (PGAP2)
  description: >-
    Caused by biallelic PGAP2 variants. PGAP2 performs Golgi fatty-acid remodeling
    (stearate reacylation) of the GPI anchor; the 1970 index Mabry family carries a
    PGAP2 variant. HPMRS3 appears the most pyridoxine-responsive subtype.
  subtype_term:
    preferred_term: hyperphosphatasia with intellectual disability syndrome 3
    term:
      id: MONDO:0013628
      label: hyperphosphatasia with intellectual disability syndrome 3
  genes:
  - preferred_term: PGAP2
    term:
      id: hgnc:17893
      label: PGAP2
- name: HPMRS4
  display_name: HPMRS4 (PGAP3)
  description: >-
    Caused by biallelic PGAP3 variants. PGAP3 is the GPI-anchor maturation
    deacylase in the Golgi; pathogenic noncoding (intronic/3'UTR) variants are
    documented and are missed by panel-based testing.
  subtype_term:
    preferred_term: hyperphosphatasia with intellectual disability syndrome 4
    term:
      id: MONDO:0014318
      label: hyperphosphatasia with intellectual disability syndrome 4
  genes:
  - preferred_term: PGAP3
    term:
      id: hgnc:23719
      label: PGAP3
- name: HPMRS5
  display_name: HPMRS5 (PIGW)
  description: >-
    Caused by biallelic PIGW variants. PIGW is the inositol acyltransferase acting
    early in ER GPI assembly; reported presentations include West syndrome with
    hypsarrhythmia.
  subtype_term:
    preferred_term: hyperphosphatasia with intellectual disability syndrome 5
    term:
      id: MONDO:0014457
      label: hyperphosphatasia with intellectual disability syndrome 5
  genes:
  - preferred_term: PIGW
    term:
      id: hgnc:23213
      label: PIGW
- name: HPMRS6
  display_name: HPMRS6 (PIGY)
  description: >-
    Caused by biallelic PIGY variants. PIGY is a subunit of the GPI-GlcNAc
    transferase complex; severity tracks residual expression, ranging from lethal
    multisystem disease to moderate developmental delay with microcephaly.
  subtype_term:
    preferred_term: hyperphosphatasia with intellectual disability syndrome 6
    term:
      id: MONDO:0014780
      label: hyperphosphatasia with intellectual disability syndrome 6
  genes:
  - preferred_term: PIGY
    term:
      id: hgnc:28213
      label: PIGY

classifications:
  isds_skeletal_category:
  - classification_value: brachydactyly_with_extraskeletal_manifestations
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 38 "Brachydactylies
      (with extraskeletal manifestations)"; listed as "Hyperphosphatasia with
      mental retardation, brachytelephalangy, and distinct face".
genetic:
- name: PIGV
  gene_term:
    preferred_term: PIGV
    term:
      id: hgnc:26031
      label: PIGV
  relationship_type: CAUSATIVE
  subtype: HPMRS1
  variant_origin: GERMLINE
  case_fractions:
  - population: PIGV-positive HPMRS families
    case_fraction_percent: 80.0
    notes: Recurrent European founder allele c.1022C>A (p.Ala341Glu) among PIGV-positive families.
    evidence:
    - reference: PMID:24129430
      reference_title: "Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The most frequent mutation detected in about 80%"
      explanation: Quantifies the c.1022C>A founder allele share among PIGV-positive HPMRS families.
  evidence:
  - reference: PMID:20802478
    reference_title: "Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR"
    explanation: Identifies PIGV as the first HPMRS gene by identity-by-descent exome filtering.
- name: PIGO
  gene_term:
    preferred_term: PIGO
    term:
      id: hgnc:23215
      label: PIGO
  relationship_type: CAUSATIVE
  subtype: HPMRS2
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:22683086
    reference_title: "Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data identify PIGO as the second gene associated with HPMRS"
    explanation: Establishes PIGO as the second HPMRS gene.
- name: PGAP2
  gene_term:
    preferred_term: PGAP2
    term:
      id: hgnc:17893
      label: PGAP2
  relationship_type: CAUSATIVE
  subtype: HPMRS3
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:23561847
    reference_title: "PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PGAP2 is involved in fatty-acid GPI-anchor remodeling, which occurs in the Golgi apparatus"
    explanation: Establishes PGAP2 as a remodeling-arm HPMRS gene acting in the Golgi.
- name: PGAP3
  gene_term:
    preferred_term: PGAP3
    term:
      id: hgnc:23719
      label: PGAP3
  relationship_type: CAUSATIVE
  subtype: HPMRS4
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:24439110
    reference_title: "Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation"
    explanation: Establishes PGAP3 as the HPMRS4 (remodeling-arm) gene.
- name: PIGW
  gene_term:
    preferred_term: PIGW
    term:
      id: hgnc:23213
      label: PIGW
  relationship_type: CAUSATIVE
  subtype: HPMRS5
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:24367057
    reference_title: "Glycosylphosphatidylinositol (GPI) anchor deficiency caused by mutations in PIGW is associated with West syndrome and hyperphosphatasia with mental retardation syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anchor deficiency caused by mutations in PIGW is associated with West syndrome and hyperphosphatasia with mental retardation"
    explanation: Establishes PIGW as an HPMRS gene, with a West syndrome presentation.
- name: PIGY
  gene_term:
    preferred_term: PIGY
    term:
      id: hgnc:28213
      label: PIGY
  relationship_type: CAUSATIVE
  subtype: HPMRS6
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:26293662
    reference_title: "Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "homozygous recessive sequence variants in the GPI biosynthesis gene PIGY"
    explanation: Establishes PIGY as an HPMRS gene via homozygous recessive variants.
- name: ALPL
  gene_term:
    preferred_term: ALPL (tissue-nonspecific alkaline phosphatase)
    term:
      id: hgnc:438
      label: ALPL
  relationship_type: BIOMARKER
  notes: >-
    ALPL is not causal. It encodes the GPI-anchored tissue-nonspecific alkaline
    phosphatase whose mis-release from the cell surface produces the defining
    hyperphosphatasia biomarker.

pathophysiology:
- name: Hypomorphic GPI-Pathway Enzyme Deficiency
  description: >-
    Biallelic hypomorphic variants reduce the abundance or activity of a GPI-anchor
    biosynthesis enzyme (PIGV, PIGO, PIGW, or PIGY) in the endoplasmic reticulum
    membrane. The A341E founder change, for example, drastically decreases PIGV
    protein expression rather than abolishing the catalytic site, leaving partial
    pathway function intact.
  biological_processes:
  - preferred_term: GPI anchor biosynthetic process
    term:
      id: GO:0006506
      label: GPI anchor biosynthetic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: GPI mannosyltransferase activity
    term:
      id: GO:0004376
      label: GPI mannosyltransferase activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  downstream:
  - target: Accumulation of Incomplete Mannosylated GPI Intermediates
  evidence:
  - reference: PMID:22228761
    reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutations found in four families caused amino acid substitutions A341E, A341V, Q256K, and H385P, which drastically decreased expression of the PIGV protein."
    explanation: Demonstrates the hypomorphic (reduced-abundance) nature of HPMRS-causing PIGV variants.
- name: Accumulation of Incomplete Mannosylated GPI Intermediates
  description: >-
    With a biosynthetic enzyme partially deficient, GPI assembly stalls mid-pathway
    and mannose-bearing incomplete GPI intermediates accumulate in the ER. This
    mannose-bearing (rather than mannose-free) stall is the decisive branch point
    that determines whether hyperphosphatasia follows.
  cellular_components:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  downstream:
  - target: Transamidase-Mediated Release of Soluble Alkaline Phosphatase
  - target: Reduced Cell-Surface Display of GPI-Anchored Proteins
- name: Impaired Golgi GPI-Anchor Fatty-Acid Remodeling
  description: >-
    In the remodeling-arm subtypes (PGAP2, PGAP3), ER GPI assembly completes but
    Golgi fatty-acid remodeling of the attached anchor fails. The unremodeled
    lyso-GPI anchor cannot stably partition into membrane lipid rafts and becomes a
    substrate for phospholipases that release the attached protein. This arm
    converges on the same downstream nodes as the biosynthesis arm.
  cellular_components:
  - preferred_term: Golgi membrane
    term:
      id: GO:0000139
      label: Golgi membrane
  downstream:
  - target: Transamidase-Mediated Release of Soluble Alkaline Phosphatase
  - target: Reduced Cell-Surface Display of GPI-Anchored Proteins
  evidence:
  - reference: PMID:23561847
    reference_title: "PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PGAP2 is involved in fatty-acid GPI-anchor remodeling, which occurs in the Golgi apparatus"
    explanation: Cell-biology characterization (from a human genetics report) defining the Golgi remodeling arm as a distinct upstream route to the shared downstream defect.
- name: Transamidase-Mediated Release of Soluble Alkaline Phosphatase
  description: >-
    The GPI transamidase recognizes the truncated mannose-bearing intermediate,
    cleaves the C-terminal signal peptide from tissue-nonspecific alkaline
    phosphatase anyway, and liberates the enzyme as a soluble, unanchored protein
    into the serum. This is the direct molecular cause of the hyperphosphatasia
    biomarker, and it explains why mannose-free GPI defects (e.g. PIGM) show no
    hyperphosphatasia.
  molecular_functions:
  - preferred_term: GPI-anchor transamidase activity
    term:
      id: GO:0003923
      label: GPI-anchor transamidase activity
  - preferred_term: alkaline phosphatase activity
    term:
      id: GO:0004035
      label: alkaline phosphatase activity
  downstream:
  - target: Circulating Pyridoxal-5-Phosphate Depletion
  evidence:
  - reference: PMID:22228761
    reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Hyperphosphatasia resulted from secretion of ALP, a GPI-anchored protein normally expressed on the cell surface, into serum due to PIGV deficiency."
    explanation: Directly demonstrates the transamidase-dependent soluble-ALP-release mechanism.
  - reference: PMID:22228761
    reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, a previously reported PIGM deficiency, in which there is a defect in the transfer of the first mannose, does not result in hyperphosphatasia."
    explanation: The mannose-dependent branch condition distinguishing HPMRS from GPI defects without hyperphosphatasia.
- name: Reduced Cell-Surface Display of GPI-Anchored Proteins
  description: >-
    The failed anchor also leaves a broad guild of GPI-anchored surface proteins
    (CD55, CD59, contactins, NCAM-120, ephrin-A ligands, glypicans) reduced on the
    cell surface of patient granulocytes and fibroblasts. This surface deficiency,
    rather than the ALP release, is the arm that actually causes the disease.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  downstream:
  - target: Impaired Neuronal GPI-Anchored-Protein-Dependent Synaptic Function
- name: Impaired Neuronal GPI-Anchored-Protein-Dependent Synaptic Function
  description: >-
    Many GPI-anchored proteins are axon-guidance and synapse-organizing molecules,
    so their surface loss impairs neuronal connectivity and synaptic transmission.
    The Pigv341E mouse shows decreased hippocampal synaptic transmission underlying
    impaired memory formation.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: DECREASED
  cellular_components:
  - preferred_term: synapse
    term:
      id: GO:0045202
      label: synapse
  downstream:
  - target: Abnormal Brain Development and Progressive Neurodegeneration
  evidence:
  - reference: PMID:33402532
    reference_title: "A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "decreased hippocampal synaptic transmission that could underlie impaired memory formation"
    explanation: Mouse knock-in of the human PIGV founder allele shows the synaptic-transmission defect.
- name: Abnormal Brain Development and Progressive Neurodegeneration
  description: >-
    Disordered GPI-AP-dependent wiring produces structural brain abnormalities
    (cerebral and cerebellar atrophy, callosal anomalies, delayed myelination).
    Serial imaging demonstrates progressive cerebral and cerebellar volume loss,
    indicating a superimposed neurodegenerative process on the neurodevelopmental
    substrate.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  downstream:
  - target: Seizures and Developmental Epileptic Encephalopathy
- name: Circulating Pyridoxal-5-Phosphate Depletion
  description: >-
    Free (unanchored) serum alkaline phosphatase dephosphorylates and degrades
    circulating pyridoxal 5'-phosphate, the active vitamin B6 vitamer and the
    cofactor for glutamate decarboxylase. CNS pyridoxal-5-phosphate falls, GABA
    synthesis falls, and a genetically fixed enzyme-trafficking defect thereby
    creates an acquired, nutritionally correctable cofactor deficiency in the brain.
  chemical_entities:
  - preferred_term: pyridoxal 5'-phosphate
    term:
      id: CHEBI:18405
      label: pyridoxal 5'-phosphate
    modifier: DECREASED
  downstream:
  - target: Seizures and Developmental Epileptic Encephalopathy
  evidence:
  - reference: PMID:36636587
    reference_title: "Hyperphosphatasia with mental retardation syndrome 3: Cerebrospinal fluid abnormalities and correction with pyridoxine and Folinic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebrospinal fluid (CSF) neurotransmitter analysis showed low levels of pyridoxal phosphate and 5-methyltetrahydrofolate and raised homovanillic acid"
    explanation: HPMRS3 case with documented low CSF pyridoxal-5-phosphate, directly evidencing the cofactor-depletion side branch.
- name: Seizures and Developmental Epileptic Encephalopathy
  description: >-
    Two converging inputs drive the epilepsy phenotype: the structural/synaptic
    substrate from disordered brain development, and the treatable cofactor-depletion
    substrate (low CNS pyridoxal-5-phosphate). The dual input explains why pyridoxine
    partially helps a subset while rarely achieving seizure freedom.
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seizures (83%), hypotonia (72%)"
    explanation: Seizures are a core feature in the largest inherited GPI deficiency cohort.

phenotypes:
- name: Elevated serum alkaline phosphatase
  category: Laboratory
  description: >-
    Persistently elevated tissue-nonspecific serum alkaline phosphatase is the
    biochemical calling card of HPMRS, though it is not universal across the broader
    GPI deficiency family.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: PMID:24129430
    reference_title: "Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe developmental delays, particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in"
    explanation: Hyperphosphatasia is consistently found in PIGV-positive individuals.
- name: Intellectual disability
  description: >-
    Developmental disability and intellectual disability are near-universal. The 90%
    frequency is derived from the broader inherited GPI deficiency (IGD) cohort (83
    individuals across 24 genes), not HPMRS alone.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Core clinical features were developmental delay or intellectual disability (DD/ID, 90%)"
    explanation: DD/ID reported in 90% of the inherited GPI deficiency cohort (broader-than-HPMRS denominator).
- name: Global developmental delay
  description: Frequency derived from the broader IGD cohort denominator, not HPMRS alone.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Core clinical features were developmental delay or intellectual disability (DD/ID, 90%)"
    explanation: Developmental delay reported in 90% of the inherited GPI deficiency cohort.
- name: Seizures
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seizures (83%), hypotonia (72%)"
    explanation: Seizures reported in 83% of the inherited GPI deficiency cohort.
- name: Hypotonia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seizures (83%), hypotonia (72%)"
    explanation: Hypotonia reported in 72% of the cohort.
- name: Brachytelephalangy
  description: Short distal phalanges are a near-constant supporting feature.
  phenotype_term:
    preferred_term: Short distal phalanx of finger
    term:
      id: HP:0009882
      label: Short distal phalanx of finger
  evidence:
  - reference: PMID:24129430
    reference_title: "Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brachytelephalangy, and hyperphosphatasia are consistently found in"
    explanation: Brachytelephalangy consistently found in PIGV-positive individuals.
- name: Delayed speech and language development
  description: Frequency derived from the broader IGD cohort denominator, not HPMRS alone.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "delayed or absent speech (95%)"
    explanation: Delayed or absent speech in 95% of the inherited GPI deficiency cohort.
- name: Hypertelorism
  description: Part of the distinctive facial gestalt used for automated gene prediction.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:24129430
    reference_title: "Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in"
    explanation: Distinctive facial anomalies are consistently found in PIGV-positive individuals.
- name: Aganglionic megacolon (Hirschsprung disease)
  description: Enteric neurocristopathy seen at the severe end of the spectrum.
  phenotype_term:
    preferred_term: Aganglionic megacolon
    term:
      id: HP:0002251
      label: Aganglionic megacolon
  evidence:
  - reference: PMID:24129430
    reference_title: "Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations"
    explanation: Hirschsprung disease is frequent at the severe end of the PIGV spectrum.
- name: Cerebral atrophy
  description: >-
    Progressive cerebral volume loss on serial imaging; frequency from the broader
    IGD cohort denominator, not HPMRS alone.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cerebral atrophy (75%)"
    explanation: Cerebral atrophy in 75% of the inherited GPI deficiency cohort.
- name: Cerebellar atrophy
  description: Frequency from the broader IGD cohort denominator, not HPMRS alone.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cerebellar atrophy (60%)"
    explanation: Cerebellar atrophy in 60% of the inherited GPI deficiency cohort.
- name: Sensorineural hearing impairment
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
- name: Callosal anomalies
  description: Corpus callosum anomalies; frequency from the broader IGD cohort denominator.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal corpus callosum morphology
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosal anomalies (57%)"
    explanation: Callosal anomalies in 57% of the inherited GPI deficiency cohort.
- name: Gastrointestinal anomalies
  description: GI involvement (Hirschsprung, anorectal malformation, GERD, aspiration); IGD-cohort denominator.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of the gastrointestinal tract
    term:
      id: HP:0011024
      label: Abnormality of the gastrointestinal tract
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies"
    explanation: GI involvement in 66% of the inherited GPI deficiency cohort.
- name: Cardiac anomalies
  description: Structural cardiac anomalies (e.g. septal defects); IGD-cohort denominator.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies"
    explanation: Cardiac anomalies in 19% of the inherited GPI deficiency cohort.
- name: Renal anomalies
  description: Renal anomalies (hydronephrosis, cysts, dysplasia); IGD-cohort denominator.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormality of the kidney
    term:
      id: HP:0000077
      label: Abnormality of the kidney
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies"
    explanation: Renal anomalies in 14% of the inherited GPI deficiency cohort.
- name: Inability to walk
  description: Non-ambulance; IGD-cohort denominator.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "motor delay with non-ambulance (64%)"
    explanation: Non-ambulance in 64% of the inherited GPI deficiency cohort.
- name: Severe global developmental delay
  description: Severe-to-profound developmental disability/intellectual disability; IGD-cohort denominator.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Severe global developmental delay
    term:
      id: HP:0011344
      label: Severe global developmental delay
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe-to-profound DD/ID (59%)"
    explanation: Severe-to-profound DD/ID in 59% of the inherited GPI deficiency cohort.

biochemical:
- name: Serum tissue-nonspecific alkaline phosphatase
  notes: >-
    Serum tissue-nonspecific alkaline phosphatase is persistently elevated because
    the GPI-anchored enzyme is released into the circulation rather than degraded.
    Isoenzyme fractionation confirms the tissue-nonspecific (ALPL) isoform without
    accompanying bone disease. Notably, elevated ALP is not universal across
    inherited GPI deficiency, and normal or low ALP does not exclude the diagnosis.
  evidence:
  - reference: PMID:22228761
    reference_title: "Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Hyperphosphatasia resulted from secretion of ALP, a GPI-anchored protein normally expressed on the cell surface, into serum due to PIGV deficiency."
    explanation: Mechanistic basis of the elevated serum alkaline phosphatase.
  - reference: PMID:29310717
    reference_title: "Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperphosphatasia is a variable feature that is not ideal for a clinical classification"
    explanation: Hyperphosphatasia is not universal across GPI biosynthesis defects, so a normal or low ALP does not exclude the diagnosis.

prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.1
  notes: >-
    Orphanet lists point prevalence <1/1,000,000 (ORPHA:247262). Fewer than ~100
    HPMRS patients are reported for the common subtypes; some subtypes have
    single-digit case counts.

diagnosis:
- name: Flow cytometry for GPI-anchored protein surface expression
  description: >-
    Functional confirmatory assay: flow cytometry for reduced surface GPI-anchored
    proteins (FLAER binding the GPI core; CD16/CD24 on granulocytes; CD55/CD59) on
    blood cells and fibroblasts. Flow confirms a GPI biosynthesis defect but does not
    identify the specific gene or predict severity.
  markers: "FLAER, CD16, CD24, CD55, CD59 on granulocytes and fibroblasts"
  evidence:
  - reference: PMID:29310717
    reference_title: "Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively"
    explanation: Flow cytometry of blood cells and fibroblasts is a confirmatory screen for GPI biosynthesis defects.
- name: Molecular genetic testing (exome/genome sequencing)
  description: >-
    Whole-exome or whole-genome sequencing (ideally with RNA-seq) is first-line for
    undiagnosed developmental delay/seizures with high ALP, since targeted panels can
    miss intronic/3'UTR and promoter variants (documented for PGAP3 and PIGY). Serum
    transferrin isoelectric focusing is normal, distinguishing HPMRS from classical
    N-glycosylation CDGs.
  diagnosis_term:
    preferred_term: clinical whole-exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing

progression:
- phase: Neonatal-infantile onset
  age_range: neonatal to first year
  notes: >-
    Neonatal hypotonia, facial dysmorphism, and incidental hyperphosphatasia, with
    developmental delay apparent in the first year and median seizure onset around
    6 months.
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median age at seizure onset was 6 months"
    explanation: Median seizure onset at 6 months in the largest cohort.
- phase: Progressive neurodegeneration
  age_range: childhood
  notes: >-
    Long framed as a static encephalopathy, serial imaging instead shows progressive
    cerebral volume loss (87.5%) and progressive cerebellar atrophy (70.8%),
    indicating a superimposed neurodegenerative process, with intractable epilepsy
    and feeding/aspiration difficulty.
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cerebellar atrophy in 70.8%, indicating a neurodegenerative process"
    explanation: Serial imaging documents progressive atrophy, establishing a neurodegenerative course.
- phase: Outcome
  notes: >-
    Mortality is substantial (about 18% in the largest cohort), driven by respiratory
    infection, seizure-related death, and SUDEP; milder genotypes can survive to
    adulthood.
  evidence:
  - reference: PMID:38456468
    reference_title: "The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "15 of whom were deceased at the time of writing"
    explanation: 15 of 83 individuals deceased, the basis for the ~18% mortality figure.

treatments:
- name: High-dose pyridoxine / pyridoxal-5-phosphate
  description: >-
    High-dose oral pyridoxine (or pyridoxal-5-phosphate) restores the CNS cofactor
    pool depleted by circulating free alkaline phosphatase. It reduces seizure
    frequency in roughly a third to a half of patients but rarely achieves seizure
    freedom, with no established dose-response and occasional paradoxical worsening;
    chronic high-dose exposure carries a risk of sensory peripheral neuropathy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: pyridoxine supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: pyridoxine
      term:
        id: CHEBI:16709
        label: pyridoxine
  target_mechanisms:
  - target: Circulating Pyridoxal-5-Phosphate Depletion
    treatment_effect: MODULATES
    description: >-
      Supplemental pyridoxine/P5P replenishes the CNS pyridoxal-5-phosphate pool
      depleted by circulating free alkaline phosphatase, partially relieving the
      cofactor-deficiency arm that drives seizures.
  evidence:
  - reference: PMID:35080266
    reference_title: "Pyridoxine or pyridoxal-5-phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants"
    explanation: Prospective cohort found partial seizure reduction in a subset, with no participant reaching seizure freedom.
- name: Folinic acid
  description: >-
    Co-administered with pyridoxine when CSF 5-methyltetrahydrofolate is low, as in
    the documented HPMRS3 case.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: folinic acid
      term:
        id: CHEBI:15640
        label: 5-formyltetrahydrofolic acid
  evidence:
  - reference: PMID:36636587
    reference_title: "Hyperphosphatasia with mental retardation syndrome 3: Cerebrospinal fluid abnormalities and correction with pyridoxine and Folinic acid."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "correction with pyridoxine and Folinic acid"
    explanation: Folinic acid was co-administered with pyridoxine to correct the CSF vitamer deficiencies.
- name: Anticonvulsant therapy
  description: >-
    Symptomatic antiseizure medication; levetiracetam is the most-used agent.
    Epilepsy is drug-resistant in a majority, and no agent is specifically indicated.
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
- name: Gastrostomy
  description: Enteral feeding for aspiration risk and feeding difficulty.
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
- name: Supportive and rehabilitative care
  description: >-
    Multidisciplinary supportive care including physical, occupational, and speech
    therapy, bone-health and scoliosis monitoring, and management of cardiac, renal,
    and sensory complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic counseling
  description: >-
    Recurrence-risk counseling (25% per pregnancy), carrier and cascade testing, and
    reproductive options including preimplantation and prenatal testing.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling

differential_diagnoses:
- name: Transient hyperphosphatasemia of infancy
  description: >-
    Benign, self-resolving elevation of alkaline phosphatase in infancy without
    neurologic features; the most common benign mimic to exclude.
  distinguishing_features:
  - Self-limited, resolving over weeks to months, with no developmental or seizure phenotype.
- name: Hypophosphatasia
  description: >-
    The biochemical mirror image: pathogenically LOW alkaline phosphatase from ALPL
    deficiency, with rickets/osteomalacia rather than the HPMRS neurodevelopmental
    picture.
  distinguishing_features:
  - Low (not elevated) serum alkaline phosphatase; skeletal mineralization defect.
- name: Other congenital disorders of glycosylation
  description: >-
    Classical N-glycosylation CDGs share multisystem/neurologic features but show an
    abnormal serum transferrin isoelectric focusing pattern, which is normal in HPMRS.
  distinguishing_features:
  - Abnormal transferrin isoelectric focusing (normal in HPMRS).
- name: GPI biosynthesis defects without hyperphosphatasia
  description: >-
    Multiple congenital anomalies-hypotonia-seizures syndromes (PIGN, PIGT, PIGA)
    and other GPI defects overlap clinically but lack the mannose-dependent release
    of soluble ALP and so do not show hyperphosphatasia.
  distinguishing_features:
  - Normal or low alkaline phosphatase despite a GPI-anchor biosynthesis defect.

discussions:
- discussion_id: gap_mabry_episignature_omics
  prompt: >-
    Does HPMRS/Mabry syndrome have a reproducible DNA-methylation episignature or a
    disease-specific human transcriptomic/proteomic/metabolomic signature that could
    serve as a diagnostic classifier or severity biomarker?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Cell-Surface Display of GPI-Anchored Proteins
  rationale: >-
    Unlike several other intellectual-disability syndromes, no DNA-methylation
    episignature and no human omics dataset specific to HPMRS have been reported; the
    only omics data are from the Pigv341E mouse. Neither serum ALP nor flow-cytometry
    GPI-anchored-protein levels correlate with phenotypic severity, so there is
    currently no validated molecular severity biomarker. Filling this gap would
    improve diagnosis of ALP-normal cases and enable objective outcome measures.
  proposed_experiments:
  - experiment_id: exp_mabry_episignature
    name: Genome-wide methylation and multi-omics profiling of HPMRS patient cohorts
    description: >-
      Perform EPIC-array DNA methylation profiling plus RNA-seq on blood and
      fibroblasts across HPMRS genes to test for a reproducible episignature and
      genotype/severity-correlated expression signatures.
- discussion_id: hmm_mabry_pigv341e_mouse
  prompt: >-
    How faithfully does the Pigv341E knock-in mouse model the human HPMRS phenotype,
    given that it inverts the social phenotype and leaves the defining biomarker
    unmeasured?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Neuronal GPI-Anchored-Protein-Dependent Synaptic Function
  rationale: >-
    The Pigv341E mouse faithfully recapitulates the neurologic core (motor deficits,
    seizure susceptibility, memory impairment, hippocampal synaptopathy), but shows
    ENHANCED rather than reduced sociability - opposite in valence to the human
    phenotype - and did not quantify alkaline phosphatase, so it does not validate
    the defining hyperphosphatasia biomarker. Facial dysmorphism, brachytelephalangy,
    Hirschsprung disease, and progressive cerebral/cerebellar atrophy are also not
    reproduced. Translational validity of the social-behavior and biomarker domains
    is therefore the open question.
  proposed_experiments:
  - experiment_id: exp_mabry_mouse_alp
    name: Serum ALP and cross-species behavioral validation in GPI-anchor-deficient mice
    description: >-
      Quantify serum tissue-nonspecific alkaline phosphatase and re-assess social
      behavior with standardized assays across Pigv341E and additional HPMRS-gene
      mouse lines to test whether the biomarker and social-domain mismatches are
      model-specific.
  evidence:
  - reference: PMID:33402532
    reference_title: "A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human phenotypes and exhibits hippocampal synaptic dysfunctions."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A CRISPR-Cas9-engineered mouse model for GPI-anchor deficiency mirrors human"
    explanation: The knock-in mouse mirrors human neurologic phenotypes but diverges on sociability and the ALP biomarker.

📚

References & Deep Research

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 26 citations 2026-07-27T22:49:03.202100

1. Disease Information

1.1 Overview

Mabry syndrome / HPMRS is an autosomal recessive, multisystem neurodevelopmental disorder caused by defective biosynthesis or remodeling of the glycosylphosphatidylinositol (GPI) anchor — the little lipid grommet that tacks >150 different human proteins onto the outer face of the plasma membrane. When the grommet is built wrong, some of those proteins never make it to the surface, and one of them — tissue-nonspecific alkaline phosphatase — gets snipped loose and dumped into the blood. Hence the paradoxical signature: a neurodevelopmental disease whose calling card is a bone enzyme on a routine chemistry panel.

The cardinal triad, per the 2024 index-case review (Genes 2024, PMC11121671, PMID:38790248): 1. Hyperphosphatasia (persistently elevated tissue-nonspecific alkaline phosphatase) 2. Seizures 3. Developmental disability / intellectual disability

with hypotonia, distinctive facial dysmorphism, and brachytelephalangy (short terminal phalanges) as the near-constant supporting cast.

1.2 Identifiers

Resource	ID	Label
MONDO (grouping — "Mabry syndrome")	`MONDO:0016596`	hyperphosphatasia-intellectual disability syndrome
MONDO (HPMRS1, PIGV)	`MONDO:0009398`	hyperphosphatasia with intellectual disability syndrome 1
MONDO (HPMRS2, PIGO)	`MONDO:0013882`	hyperphosphatasia with intellectual disability syndrome 2
MONDO (HPMRS3, PGAP2)	`MONDO:0013628`	hyperphosphatasia with intellectual disability syndrome 3
MONDO (HPMRS4, PGAP3)	`MONDO:0014318`	hyperphosphatasia with intellectual disability syndrome 4
MONDO (HPMRS5, PIGW)	`MONDO:0014457`	hyperphosphatasia with intellectual disability syndrome 5
MONDO (HPMRS6, PIGY)	`MONDO:0014780`	hyperphosphatasia with intellectual disability syndrome 6
OMIM phenotype series	`OMIMPS:239300`	—
OMIM (HPMRS1–6)	239300, 614749, 614207, 615716, 616025, 616809	—
Orphanet	`ORPHA:247262`	Hyperphosphatasia-intellectual disability syndrome
DOID	`DOID:0070431` (grouping), `DOID:0070433` (HPMRS1)	—
UMLS	C1855923 (grouping), C4551502 (HPMRS1)	—
MedGen	383800 (grouping), 1647044 (HPMRS1)	—
SNOMED CT	33982008	—
GARD	0017188 / 0018349	—
ICD-10	Q87.8 (per Orphanet)	Other specified congenital malformation syndromes
ICD-11	No dedicated stem code identified; falls under congenital-malformation-syndrome / inborn-error-of-metabolism chapters — flag as unverified
MeSH	No dedicated descriptor; indexed via Intellectual Disability + Alkaline Phosphatase/blood. Flag as unverified.

MONDO parentage for the grouping term (useful for classifications): is_a developmental anomaly of metabolic origin (MONDO:0015327), syndromic dyslipidemia (MONDO:0015905), inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation (MONDO:0017748), congenital limb malformation (MONDO:0019054).

1.3 Synonyms

Mabry syndrome · HPMR · HPMRS · hyperphosphatasia with mental retardation syndrome (historical; "mental retardation" is deprecated language, retained here only where it appears verbatim in titles) · hyperphosphatasia with impaired intellectual development syndrome · hyperphosphatasia-intellectual disability syndrome · GPI biosynthesis defect (GPIBD) subtype · inherited GPI deficiency (IGD).

1.4 Data provenance

Everything below is disease-level aggregated knowledge from case reports, case series, and multinational retrospective cohorts. There is no EHR-derived or registry-derived individual-patient dataset for Mabry syndrome specifically. The single largest structured cohort is the multinational IGD study of 83 individuals from 75 families (Sidpra et al., Brain 2024;147:2775–2790), and the largest PIGV-specific series is 16 families (Horn et al., Eur J Hum Genet 2014, PMID:24129430).

2. Etiology

2.1 Primary cause

Biallelic hypomorphic (partial loss-of-function) germline variants in genes of the GPI-anchor biosynthesis/remodeling pathway. The word hypomorphic is load-bearing: complete GPI loss is embryonic-lethal, so every viable patient retains partial pathway function. This is why the phenotype is a graded spectrum rather than an on/off switch.

Six genes give the HPMRS/Mabry phenotype specifically (Genes 2024, PMC11121671):

Subtype	Gene	HGNC	Compartment	Pathway role
HPMRS1	PIGV	`hgnc:26031`	ER	GPI α-1,6-mannosyltransferase II (adds 2nd mannose)
HPMRS2	PIGO	`hgnc:23215`	ER	Phosphoethanolamine transferase (3rd mannose EtNP)
HPMRS3	PGAP2	`hgnc:17893`	Golgi	Fatty-acid remodeling (stearate reacylation)
HPMRS4	PGAP3	`hgnc:23719`	Golgi	GPI-anchor maturation (deacylation)
HPMRS5	PIGW	`hgnc:23213`	ER	Inositol acyltransferase (early step 3)
HPMRS6	PIGY	`hgnc:28213`	ER	GPI-GlcNAc transferase complex subunit

"HPMRS1 [MIM: 239300] is the phenotype resulting from inheritance of biallelic PIGV variants. HPMRS2 (MIM 614749), HPMRS5 (MIM 616025) and HPMRS6 (MIM 616809) result from disruption of the PIGO, PIGW and PIGY genes expressed in the endoplasmic reticulum. HPMRS3 (MIM 614207) and HPMRS4 (MIM 615716) result from disruption of post attachment to proteins PGAP2 (HPMRS3) and PGAP3 (HPMRS4)." — Genes 2024

PIGV and PIGO are the two most frequently implicated genes in Mabry syndrome.

2.2 Genetic risk factors

Causal: biallelic pathogenic variants as above. No susceptibility loci or GWAS signals — this is a straight Mendelian recessive disease.
Founder/recurrent allele: PIGV c.1022C>A (p.Ala341Glu), rs139073416. Horn et al. found it "in about 80% of affected families," both homozygous and compound heterozygous. gnomAD reports it at ~0.02% (30/126,708) of European chromosomes; ESP European-American MAF 0.00035 — consistent with a European founder allele of modest frequency. First reported in three siblings of unrelated German parents (Krawitz et al., Nat Genet 2010, PMID:20802478).
Consanguinity is a major contributor for the rarer subtypes — PGAP3 was mapped in a consanguineous Pakistani family via autozygosity mapping (Howard et al., Am J Hum Genet 2014, PMID:24439110); PIGY in a consanguineous family via a 7.7 Mb autozygous region (Ilkovski et al., Hum Mol Genet 2015, PMID:26293662).
Modifier genes: none established. Digenic inheritance across two GPI genes has been specifically tested and excluded in at least one index case — the paper title says it plainly: "Excluding Digenic Inheritance of PGAP2 and PGAP3 Variants in Mabry Syndrome (OMIM 239300) Patient". Do not curate a digenic inheritance block for this disease.

2.3 Environmental risk factors

None known. No toxin, exposure, infection, diet, occupational, or lifestyle factor has been associated with disease occurrence. Parental age, sex, and geography carry no reported risk signal beyond consanguinity/founder effects.

2.4 Protective factors

None known genetically. Environmentally the only "protective" thing in the literature is downstream and therapeutic, not preventive: pyridoxine (vitamin B6) supplementation appears to protect against seizure burden in a subset (see §12). No evidence for dietary or lifestyle primary prevention.

2.5 Gene–environment interactions

The one credible G×E axis is nutrient-level, and it is elegant: elevated ALP in the circulation degrades pyridoxal 5′-phosphate (PLP), the active B6 vitamer, reducing its availability across the blood-brain barrier. Less PLP → less GABA synthesis (PLP is the cofactor for glutamate decarboxylase) → seizures. So a genetic enzyme-trafficking defect creates an acquired, nutritionally correctable cofactor deficiency in the CNS. Documented directly in CSF: an HPMRS3 patient had CSF PLP 8 nmol/L (ref 10–37) and CSF 5-MTHF 66 nmol/L (ref 72–172), both normalizing on pyridoxine 100 mg BD + folinic acid 15 mg daily (Messina et al., JIMD Rep 2023, PMID:36636587).

3. Phenotypes

3.1 Core phenotypes — PIGV/HPMRS1 (HPO annotations for OMIM:239300, with n/N frequencies)

Phenotype	HPO term	Frequency (HPO/OMIM)
Elevated circulating alkaline phosphatase	`HP:0003155`	7/7 (100%)
Intellectual disability	`HP:0001249`	7/7
Global developmental delay	`HP:0001263`	7/7
Short distal phalanx of finger (brachytelephalangy)	`HP:0009882`	7/7
Absent speech	`HP:0001344`	6/6
Hypotonia	`HP:0001252`	5/5
Hypertelorism	`HP:0000316`	6/7
Wide nasal bridge	`HP:0000431`	6/7
Broad nasal tip	`HP:0000455`	6/7
Downturned corners of mouth	`HP:0002714`	6/7
Seizure	`HP:0001250`	3/5
Abnormal rectum morphology	`HP:0002034`	4/7
Sensorineural hearing impairment	`HP:0000407`	2/3
Delayed ossification of carpal bones	`HP:0001216`	2/3
Constipation	`HP:0002019`	2/5
Anteriorly placed anus	`HP:0001545`	2/5
Aganglionic megacolon (Hirschsprung)	`HP:0002251`	1/7
Cleft palate	`HP:0000175`	1/7
Cleft upper lip	`HP:0000204`	1/7
Hydrocephalus	`HP:0000238`	1/3

Additional HPO-annotated features without hard counts: severe intellectual disability HP:0010864, tented upper lip vermilion HP:0010804, thin upper lip vermilion HP:0000219, midface retrusion HP:0011800, short philtrum HP:0000322, short nose HP:0003196, long palpebral fissure HP:0000637, upslanted palpebral fissure HP:0000582, highly arched eyebrow HP:0002553, posteriorly rotated ears HP:0000358, malar flattening HP:0000272, mandibular prognathia HP:0000303, plagiocephaly HP:0001357, small nail HP:0001792, hyperconvex nail HP:0001795, tapered finger HP:0001182, short toe HP:0001831, delayed myelination HP:0012448, cerebral cortical atrophy HP:0002120, athetosis HP:0002305, abnormal renal morphology HP:0012210, abnormal heart morphology HP:0001627, abnormally large globe HP:0001090, feeding difficulties HP:0011968.

3.2 Pan-IGD cohort frequencies (n=83, Sidpra 2024 Brain)

This is the highest-quality frequency dataset available, though it spans all GPI genes, not Mabry-only. Curate it with an explicit note that the denominator is the broader IGD population.

"Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%)."

Domain	Feature	Freq	HPO
Neuro	Delayed/absent speech	95%	`HP:0000750` / `HP:0001344`
Neuro	DD/ID	90%	`HP:0001263` / `HP:0001249`
Neuro	Seizures	83%	`HP:0001250`
Neuro	Hypotonia	72%	`HP:0001252`
Neuro	Motor symptoms	64%	`HP:0002194`
Neuro	Non-ambulant	64%	—
Neuro	Severe-to-profound DD/ID	59%	`HP:0011344`
Neuro	Developmental epileptic encephalopathy	51% (35/69 with seizures)	—
Neuro	Intractable/drug-resistant epilepsy	57% (40/70)	—
Imaging	Cerebral atrophy	75%	`HP:0002059`
Imaging	Cerebellar atrophy	60%	`HP:0001272`
Imaging	Symmetric restricted diffusion, central tegmental tracts	60% (31/52 DWI)	—
Imaging	Callosal anomalies	57%	`HP:0002079`
Imaging	Hippocampal atrophy	19%	—
Imaging	Diffuse leukodystrophy	16%	—
Imaging	Craniosynostosis	16%	`HP:0001363` (verify)
Imaging	Delayed myelination	12%	`HP:0012448`
Systemic	Any multisystem involvement	72%	—
GI	Any GI involvement	66%	—
GI	Aspiration risk	47%	—
GI	GERD	43%	—
GI	Constipation	23%	`HP:0012450`
MSK	Musculoskeletal anomalies	37%	—
MSK	Scoliosis	27%	—
MSK	Osteopenia	19% (11/59)	`HP:0000938`
Cardiac	Cardiac disease	19%	—
Cardiac	Septal defects	16%	`HP:0001631` / `HP:0001629`
Renal	Renal involvement	17%	—
Renal	Hydronephrosis	15%	`HP:0000126`
Renal	Renal cysts	5%	`HP:0000107`
Renal	Renal dysplasia	4%	`HP:0000110`
Dysmorphism	Any dysmorphic feature	83%	—
Biochem	Elevated ALP	25% (17/68)	`HP:0003155`

Critical curation caveat on that last row. In the broad IGD cohort only 25% had elevated ALP; 66% were normal and 9% were low. This is the single most important nuance in the disease: hyperphosphatasia is definitional for HPMRS/Mabry but is not universal across GPI defects, and — importantly — is not even fully reliable within HPMRS. A South African report describes two PGAP3-related Mabry patients with unusually low ALP. Curate hyperphosphatasia as a defining feature of the HPMRS subgroup with frequency: VERY_FREQUENT at the Mabry level, not as an obligate finding across GPI disease.

Seizure semiology in the cohort (of 69 with seizures): focal motor 23%, epileptic spasms 23% (HP:0011097), generalized tonic-clonic 20% (HP:0002069), generalized myoclonic 20% (HP:0032794), status epilepticus 10%.

3.3 Phenotype characteristics

Onset: neonatal to infantile. Median age at seizure onset 5.9 months (IQR 2.0–10.0). Developmental delay is apparent in the first year. Hyperphosphatasia is present from infancy and persists.
Severity: variable-to-severe; 59% severe-to-profound DD/ID. Horn et al.: "the severe end of the clinical spectrum presents as a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations."
Progression: this is the sleeper finding. The disease was long framed as static-encephalopathy-plus-epilepsy, but serial imaging says otherwise — progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, "indicating a neurodegenerative process." Cognitive/motor phenotype is largely static-to-slowly-declining; epilepsy is chronic and often refractory.
Course pattern: chronic, lifelong. Seizures episodic on a chronic substrate. Interestingly, the 1970 index patients stopped having spontaneous seizures in adulthood and came off anticonvulsants — evidence that the epilepsy phenotype can attenuate with age in milder genotypes.

3.4 Quality of life

No EQ-5D / SF-36 / PROMIS data exist for Mabry syndrome. Functional proxies from the Sidpra cohort: non-ambulance 64%, absent/delayed speech 95%, ongoing enteral feeding and cortical visual impairment both significantly more likely in the DEE group (P<0.001 and P=0.007). Behavioral: ASD 4.8%, ADHD 2.4%. Practical burden is dominated by intractable epilepsy, feeding/aspiration, and total care dependence.

4. Genetic / Molecular Information

4.1 Causal genes

PIGV (hgnc:26031, OMIM 610274, chromosome 1p36.11) — encodes GPI mannosyltransferase 2 / GPI-MT-II, an ER membrane enzyme adding the second mannose* to the GPI glycan backbone. Aliases: GPI-MT-II, PIG-V, dol-P-Man dependent GPI mannosyltransferase II. This is the flagship gene.

Others as tabled in §2.1. ALPL (hgnc:438, tissue-nonspecific alkaline phosphatase) is not causal but is the biomarker substrate — it's the GPI-anchored protein whose mis-release produces the hyperphosphatasia.

4.2 Pathogenic variants

PIGV c.1022C>A, p.(Ala341Glu) — NM_017837.4, rs139073416, ClinVar VCV000001284, classified Pathogenic. Missense. Present in ~80% of PIGV-positive families. Functionally: "Expression of the p.Ala341Glu variant protein was drastically reduced as compared to wild type" — so it behaves as a hypomorph via reduced protein abundance/stability, not catalytic-site abolition.

Other PIGV variants from Horn et al. (all novel at time of report): c.176T>G, c.53G>A, c.905T>C, c.1405C>T.

PIGO — compound heterozygous variants; mechanistically heterogeneous: "The mutant transcripts are aberrantly spliced, decrease the membrane stability of the protein, or impair enzyme function such that GPI-anchor synthesis is affected and the level of GPI-anchored substrates localized at the cell surface is reduced" (Krawitz et al., AJHG 2012, PMID:22683086).

PGAP2 — c.46C>T p.(Arg16Trp), c.380T>C p.(Leu127Ser), c.479C>T p.(Thr160Ile) in the original report; transfection into PGAP2-null cells "showed only partial restoration of GPI-anchored marker proteins, CD55 and CD59, on the cell surface" — direct in vitro demonstration of the hypomorph model. The 1970 index family carries c.881C>T p.(Thr294Met). Also c.103del p.(Leu35Serfs*90) and c.134A>G p.(His45Arg).

PGAP3 — c.275G>A p.(Gly92Asp) homozygous; c.439dupC p.(Leu147Profs16) (frameshift → nonsense-mediated decay); c.914A>G p.(Asp305Gly); c.314C>G p.(Pro105Arg). PGAP3 also has rare noncoding (intronic and 3′UTR) pathogenic variants*, which panel-based testing routinely misses (Knaus et al., Hum Mutat 2016, PMC5084765).

PIGW — compound heterozygous NM_178517: c.211A>C, c.499A>G (Chiyonobu et al., J Med Genet 2014, PMID:24367057).

PIGY — c.137T>C p.(Leu46Pro) homozygous (severe: dysmorphism, seizures, severe DD, cataracts, early death); and a promoter variant c.-540G>A predicted to disrupt an SP1 consensus binding site and shown to reduce gene expression (milder: moderate DD + microcephaly). Ilkovski et al. explicitly flag the lesson: "the potential importance of analysing variants detected in 5′-UTR regions despite their typically low coverage in exome data."

Origin: exclusively germline, biallelic. No somatic contribution. No chromosomal abnormalities, aneuploidy, or CNV mechanism reported as a primary cause (though CMA remains part of a broad DD workup).

Functional consequence class: partial loss of function (hypomorphic) across the board. Complete null alleles are not compatible with life in this pathway — every reported patient retains residual GPI synthesis.

4.3 Modifier genes / epigenetics

No modifier genes established. No DNA-methylation or histone-modification signature has been reported for HPMRS (unlike, say, the well-characterized episignatures for some other ID syndromes). This is a genuine knowledge gap worth curating as kind: KNOWLEDGE_GAP.

5. Environmental Information

Not applicable. No environmental factors, lifestyle factors, or infectious agents contribute to causation. The disease is fully genetically determined. The only environmental variable of consequence is B6 vitamer availability, which is a therapeutic lever rather than an etiologic one (§2.5, §12).

6. Mechanism / Pathophysiology

Here is where it gets genuinely lovely. Think of the GPI anchor as a lipid anchor-bolt built stepwise on the ER membrane, then handed off to a rivet gun (the GPI transamidase) that swaps a protein's C-terminal signal peptide for the anchor. Two ways to break it: build a bad bolt (PIGV/PIGO/PIGW/PIGY, ER), or fumble the finishing work after riveting (PGAP2/PGAP3, Golgi). Both routes end with alkaline phosphatase floating free in the blood — but for different reasons.

6.1 The causal chain — biosynthesis arm (PIGV, PIGO, PIGW, PIGY)

Node 1 — Hypomorphic GPI-pathway enzyme deficiency (biological_scale: MOLECULAR) Reduced enzyme abundance/activity in the ER. GO: GPI anchor biosynthetic process GO:0006506; GPI mannosyltransferase activity GO:0004376; mannosyltransferase activity GO:0000030; located in endoplasmic reticulum membrane GO:0005789. ↓ Node 2 — Accumulation of incomplete, mannose-bearing GPI intermediates (MOLECULAR) The pathway stalls mid-assembly. This is the mechanistically decisive step. ↓ Node 3a — Transamidase-mediated release of soluble alkaline phosphatase (MOLECULAR) The killer insight from Murakami et al., J Biol Chem 2012;287:6318–25, PMID:22228761: the GPI transamidase doesn't just refuse to work — it works badly. It recognizes the truncated mannose-bearing intermediate, cleaves the C-terminal hydrophobic signal peptide off ALP anyway, and releases the enzyme as a soluble, unanchored protein into the medium/serum. GO: alkaline phosphatase activity GO:0004035.

The 2024 review states the model concretely: "the proximity of the nascent peptide to an incomplete GPI anchor with at least one mannose may result in the recruitment of a portion of the transamidase, PIGU, that directs the catalytic subunit, PIGK, to cleave the GPI recognition sequence and liberate the non-GPI-anchored, soluble AP."

The elegant control experiment: in PIGM deficiency, only non-mannosylated intermediates (GlcN-acyl-PI) accumulate, the transamidase is not efficiently engaged, ALP is degraded intracellularly — and there is no hyperphosphatasia. That's why some GPI defects have high ALP and others don't. It's a mannose-dependent switch. This belongs in the pathophysiology graph as an explicit branch condition. ↓ Node 3b — Reduced cell-surface display of GPI-anchored proteins (CELLULAR) CD55, CD59, CD16, FLAER-binding GPI core all reduced on granulocytes and fibroblasts. Ilkovski measured "significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (~20–50% compared with controls)." This is the arm that actually causes the disease; the ALP release is mostly the arm that causes the lab abnormality. ↓ Node 4 — Impaired neuronal GPI-AP-dependent signaling and synaptic function (CELLULAR) GPI-APs include ephrin-A ligands, contactins, NCAM-120, Thy-1, glypicans, RECK, prion protein — a whole guild of axon-guidance, synapse-organizing and cell-adhesion molecules. GO: chemical synaptic transmission GO:0007268; synapse GO:0045202. Mouse data (§15) show reduced hippocampal synaptophysin, decreased excitatory synaptic transmission, elevated paired-pulse ratio, and downregulated Abl1 across cell types — Abl1 interacts with multiple EphrinA receptors, tying the transcriptomic hit back to GPI-anchored ephrin signaling. ↓ Node 5a — Abnormal brain development and progressive neurodegeneration (TISSUE) Cerebral atrophy 75%, cerebellar atrophy 60%, callosal anomalies 57%, delayed myelination; serial imaging shows progression in 87.5%/70.8%. UBERON: brain UBERON:0000955, cerebellum UBERON:0002037, hippocampal formation UBERON:0002421, corpus callosum UBERON:0002336. ↓ Node 5b — Circulating pyridoxal-5′-phosphate depletion (ORGANISM) Free serum/tissue ALP degrades PLP; CSF PLP falls; GABA synthesis falls. Direct human evidence: CSF PLP 8 nmol/L (ref 10–37), CSF 5-MTHF 66 (ref 72–172), both correcting on supplementation. ↓ Node 6 — Seizures and developmental epileptic encephalopathy (ORGANISM) Two converging inputs: the structural/synaptic substrate (Node 5a) and the cofactor-deficiency substrate (Node 5b). The second is the treatable one — which is exactly why pyridoxine helps some patients partially and never achieves seizure freedom in most: you can top up the cofactor, but you can't rebuild the synapse.

6.2 The causal chain — remodeling arm (PGAP2, PGAP3)

Divergent from Node 2 onward, and mechanistically distinct even though the endpoint looks the same:

PGAP3 deficiency: failure to deacylate the sn-2 unsaturated fatty acid. The unremodeled anchor is a substrate for GPI-specific phospholipase C, which releases the protein.
PGAP2 deficiency: failure to reacylate with stearic acid. Phospholipase D then "cleaves the lyso-GPI intermediate, resulting in transport of the unstable anchor and its attached protein, alkaline phosphatase, to the extracellular compartment."

Either way the anchor fails to partition into lipid rafts — PGAP2/3 remodeling "is required for stable association between GPI-anchored proteins and the cell-surface membrane rafts." GO: Golgi membrane GO:0000139.

Curation note: the biosynthesis arm and remodeling arm should be two distinct pathophysiology sub-branches converging on a shared downstream node ("soluble ALP release" + "GPI-AP surface deficiency"). This is a textbook case for a mechanism module if dismech ever factors out GPI anchor biosynthesis defect as a conserved module — the same trigger→consequence chain recurs across ~24 genes and ~20 named disorders.

6.3 Phenotype-stage correlation (mechanistically meaningful)

Sidpra 2024 found synthesis-stage gene variants → significantly shorter time to seizure onset (median 5.6 mo) than transamidase/remodeling-stage variants (median 7.0 mo), log-rank P = 0.046. And the 2024 Genes HPO analysis across 152 patients / 22 genes found biosynthesis defects → 33% abnormal digit morphology vs remodeling defects → 6.7%, with biosynthesis defects showing greater muscle/tendon/joint involvement. So the step in the pathway is itself a phenotype-modifying variable. Worth an explicit mechanistic_hypotheses group.

6.4 Cell types, compartments, immune, metabolic

Cell types (CL): neuron CL:0000540 (primary target), microglial cell CL:0000129 (transcriptomically most-perturbed cluster in the Pigv mouse — 306 genes downregulated in one microglial subgroup, enriched for small-GTPase-mediated signal transduction), neutrophil/granulocyte CL:0000775 (diagnostic readout tissue), fibroblast CL:0000057 (diagnostic readout), osteoblast CL:0000062 (ALPL source).
Subcellular (GO CC): endoplasmic reticulum membrane GO:0005789 (PIGV/PIGO/PIGW/PIGY), Golgi membrane GO:0000139 (PGAP2/PGAP3), plasma membrane / lipid raft microdomains. (Note: GO:0031225 "anchored component of membrane" and GO:0016254 "preassembly of GPI anchor in ER membrane" are both obsolete in current GO — do not use them.)
Immune involvement: mechanistically present but clinically quiet. CD55 and CD59 are complement regulators; their loss is what causes paroxysmal nocturnal hemoglobinuria in somatic PIGA mutation. In inherited GPI deficiency the loss is partial and the hemolytic phenotype does not occur — a nice negative result to record. The Pgap3-knockout mouse does show "altered T cell proliferation response and increased susceptibility to EAE."
Metabolic: no classical intermediary-metabolism block. Serum transferrin and transferrin isoelectric focusing are normal (22 and 19 individuals tested) — so despite being classified as a CDG, HPMRS does not produce the N-glycosylation transferrin abnormality. Clinically important: a normal CDG transferrin screen does not exclude this disease.
Tissue damage mechanism: not oxidative/ischemic/fibrotic. It is developmental mis-wiring plus progressive volume loss — a neurodevelopmental-then-neurodegenerative dual process.
Molecular profiling available: single-cell RNA-seq of Pigv341E mouse hippocampus (see §15) is the only omics dataset. No human transcriptomic, proteomic, metabolomic, lipidomic, spatial, or CRISPR-screen data specific to Mabry syndrome. Substantial gap.

7. Anatomical Structures Affected

Primary organ: brain (UBERON:0000955) — cerebral cortex, cerebellum (UBERON:0002037), hippocampal formation (UBERON:0002421), corpus callosum (UBERON:0002336), central tegmental tracts (brainstem; symmetric restricted diffusion in 60% is a notably specific radiologic sign).

Body systems (with cohort frequencies): nervous (≈100%), gastrointestinal (66%; colon UBERON:0001155 — Hirschsprung, anorectal malformation, constipation, GERD, aspiration), musculoskeletal (37%; bone element UBERON:0001474 — brachytelephalangy, scoliosis, osteopenia, delayed carpal ossification), cardiovascular (19%; heart UBERON:0000948 — septal defects), renal/urinary (17%; kidney UBERON:0002113 — hydronephrosis, cysts, dysplasia, vesicoureteral anomalies), auditory (sensorineural hearing loss), visual (cortical visual impairment; cataracts in severe PIGY), craniofacial (dysmorphism in 82–83%).

Lateralization: bilateral and symmetric throughout. The central-tegmental-tract diffusion restriction is explicitly described as symmetric.

Tissue types: neural tissue (neurons, glia) primary; enteric nervous system (neural crest derivative — the Hirschsprung link is a neurocristopathy signal worth flagging); bone and connective tissue secondary.

8. Temporal Development

Onset: congenital/neonatal-to-infantile. Hypotonia and dysmorphism at birth; developmental delay within the first year; median seizure onset 5.9 months (IQR 2.0–10.0). Orphanet lists age of onset as infancy/neonatal.
Onset pattern: chronic/insidious for the developmental phenotype; seizures may present acutely, sometimes as West syndrome with hypsarrhythmia (the PIGW index case).
Stages: no formal staging system exists. A pragmatic natural-history framing: (1) neonatal hypotonia + dysmorphism + incidental hyperphosphatasia; (2) infantile seizure onset ± developmental epileptic encephalopathy; (3) childhood plateau with intractable epilepsy, feeding difficulty, non-ambulance; (4) progressive volume loss on serial imaging; (5) in milder genotypes, possible adult seizure remission.
Progression rate: variable, generally slow. Severe end = death in early childhood; mild end = survival to adulthood with stable disability.
Course: chronic and lifelong; epilepsy is relapsing/refractory in 57%.
Remission: spontaneous seizure remission in adulthood is documented in the 1970 index patients — "During adulthood, however, 1-VI-4 and 1-VI-16 no longer experienced spontaneous seizures and were no longer administered anticonvulsants." Treatment-induced complete seizure control on pyridoxine occurred in 4/22 trialed individuals.
Critical periods: the first year — seizure onset window and the period of maximal synaptogenesis. The AAV gene-therapy mouse work delivered vector on postnatal day 1, implying a narrow neonatal therapeutic window for any future disease-modifying approach.

9. Inheritance and Population

Prevalence: <1 / 1,000,000 (Orphanet ORPHA:247262). In PrevalenceClassEnum terms → BELOW_1_IN_1000000, rate_per_100000 ≈ 0.1 or lower, measure_type: POINT_PREVALENCE. Fewer than ~100 HPMRS patients reported for the common subtypes; some subtypes (PIGY, PIGW) have single-digit case counts. The broader review counts 1–85 reported cases per gene across all 24 IGD genes and states plainly: "there are currently no established diagnostic guidelines for this rare disease."
Denominator context: the Deciphering Developmental Disorders study suggests GPI biosynthesis disorders collectively account for ~0.15% of individuals with developmental disability — a useful CASES_IN_LITERATURE-adjacent figure, but note it's the whole GPIBD family, not Mabry alone.
Incidence: not established.
Inheritance: autosomal recessive (HP:0000007) for all six subtypes. Recurrence risk 25% per pregnancy.
Penetrance: complete in biallelic carriers, as far as reported. No non-penetrant homozygotes described.
Expressivity: highly variable, both between and within genes. Horn: "PIGV mutations are the major cause of HPMRS, which displays a broad clinical variability regarding associated malformations and growth patterns." PIGY is the extreme case — the same gene gives lethal multisystem disease (p.Leu46Pro) and moderate DD + microcephaly (promoter variant), tracking residual expression level.
Anticipation: none — no repeat expansion mechanism.
Germline mosaicism: not reported.
Founder effect: PIGV c.1022C>A in Europeans (German/Northern European), ~0.02% European allele frequency in gnomAD.
Carrier frequency: not systematically established. Back-of-envelope from the PIGV A341E European AF of ~2.4×10⁻⁴ → carrier frequency ~1/2,100 for that allele alone. Treat as an estimate, not a sourced figure.
Consanguinity: a major factor for PGAP3, PIGY, PGAP2 — several index families were consanguineous (Pakistani, Saudi, South African cohorts).
Population/geography: reported worldwide — Germany, Netherlands, Canada, USA, Japan, Pakistan, Saudi Arabia, Italy, South Africa, UK. PIGV skews European; PGAP3 is over-represented in South Asian and Middle Eastern consanguineous populations.
Sex ratio: 1:1, as expected for autosomal recessive. No sex bias reported.
Age distribution: overwhelmingly pediatric in published series (median follow-up 2.9 years). The oldest individual in the Sidpra cohort was 20 years (compound heterozygous PIGT). The 1970 index patients born 1952 and 1958 survived into their 60s — so long survival is achievable at the mild end.

10. Diagnostics

10.1 Laboratory / biomarkers

Serum alkaline phosphatase (LOINC 6768-6, Alkaline phosphatase [Enzymatic activity/volume] in Serum or Plasma). Persistently elevated, typically the entry point to diagnosis. Caveat, restated because it matters: elevated in only 25% of the broad IGD cohort; normal or even low ALP does not exclude Mabry, particularly PGAP3. Isoenzyme fractionation confirms it is tissue-nonspecific ALP (ALPL), not the intestinal or placental isoform, and it is not accompanied by bone disease.
Flow cytometry for GPI-anchored proteins — the functional confirmatory assay. Panel: CD16 and CD24 on granulocytes; CD14 on monocytes; CD55 and CD59 on granulocytes/erythrocytes/fibroblasts; FLAER (fluorescently-labeled aerolysin), which "pan-specifically recognize[s] the core GPI structure." Chiyonobu: "flow cytometric analysis of blood cells is effective in screening IGD." One important limitation from Knaus 2018: "Flow cytometric markers" showed no gene-specific patterns and no correlation with phenotypic severity — flow tells you whether, not which or how bad.
CSF neurotransmitter/vitamer panel — CSF pyridoxal 5′-phosphate, 5-methyltetrahydrofolate, homovanillic acid. Underused and directly actionable, since low PLP/5-MTHF predicts response to pyridoxine + folinic acid.
Serum transferrin isoelectric focusing — normal. Do not use to screen for this CDG.

10.2 Imaging

Brain MRI including DWI. Look for: cerebral atrophy, cerebellar atrophy, callosal anomalies, and the relatively distinctive symmetric restricted diffusion of the central tegmental tracts (60%). Serial MRI is warranted given documented progression. Hand radiographs for brachytelephalangy and delayed carpal ossification. Renal ultrasound, echocardiography. Contrast enema / rectal suction biopsy if Hirschsprung is suspected.

10.3 Electrophysiology

EEG — may show hypsarrhythmia (West syndrome presentation, documented with PIGW). Otherwise variable epileptiform patterns matching the mixed semiology.

10.4 Genetic testing

Recommended tiering: 1. Whole exome or whole genome sequencing as first-line for undiagnosed DD/ID + seizures ± high ALP. The 2024 review argues explicitly for WGS combined with RNA sequencing as "a first line diagnostic method," because "traditional panel-based approaches may miss intronic and 3′UTR variants" — a warning earned the hard way by the noncoding PGAP3 and promoter PIGY variants. 2. Targeted GPI-pathway gene panel — historically productive: Hansen/Krawitz "developed a diagnostic gene panel for targeting all known genes encoding proteins in the GPI-anchor-synthesis pathway." Must cover all ~31 pathway genes plus UTRs/promoters to be adequate. 3. Single-gene PIGV testing — reasonable only in a classic phenotype with the c.1022C>A founder allele suspected. 4. CMA/karyotype/FISH — part of a generic DD workup; will not diagnose this disease. 5. mtDNA / repeat expansion testing — not applicable.

Automated facial phenotyping is a genuinely useful diagnostic adjunct here. Knaus 2018 found "facial recognition software achieved the highest accuracy in predicting the disease-causing gene" — beating flow cytometry and clinical features. The 2024 review adds: "automated facial analysis, for example by GestaltMatcher, enables more accurate gene assignment in GPI patients compared to experienced clinicians." Patients with PIGV and PGAP3 variants have the most distinctive facial gestalts.

10.5 Clinical criteria and differential

No formal consensus diagnostic criteria exist. Horn's working criteria: intellectual disability + elevated serum alkaline phosphatase as minimal criteria.

Differential diagnosis (all should be curated as differentials): - Transient hyperphosphatasemia of infancy — benign, self-resolving in weeks-to-months, no neurologic features. The single most common thing to rule out. - Hypophosphatasia (MONDO ALPL) — the exact mirror image: low ALP. Conceptually satisfying to hold both in mind. - Vitamin D deficiency rickets, healing fractures, Paget disease, hepatobiliary disease, bone tumors — non-genetic causes of raised ALP. - Other GPI biosynthesis defects without hyperphosphatasia — MCAHS (multiple congenital anomalies-hypotonia-seizures syndrome; PIGN, PIGT, PIGA), PIGA-related DEE, PGAP1-related ID. Knaus 2018 argues for collapsing these labels: "The authors recommend unified classification as GPIBDs given overlapping clinical presentations and biochemical findings across both syndrome categories." - Other CDGs — distinguishable by abnormal transferrin IEF (abnormal in classical CDG, normal in HPMRS). - Pyridoxine-dependent epilepsy (ALDH7A1) and PNPO deficiency — both B6-responsive, both in the seizure differential; distinguished by α-AASA/pipecolic acid and by genotype. - Kabuki syndrome, Coffin-Siris, and other dysmorphic ID syndromes on gestalt alone.

10.6 Screening

Newborn screening: not included in any national NBS panel. No validated screening assay.
Carrier screening: PIGV/PIGO/PGAP2/PGAP3 appear on some expanded carrier screening panels; no population program.
Cascade testing: standard for at-risk siblings and for reproductive planning in known families.

11. Outcome / Prognosis

Mortality: 15/83 (18%) deceased at time of writing in the Sidpra cohort, with median survival 1.5 years (IQR 1.4–2.8) among those who died. Causes: respiratory failure secondary to recurrent infection (5/15), seizure-related death (5/15 — 3 post-ictal cardiorespiratory failure, 2 intractable status epilepticus), SUDEP (4/15), GI complications (1/15). Note the SUDEP signal is echoed in the Mabry index family, where two members "died of sudden unexpected nocturnal frontal lobe epilepsy (SUDEP) despite anticonvulsant medication." SUDEP risk counseling is warranted.
Survival at the mild end: the 1970 index patients (born 1952 and 1958, PGAP2 p.Thr294Met) survived into their 60s with relative phenotypic stability. Oldest in the modern cohort: 20 years. So the survival distribution is genuinely bimodal — severe genotypes die in infancy/early childhood; mild ones reach adulthood.
No 5-/10-year survival statistics exist. Do not fabricate them.
Morbidity: severe. Non-ambulant 64%, absent/delayed speech 95%, severe-to-profound DD/ID 59%, intractable epilepsy 57%, ongoing enteral feeding in the DEE group, cortical visual impairment, osteopenia 19%.
Recovery potential: none for the neurodevelopmental phenotype. Seizure burden is partially modifiable.
Prognostic factors (all statistically supported in Sidpra 2024):
Developmental epileptic encephalopathy (51%) is the dominant adverse prognostic marker → intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), cortical visual impairment (P=0.007).
Conversely, developmental encephalopathy without DEE → significantly more likely to achieve seizure control (P=0.003) and to achieve it on monotherapy (P=0.010).
Pathway stage: synthesis-stage genes → earlier seizure onset (P=0.046).
Neuroimaging features are described as "prognostic and biologically significant" — cerebral atrophy, cerebellar atrophy, callosal anomalies, central tegmental tract restricted diffusion.
Prognostic biomarkers: none validated. ALP level does not correlate with severity, and neither do flow-cytometry GPI-AP levels (Knaus 2018: no correlation with phenotypic severity). Genotype (specific variant + pathway stage) is currently the best predictor. Sidpra used unsupervised hierarchical clustering to identify "novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management."

12. Treatment

There is no disease-modifying therapy in clinical use. Management is supportive plus one intriguing partially-effective cofactor intervention.

12.1 Pyridoxine / pyridoxal-5′-phosphate — the signature intervention

MAXO: MAXO:0001131 pyridoxine supplementation (also MAXO:0001129 vitamin supplementation, MAXO:0000761 B vitamin supplementation). CHEBI: CHEBI:16709 pyridoxine, CHEBI:18405 pyridoxal 5′-phosphate. Modality: SMALL_MOLECULE.

Rationale: soluble ALP degrades PLP → CNS PLP deficiency → reduced glutamate decarboxylase activity → reduced GABA → seizures. Supplementation restores the cofactor pool.

Evidence, in order of rigor: - Prospective open-label multicenter pilot, n=9, Japan — oral pyridoxine 20–30 mg/kg/day for 1 year: "One year of daily high-dose pyridoxine treatment was effective in the treatment of seizures in more than half of our patients with IGDs and modestly improved development in the majority of them." - Prospective cohort, n=7, ages 5–23, 3 months, pyridoxine 20–30 mg/kg/day ± switch to P5P (Bayat et al., Dev Med Child Neurol 2022;64:789–798, PMID:35080266): "more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants." Critically: "no participants reached seizure freedom" and electrophysiological improvement was minimal. Conclusion: "pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency." - Retrospective cohort, n=22 trialed of 83 (Sidpra 2024): complete seizure control in 4, partial in 3. One individual had a paradoxical increase in seizure frequency. "No association was found between pyridoxine dose and seizure control." - Case-level, HPMRS3, with biochemical target engagement (Messina 2023): pyridoxine 100 mg twice daily + folinic acid 15 mg daily → complete normalization of CSF PLP, 5-MTHF, and HVA, "with concurrent improvements in speech and fine motor skills." - Case series, HPMRS3 + HPMRS4 (Mol Syndromol 2025/2026, PMID:41064048): high-dose pyridoxine, patient 1 "no seizures...during follow-up," patient 2 "no seizures...during the 8-month follow-up."

Honest summary for the KB: response rate roughly 30–55% for meaningful seizure reduction, seizure freedom uncommon, no dose-response relationship established, occasional paradoxical worsening, and PGAP2/HPMRS3 appears the most responsive subtype. The 2024 review calls for standardizing dosing and defining the "dose, route of administration and vitamer species that produces seizure suppression in 50% of patients." Also worth noting: high-dose pyridoxine carries a real risk of sensory peripheral neuropathy at chronic high exposure — a monitoring requirement that the primary literature underplays.

Folinic acid (CHEBI:15640 5-formyltetrahydrofolic acid) — co-administered where CSF 5-MTHF is low; 15 mg daily in the reported case.

12.2 Antiseizure medication

MAXO: MAXO:0000167 anticonvulsant agent therapy. No agent is specifically indicated. Levetiracetam (CHEBI:6437) was the most-used, appearing in "38.5% of individuals (15/39) as part of a polytherapeutic regimen." 57% have drug-resistant epilepsy. No individuals underwent epilepsy surgery in the 83-person cohort — surgical candidacy is essentially absent given the diffuse/genetic substrate. Ketogenic diet (MAXO:0030010) has not been systematically evaluated — a gap.

12.3 Supportive and rehabilitative

Physical therapy MAXO:0000011, occupational therapy MAXO:0001351, speech therapy MAXO:0000930
Gastrostomy MAXO:0001346 for aspiration risk (47%) and feeding difficulty
Supportive care MAXO:0000950
Surgical: Hirschsprung pull-through, anorectal malformation repair, cardiac septal defect repair, cleft palate repair, scoliosis management
Bone health monitoring given 19% osteopenia
Genetic counseling MAXO:0000079

12.4 Experimental / advanced therapeutics

AAV gene therapy — preclinical only. AAV-PHP.eB carrying human PIGA under a CAG promoter, delivered on postnatal day 1 into Nestin-Piga conditional knockout mice: improved neurologic function and survival, enhanced myelination, elimination of spontaneous seizures in female mice, hPIGA expression reaching endogenous levels by day 25 (Mol Ther Methods Clin Dev 2024, PMID:38572066). Safety flag: treated females surviving to 1 year developed liver tumors associated with Rian overexpression — the known AAV integration risk in neonatal delivery. Targets PIGA, not any HPMRS gene, so it's a proof-of-concept for the pathway rather than for Mabry specifically. Modality: GENE_THERAPY.
Synthetic GPI fragment supplementation — in vitro efficacy shown only.
No registered clinical trials specific to Mabry syndrome / HPMRS were identified on ClinicalTrials.gov. The CDG natural-history study at the Frontiers in CDG Consortium (FCDGC) enrolls PGAP3-CDG patients and is the most relevant ongoing study; verify its NCT before curating.
Pharmacogenomics: none established. No genotype-guided drug selection beyond the (weak) signal that PGAP2/HPMRS3 may be more pyridoxine-responsive.

13. Prevention

Primary prevention: not possible — the disease is fully determined at conception. The only lever is reproductive: genetic counseling (MAXO:0000079), carrier testing of relatives, and, for couples with a prior affected child, preimplantation genetic testing (PGT-M) or prenatal diagnosis by CVS/amniocentesis with targeted variant testing. 25% recurrence risk per pregnancy.
Secondary prevention (early detection): no newborn or population screening program. The practical secondary-prevention move is diagnostic-pathway design — checking serum ALP in any infant with unexplained developmental delay and seizures, and not dismissing a normal ALP. Earlier molecular diagnosis enables earlier pyridoxine trial and accurate counseling.
Tertiary prevention (complication avoidance): this is where most of the actionable work lives — aggressive seizure management to reduce status epilepticus and SUDEP risk; aspiration precautions and gastrostomy given 47% aspiration risk and 5/15 deaths from respiratory failure; bone density surveillance; scoliosis monitoring; renal and cardiac imaging at diagnosis; hearing and vision assessment.
Immunization: standard childhood schedule. No contraindication, no special vaccine strategy. Given respiratory-infection mortality, influenza, RSV, and pneumococcal immunization deserve emphasis as a rational (if unstudied) intervention.
Public health / environmental interventions: not applicable.
Prophylaxis: no established prophylactic medication. Rescue benzodiazepine protocols for prolonged seizures are standard practice.

14. Other Species / Natural Disease

Taxonomy: GPI anchoring is one of the deepest-conserved post-translational modifications in eukaryotes — present in yeast (Saccharomyces cerevisiae, NCBITaxon:4932), trypanosomes, Plasmodium, and all metazoa. The pathway genes have clear orthologs in Mus musculus (NCBITaxon:10090), Rattus norvegicus (10116), Danio rerio (7955), Drosophila melanogaster (7227), C. elegans (6239).
Orthologs: mouse Pigv (MGI:2442480), mouse Pgap3 (MGI:2444461), rat Pigv (RGD:1349310), plus orthologs of all six HPMRS genes.
Naturally occurring disease in other species: none reported. No OMIA entry for a spontaneous animal HPMRS phenotype; no companion-animal or wildlife equivalent. Every animal model is engineered.
Breed associations (VBO): not applicable.
Comparative pathology: yeast GPI mannosyltransferase mutants are lethal and can be complemented by trypanosomal/plasmodial PigB proteins — good evidence of deep functional conservation of the mannosyltransferase step. The mouse Pigv A341E knock-in recapitulates the human phenotype well (§15), supporting cross-species conservation of the neurodevelopmental consequence.
Zoonotic potential / cross-species transmission: not applicable — this is a germline Mendelian disorder.
Veterinary relevance: none.

15. Model Organisms

15.1 The flagship: Pigv^341E knock-in mouse

Rodríguez de los Santos et al., PNAS 2021;118:e2014481118, PMID:33402532 — CRISPR-Cas9 knock-in of the exact human founder allele at the conserved mouse residue: "we used CRISPR-Cas9 to introduce the most prevalent hypomorphic missense mutation in European patients, Pigv:c.1022C > A (p.A341E), at a site that is conserved in mice." Model type: mammalian, germline knock-in, humanized point mutation — about as faithful as a rodent model gets.

Phenotype recapitulation:

Domain	Finding	Human counterpart
Motor	Reduced rotarod latency, elevated beam-traversal latency, abnormal fore-/hindpaw gait, hindlimb clasping	Motor delay 64%, hypotonia 72%
Growth	Reduced weight from early postnatal life	Growth abnormalities reported in HPMRS
Cognition	Delayed spatial learning; "impaired long-term spatial memory at day 12" (Barnes maze); short-term working memory intact	DD/ID 90%
Species-typical behavior	Fewer marbles buried, lower-quality nests	—
Social	"enhanced social approach behavior" — increased nose-to-anogenital contacts, decreased rearing	Divergent from human; see limitations
Sleep	Reduced total sleep, more active during light phase	Circadian/sleep disturbance under-characterized in humans
Seizures	PTZ kindling: "significantly lower seizure threshold"; first seizure at 63.3 min vs 93.3 min in WT; all mutants seized vs 4 WT never seizing after 10 injections	Seizures 83%, DEE 51%
Synaptic	"decreased immunoreactivity for synaptophysin in cornu ammonis 1–stratum radiatum"; reduced EPSP amplitude; elevated paired-pulse ratio; elevated post-tetanic potentiation	Mechanistic — no direct human counterpart
Transcriptomic	scRNA-seq: Abl1 downregulated across all hippocampal cell clusters (links to GPI-anchored ephrin-A signaling); Hdc (histidine decarboxylase) elevated (candidate for sleep/circadian phenotype); 306 genes down in a microglial subgroup	Mechanistic

Limitations: mice show enhanced rather than reduced sociability — opposite in valence to human phenotypes, and a caution against over-reading the social domain. Seizures required PTZ provocation; the model is seizure-susceptible, not spontaneously epileptic. Alkaline phosphatase was not quantified, so the model does not directly validate the hyperphosphatasia biomarker. Facial dysmorphism, brachytelephalangy, Hirschsprung, and renal/cardiac anomalies are not reported. Progressive cerebral/cerebellar atrophy is not demonstrated.

Curation note: this pattern — a well-validated mouse recapitulating the neurologic core while diverging on sociability and leaving the defining biomarker unmeasured — is a good candidate for a kind: HUMAN_MODEL_MISMATCH discussion entry rather than a plain knowledge gap, per the dismech convention. Evidence source: MODEL_ORGANISM.

15.2 Other models

Pgap3 knockout mouse (MGI:2444461): "abnormal head and tail morphology, growth retardation, limb grasping, altered T cell proliferation response and increased susceptibility to EAE." Original purpose was immunological — probing fatty-acid remodeling of GPI-APs; in the KO, "GPI-APs are expressed on the cell surface without fatty acid remodeling, and fail to associate with lipid rafts." Note the phenotype includes the same limb-grasping/growth-retardation neurologic signature.
PGAP3 developmental studies: a dedicated paper on PGAP3's "novel role in brain morphogenesis and neuronal wiring at early development" (PMC7569840) — relevant to the developmental arm of the mechanism.
Nestin-Piga conditional knockout mouse — CNS-specific Piga deletion from E11.5; used as the gene-therapy testbed. Severe: untreated survival ~3 weeks (males) to ~3 months (females). Models a different gene but the same pathway.
CHO cell mutant lines defective at defined GPI biosynthesis steps — the workhorse in vitro system. Murakami used these to demonstrate the transamidase-dependent ALP-release mechanism; Howard used CHO complementation to validate PGAP3 missense pathogenicity; Krawitz/Hansen used PGAP2-null cells for CD55/CD59 rescue assays. Evidence source: IN_VITRO.
Patient-derived skin fibroblasts — used for CD55/CD59 flow cytometry (20–50% of control levels in PIGY patients). IN_VITRO.
Yeast complementation assays for GPI mannosyltransferase function. IN_VITRO.
Not available: no zebrafish, Drosophila, C. elegans, iPSC-derived neuron, organoid, or MorPhiC model of any HPMRS gene was identified. Given that PIGV/PGAP3 are strong candidates for iPSC-derived neuronal phenotyping, this is a real and citable gap.

Databases: MGI (Pigv MGI:2442480, Pgap3 MGI:2444461), RGD (Pigv RGD:1349310), IMPC/KOMP for pathway-gene knockouts, Alliance of Genome Resources for orthology.

16. Curation summary — suggested dismech structure

dismech section	Recommended content
`disease_term`	`MONDO:0016596` if entry is "Mabry syndrome"; `MONDO:0009398` only if renamed to HPMRS1
`has_subtypes`	HPMRS1–6, names `HPMRS1`…`HPMRS6`, `display_name` with gene
`inheritance`	Autosomal recessive, `HP:0000007`
`genetic`	6 genes with HGNC terms as tabled; `case_fractions` for PIGV (~80% of PIGV-positive families carry c.1022C>A)
`pathophysiology`	Two-arm chain per §6: biosynthesis (MOLECULAR→CELLULAR) and remodeling (MOLECULAR), converging on soluble-ALP-release + GPI-AP surface deficiency, → synaptic dysfunction (CELLULAR) → brain atrophy (TISSUE) → seizures/DD (ORGANISM); plus the PLP-depletion side branch
`phenotypes`	§3.1 for HPMRS1 with n/N frequencies; §3.2 pan-IGD frequencies with explicit denominator note
`biochemical`	Serum ALP with `reference_ranges`; CSF PLP (ref 10–37 nmol/L) and CSF 5-MTHF (ref 72–172 nmol/L) with `interpretation_bands`
`prevalence`	`BELOW_1_IN_1000000`, `POINT_PREVALENCE`, source `ORPHA:247262`
`treatments`	Pyridoxine (`MAXO:0001131` + `CHEBI:16709`), folinic acid, anticonvulsant therapy (`MAXO:0000167`), gastrostomy, PT/OT/speech, genetic counseling
`discussions`	`KNOWLEDGE_GAP`: no episignature, no human omics, no ketogenic-diet data, no NCT-registered interventional trial. `HUMAN_MODEL_MISMATCH`: Pigv341E sociability inversion + unmeasured ALP
`mechanistic_hypotheses`	(a) mannose-dependent transamidase switch explains why some GPI defects have hyperphosphatasia and others don't — `status: ESTABLISHED`; (b) ALP-mediated PLP depletion as the treatable seizure mechanism — `status: EMERGING`; (c) pathway-stage-determines-phenotype — `status: EMERGING`

Two things to double-check before you commit: the ICD-11 code and the MeSH descriptor are both unverified above — I'd leave them out rather than guess. And run just fetch-reference on every PMID here before quoting; the abstracts above came from PubMed/PMC directly, but the dismech snippet validator wants its own cache, and a couple of the quotes are stitched from PMC full text rather than the abstract proper, which will fail substring matching.

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Classifications

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

Deep Research

1. Disease Information

1.1 Overview

1.2 Identifiers

1.3 Synonyms

1.4 Data provenance

2. Etiology

2.1 Primary cause

2.2 Genetic risk factors

2.3 Environmental risk factors

2.4 Protective factors

2.5 Gene–environment interactions

3. Phenotypes

3.1 Core phenotypes — PIGV/HPMRS1 (HPO annotations for OMIM:239300, with n/N frequencies)

3.2 Pan-IGD cohort frequencies (n=83, Sidpra 2024 Brain)

3.3 Phenotype characteristics

3.4 Quality of life

4. Genetic / Molecular Information

4.1 Causal genes

4.2 Pathogenic variants

4.3 Modifier genes / epigenetics

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 The causal chain — biosynthesis arm (PIGV, PIGO, PIGW, PIGY)

6.2 The causal chain — remodeling arm (PGAP2, PGAP3)

6.3 Phenotype-stage correlation (mechanistically meaningful)

6.4 Cell types, compartments, immune, metabolic

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

10.1 Laboratory / biomarkers

10.2 Imaging

10.3 Electrophysiology

10.4 Genetic testing

10.5 Clinical criteria and differential

10.6 Screening

11. Outcome / Prognosis

12. Treatment

12.1 Pyridoxine / pyridoxal-5′-phosphate — the signature intervention

12.2 Antiseizure medication

12.3 Supportive and rehabilitative

12.4 Experimental / advanced therapeutics

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

15.1 The flagship: Pigv341E knock-in mouse

15.2 Other models

16. Curation summary — suggested dismech structure

Sources

15.1 The flagship: Pigv^341E knock-in mouse