PGM2L1 Deficiency

Mendelian MONDO:0700092 Pathograph 3 Show in embeddings browser Inborn Error of Metabolism Neurodevelopmental Disorder

PGM2L1 deficiency is an ultra-rare autosomal recessive neurodevelopmental disorder caused by bi-allelic inactivating variants in PGM2L1, which encodes a paralog of phosphoglucomutase 2 that synthesizes glucose-1,6-bisphosphate and other sugar bisphosphates. PGM2L1 is highly expressed in the brain, where it accounts for locally elevated glucose-1,6-bisphosphate concentrations. Loss of PGM2L1 function markedly reduces glucose-1,6-bisphosphate and other sugar bisphosphates in patient fibroblasts, but residual concentrations remain sufficient to maximally stimulate phosphomutases, so protein glycosylation (assessed via LAMP2 and serum transferrin) is normal; the disorder is therefore not a glycosylation defect. The condition was first described in 2021 in four children with severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris, with early obesity and seizures in most. Subsequent case reports have reported additional pediatric and adult cases, expanding the phenotypic spectrum.

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1
Inheritance
2
Pathophys.
10
Phenotypes
3
Pathograph
1
Genes
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
All reported affected individuals carry bi-allelic (homozygous or compound heterozygous) inactivating PGM2L1 variants, including homozygous variants inherited from unaffected heterozygous parents.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33979636 SUPPORT Human Clinical
"Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome sequencing."
Establishes bi-allelic (autosomal recessive) inheritance of PGM2L1 loss-of-function variants.
PMID:41776821 SUPPORT Human Clinical
"WES identified a rare homozygous variant in the PGM2L1 gene (OMIM: 611,610, NM_173582.6: c.1673delC, p.Thr558Ilefs*19), which was inherited from both parents."
Independent case confirming a homozygous, biparentally-inherited PGM2L1 variant.
⚙

Pathophysiology

2
PGM2L1 Loss of Function
Bi-allelic inactivating PGM2L1 variants abolish or severely reduce the glucose-1,6-bisphosphate synthase activity of PGM2L1, a brain-enriched paralog of phosphoglucomutase 2.
PGM2L1 hgnc:20898 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PGM2L1 (hgnc:20898). hgnc:20898 is a gene from the HUGO Gene Nomenclature Committee.
Phosphoglucomutase activity GO:0004614 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves Phosphoglucomutase activity (GO:0004614). GO:0004614 is a molecular function from the Gene Ontology.
Downstream
Reduced Sugar Bisphosphate Concentrations Loss of PGM2L1 phosphoglucomutase activity reduces glucose-1,6-bisphosphate and other sugar bisphosphate concentrations in patient fibroblasts.
Show evidence (2 references)
PMID:33979636 SUPPORT Human Clinical
"We describe a genetic syndrome due to PGM2L1 deficiency. PGM2 and PGM2L1 make hexose-bisphosphates, like glucose-1,6-bisphosphate, which are indispensable cofactors for sugar phosphomutases."
Establishes PGM2L1's enzymatic role and the loss-of-function disease mechanism.
PMID:33979636 SUPPORT Human Clinical
"While PGM2 has a wide tissue distribution, PGM2L1 is highly expressed in the brain, accounting for the elevated concentrations of glucose-1,6-bisphosphate found there."
Explains the brain-predominant expression that plausibly underlies the neurodevelopmental phenotype.
Reduced Sugar Bisphosphate Concentrations
Patient fibroblasts show markedly reduced glucose-1,6-bisphosphate and other sugar bisphosphates, though residual concentrations remain sufficient to maximally stimulate phosphomutases, so protein glycosylation (LAMP2 glycosylation, serum transferrin glycosylation) is unaffected. This distinguishes PGM2L1 deficiency mechanistically from the congenital disorders of glycosylation.
Show evidence (2 references)
PMID:33979636 SUPPORT In Vitro
"Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally."
Direct biochemical evidence in patient-derived fibroblasts linking PGM2L1 loss to reduced glucose-1,6-bisphosphate.
PMID:33979636 SUPPORT Human Clinical
"Hence, the concentrations of NDP-sugars and glycosylation of the heavily glycosylated protein LAMP2 were normal. Consistent with this, serum transferrin was normally glycosylated in affected individuals. PGM2L1 deficiency does not appear to be a glycosylation defect"
Rules out a glycosylation-defect mechanism despite reduced sugar bisphosphates.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PGM2L1 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Ear 1
Ear Anomalies Abnormality of the ear HP:0000598 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the ear (HP:0000598). HP:0000598 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33979636 SUPPORT Human Clinical
"All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
Reports ear anomalies in all four originally described individuals.
Eye 1
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33979636 SUPPORT Human Clinical
"All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
Reports strabismus in all four originally described individuals.
Head and Neck 2
Dysmorphic Facial Features Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33979636 SUPPORT Human Clinical
"All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
Reports dysmorphic facial features in all four originally described individuals.
High Arched Palate High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33979636 SUPPORT Human Clinical
"All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
Reports high arched palate in all four originally described individuals.
Integument 1
Keratosis Pilaris HP:0032152 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keratosis pilaris (HP:0032152). HP:0032152 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33979636 SUPPORT Human Clinical
"All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
Reports keratosis pilaris in all four originally described individuals.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33979636 SUPPORT Human Clinical
"All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
Reports hypotonia in all four originally described individuals.
Nervous System 3
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33979636 SUPPORT Human Clinical
"All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
Reports severe developmental delay in all four originally described individuals.
Speech Delay Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33979636 SUPPORT Human Clinical
"All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
Reports severe speech delay in all four originally described individuals.
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33979636 SUPPORT Human Clinical
"Early obesity and seizures were present in three individuals."
Quantifies seizures as present in 3 of 4 originally described individuals, supporting a FREQUENT frequency band while noting the very small sample size.
PMID:41776821 SUPPORT Human Clinical
"The patient is a 1-year-old male who presented with psychomotor delays and developed seizures and impaired consciousness at 1 year of age."
Independent case report confirming seizures as a recurrent feature of PGM2L1 deficiency.
Growth 1
Early Obesity FREQUENT HP:0001513 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obesity (HP:0001513). HP:0001513 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33979636 SUPPORT Human Clinical
"Early obesity and seizures were present in three individuals."
Quantifies early obesity as present in 3 of 4 originally described individuals, supporting a FREQUENT frequency band while noting the very small sample size.
🧬

Genetic Associations

1
PGM2L1 (Bi-allelic inactivating variants in PGM2L1 cause this neurodevelopmental disorder.)
Gene: PGM2L1 hgnc:20898 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PGM2L1 (hgnc:20898). hgnc:20898 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:33979636 SUPPORT Human Clinical
"Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome sequencing."
Establishes the causative gene-disease relationship via exome sequencing in four affected individuals.
PMID:41178743 SUPPORT Human Clinical
"In 2021, biallelic pathogenic variants in the PGM2L1 gene were first linked to a neurodevelopmental disorder characterized primarily by developmental delay in four pediatric cases."
Independent replication paper confirming the PGM2L1-neurodevelopmental disorder gene-disease association and citing the original description.
🔬

Biochemical Markers

1
Glucose-1,6-bisphosphate (DECREASED)
Show evidence (1 reference)
PMID:33979636 SUPPORT In Vitro
"Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally."
Direct biochemical demonstration of reduced glucose-1,6-bisphosphate in patient fibroblasts.
{ }

Source YAML

click to show 
name: PGM2L1 Deficiency
category: Mendelian
creation_date: "2026-07-06T00:00:00Z"
synonyms:
- PGM2L1-related neurodevelopmental disorder
- Glucose-1,6-bisphosphate synthase deficiency
description: >
  PGM2L1 deficiency is an ultra-rare autosomal recessive neurodevelopmental
  disorder caused by bi-allelic inactivating variants in PGM2L1, which encodes
  a paralog of phosphoglucomutase 2 that synthesizes glucose-1,6-bisphosphate
  and other sugar bisphosphates. PGM2L1 is highly expressed in the brain, where
  it accounts for locally elevated glucose-1,6-bisphosphate concentrations.
  Loss of PGM2L1 function markedly reduces glucose-1,6-bisphosphate and other
  sugar bisphosphates in patient fibroblasts, but residual concentrations
  remain sufficient to maximally stimulate phosphomutases, so protein
  glycosylation (assessed via LAMP2 and serum transferrin) is normal; the
  disorder is therefore not a glycosylation defect. The condition was first
  described in 2021 in four children with severe developmental and speech
  delay, dysmorphic facial features, ear anomalies, high arched palate,
  strabismus, hypotonia, and keratosis pilaris, with early obesity and
  seizures in most. Subsequent case reports have reported additional
  pediatric and adult cases, expanding the phenotypic spectrum.
disease_term:
  preferred_term: PGM2L1-related neurodevelopmental disorder
  term:
    id: MONDO:0700092
    label: neurodevelopmental disorder
notes: >-
  No PGM2L1-specific MONDO term exists in the local MONDO release as of
  2026-07-06 (verified via `runoak -i sqlite:obo:mondo search "PGM2L1"` and
  by OMIM/synonym cross-check); OMIM:611610 is the PGM2L1 gene MIM, not a
  distinct phenotype MIM, and no phenotype MIM has been assigned. No Orphanet
  entry was found either. This entry is provisionally grounded to the broad
  parent class MONDO:0700092 (neurodevelopmental disorder) pending a MONDO
  new-term request; `preferred_term` carries the fully specific gene-related
  name. Only three publications describe human cases to date: the original
  4-patient series (PMID:33979636), a single-patient follow-up case report
  (PMID:41776821), and a 2-sibling adult-phenotype report (PMID:41178743).
  Given this very small evidence base, this entry is deliberately lean and
  limited to phenotypes and mechanistic claims explicitly stated in these
  sources.
parents:
- Inborn Error of Metabolism
- Neurodevelopmental Disorder
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    All reported affected individuals carry bi-allelic (homozygous or
    compound heterozygous) inactivating PGM2L1 variants, including
    homozygous variants inherited from unaffected heterozygous parents.
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome sequencing."
    explanation: Establishes bi-allelic (autosomal recessive) inheritance of PGM2L1 loss-of-function variants.
  - reference: PMID:41776821
    reference_title: "Identification of a Homozygous PGM2L1 Variant in a Male Patient With Developmental Delay and Seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES identified a rare homozygous variant in the PGM2L1 gene (OMIM: 611,610, NM_173582.6: c.1673delC, p.Thr558Ilefs*19), which was inherited from both parents."
    explanation: Independent case confirming a homozygous, biparentally-inherited PGM2L1 variant.
pathophysiology:
- name: PGM2L1 Loss of Function
  description: >
    Bi-allelic inactivating PGM2L1 variants abolish or severely reduce the
    glucose-1,6-bisphosphate synthase activity of PGM2L1, a brain-enriched
    paralog of phosphoglucomutase 2.
  gene:
    preferred_term: PGM2L1
    term:
      id: hgnc:20898
      label: PGM2L1
  molecular_functions:
  - preferred_term: Phosphoglucomutase activity
    term:
      id: GO:0004614
      label: phosphoglucomutase activity
  consequence: DECREASED
  downstream:
  - target: Reduced Sugar Bisphosphate Concentrations
    description: >
      Loss of PGM2L1 phosphoglucomutase activity reduces glucose-1,6-bisphosphate
      and other sugar bisphosphate concentrations in patient fibroblasts.
    evidence:
    - reference: PMID:33979636
      reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally."
      explanation: Direct biochemical evidence in patient-derived fibroblasts linking PGM2L1 loss to reduced glucose-1,6-bisphosphate.
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a genetic syndrome due to PGM2L1 deficiency. PGM2 and PGM2L1 make hexose-bisphosphates, like glucose-1,6-bisphosphate, which are indispensable cofactors for sugar phosphomutases."
    explanation: Establishes PGM2L1's enzymatic role and the loss-of-function disease mechanism.
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While PGM2 has a wide tissue distribution, PGM2L1 is highly expressed in the brain, accounting for the elevated concentrations of glucose-1,6-bisphosphate found there."
    explanation: Explains the brain-predominant expression that plausibly underlies the neurodevelopmental phenotype.
- name: Reduced Sugar Bisphosphate Concentrations
  description: >
    Patient fibroblasts show markedly reduced glucose-1,6-bisphosphate and
    other sugar bisphosphates, though residual concentrations remain
    sufficient to maximally stimulate phosphomutases, so protein
    glycosylation (LAMP2 glycosylation, serum transferrin glycosylation)
    is unaffected. This distinguishes PGM2L1 deficiency mechanistically from
    the congenital disorders of glycosylation.
  chemical_entities:
  - preferred_term: D-glucose 1,6-bisphosphate
    term:
      id: CHEBI:17680
      label: D-glucose 1,6-bisphosphate
  consequence: DECREASED
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally."
    explanation: Direct biochemical evidence in patient-derived fibroblasts linking PGM2L1 loss to reduced glucose-1,6-bisphosphate.
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hence, the concentrations of NDP-sugars and glycosylation of the heavily glycosylated protein LAMP2 were normal. Consistent with this, serum transferrin was normally glycosylated in affected individuals. PGM2L1 deficiency does not appear to be a glycosylation defect"
    explanation: Rules out a glycosylation-defect mechanism despite reduced sugar bisphosphates.
phenotypes:
- category: Neurological
  name: Global Developmental Delay
  description: >
    Severe developmental delay was present in all four originally reported
    individuals.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
    explanation: Reports severe developmental delay in all four originally described individuals.
- category: Neurological
  name: Speech Delay
  description: >
    Severe speech delay was present in all four originally reported
    individuals.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
    explanation: Reports severe speech delay in all four originally described individuals.
- category: Craniofacial
  name: Dysmorphic Facial Features
  description: Dysmorphic facial features were present in all four originally reported individuals.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
    explanation: Reports dysmorphic facial features in all four originally described individuals.
- category: Craniofacial
  name: Ear Anomalies
  description: Ear anomalies were present in all four originally reported individuals.
  phenotype_term:
    preferred_term: Abnormality of the ear
    term:
      id: HP:0000598
      label: Abnormality of the ear
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
    explanation: Reports ear anomalies in all four originally described individuals.
- category: Craniofacial
  name: High Arched Palate
  description: A high arched palate was present in all four originally reported individuals.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
    explanation: Reports high arched palate in all four originally described individuals.
- category: Ophthalmological
  name: Strabismus
  description: Strabismus was present in all four originally reported individuals.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
    explanation: Reports strabismus in all four originally described individuals.
- category: Neurological
  name: Hypotonia
  description: Hypotonia was present in all four originally reported individuals.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
    explanation: Reports hypotonia in all four originally described individuals.
- category: Dermatological
  name: Keratosis Pilaris
  description: Keratosis pilaris was present in all four originally reported individuals.
  phenotype_term:
    preferred_term: Keratosis pilaris
    term:
      id: HP:0032152
      label: Keratosis pilaris
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris."
    explanation: Reports keratosis pilaris in all four originally described individuals.
- category: Metabolic
  name: Early Obesity
  frequency: FREQUENT
  description: Early-onset obesity was present in three of the four originally reported individuals.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early obesity and seizures were present in three individuals."
    explanation: Quantifies early obesity as present in 3 of 4 originally described individuals, supporting a FREQUENT frequency band while noting the very small sample size.
- category: Neurological
  name: Seizures
  frequency: FREQUENT
  description: Seizures were present in three of the four originally reported individuals, and were also the presenting feature in an independently reported case.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early obesity and seizures were present in three individuals."
    explanation: Quantifies seizures as present in 3 of 4 originally described individuals, supporting a FREQUENT frequency band while noting the very small sample size.
  - reference: PMID:41776821
    reference_title: "Identification of a Homozygous PGM2L1 Variant in a Male Patient With Developmental Delay and Seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient is a 1-year-old male who presented with psychomotor delays and developed seizures and impaired consciousness at 1 year of age."
    explanation: Independent case report confirming seizures as a recurrent feature of PGM2L1 deficiency.
genetic:
- name: PGM2L1
  gene_term:
    preferred_term: PGM2L1
    term:
      id: hgnc:20898
      label: PGM2L1
  relationship_type: CAUSATIVE
  association: Bi-allelic inactivating variants in PGM2L1 cause this neurodevelopmental disorder.
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome sequencing."
    explanation: Establishes the causative gene-disease relationship via exome sequencing in four affected individuals.
  - reference: PMID:41178743
    reference_title: "Delineating the Adult Phenotype of PGM2L1 -Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2021, biallelic pathogenic variants in the PGM2L1 gene were first linked to a neurodevelopmental disorder characterized primarily by developmental delay in four pediatric cases."
    explanation: Independent replication paper confirming the PGM2L1-neurodevelopmental disorder gene-disease association and citing the original description.
biochemical:
- name: Glucose-1,6-bisphosphate
  biomarker_term:
    preferred_term: D-glucose 1,6-bisphosphate
    term:
      id: CHEBI:17680
      label: D-glucose 1,6-bisphosphate
  presence: DECREASED
  notes: >
    Measured in patient-derived fibroblasts, not blood or CSF; no clinically
    validated diagnostic assay or reference range has been reported.
  evidence:
  - reference: PMID:33979636
    reference_title: "Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally."
    explanation: Direct biochemical demonstration of reduced glucose-1,6-bisphosphate in patient fibroblasts.