HIDEA_Syndrome

Genetic MONDO:0032780 Pathograph 2 Neurologic Disorder Developmental Disorder Epileptic Encephalopathy

HIDEA syndrome (Hypotonia, Hypoventilation, Impaired Intellectual Development, Dysautonomia, Epilepsy, and Eye Abnormalities) is a severe autosomal recessive neurodevelopmental disorder caused by biallelic loss-of-function variants in P4HTM, encoding the endoplasmic reticulum transmembrane prolyl 4-hydroxylase P4H-TM. The enzyme localizes to the ER membrane with its catalytic domain in the ER lumen and contains a unique EF-hand domain suggesting calcium regulation of enzymatic activity. Loss of P4H-TM leads to dysregulated HIF-1 signaling and calcium dynamics in astrocytes, affecting gliotransmission and central respiratory control circuits.

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4
Pathophys.
13
Phenotypes
2
Pathograph
1
Genes
4
Treatments
6
References
2
Deep Research
⚙

Pathophysiology

4
P4HTM Gene Loss-of-Function
Biallelic loss-of-function variants in P4HTM result in loss of ER-resident transmembrane prolyl 4-hydroxylase activity. The enzyme contains an EF-hand domain that allows calcium-dependent regulation of its catalytic activity, linking the genetic defect to both HIF signaling and calcium homeostasis pathways.
P4HTM
Show evidence (1 reference)
PMID:30940925 SUPPORT
"Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA)."
The foundational paper establishing that biallelic P4HTM mutations cause HIDEA syndrome.
Dysregulated Astrocyte Calcium Signaling
P4H-TM is a regulator of calcium dynamics and gliotransmission in astrocytes via a HIF-1-dependent mechanism. Loss of P4H-TM impairs receptor-operated and store-operated calcium entry (ROCE/SOCE), reduces mitochondrial calcium uptake and ATP production, and attenuates gliotransmission.
Astrocyte link
Calcium ion transmembrane transport link Gliotransmitter secretion link
Central Respiratory Control Dysfunction
Loss of P4H-TM leads to impaired central respiratory control, with hypoventilation and blunted responses to hypoxia. Patients may require BiPAP support and are at risk for respiratory distress during infections.
Neuron link
Regulation of respiratory system process link Response to hypoxia link
Show evidence (1 reference)
PMID:30940925 SUPPORT
"Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype."
The foundational HIDEA paper identified hypoventilation and central sleep apnea as core features.
Mitochondrial Dysfunction
A subset of HIDEA patients show mitochondrial respiratory chain complex deficiency in muscle biopsies, suggesting that P4H-TM loss can affect mitochondrial function.
Oxidative phosphorylation link
Show evidence (1 reference)
PMID:30940925 SUPPORT
"The muscle biopsy of patient 1 showed low activity of mitochondrial respiratory chain complex III. In addition, the muscle biopsy of patient 2 was suggestive of a mitochondrial, neurometabolic disease."
Evidence from muscle biopsies showing mitochondrial respiratory chain deficiency in some HIDEA patients.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for HIDEA_Syndrome 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

13
Eye 2
Abnormal Eye Movements FREQUENT Strabismus (HP:0000486)
Show evidence (1 reference)
PMID:30940925 SUPPORT
"the common presenting features include strabismus (N = 11/13, 85%), epilepsy (N = 10/13, 77%)"
Strabismus is a common feature of HIDEA syndrome.
Visual Impairment FREQUENT Visual impairment (HP:0000505)
Show evidence (1 reference)
PMID:30940925 SUPPORT
"All the patients with P4HTM gene variants have developmental delay or intellectual disability and visual abnormalities—such as strabismus, rotating eye movements, nystagmus, or cortical blindness"
Visual abnormalities are part of the eye phenotype in HIDEA.
Head and Neck 1
Coarse Facial Features OCCASIONAL Coarse facial features (HP:0000280)
Immune 1
Recurrent Respiratory Infections FREQUENT Recurrent respiratory infections (HP:0002205)
Musculoskeletal 2
Generalized Hypotonia VERY_FREQUENT Generalized hypotonia (HP:0001290)
Show evidence (1 reference)
PMID:30940925 SUPPORT
"All the patients have hypotonia (N = 13/13), and either intellectual disability (N = 12/13) or developmental delay"
Hypotonia is present in 100% of HIDEA patients.
Scoliosis OCCASIONAL Scoliosis (HP:0002650)
Nervous System 5
Global Developmental Delay VERY_FREQUENT Global developmental delay (HP:0001263)
Show evidence (1 reference)
PMID:30940925 SUPPORT
"All the patients have hypotonia (N = 13/13), and either intellectual disability (N = 12/13) or developmental delay"
Global developmental delay is a core feature of the syndrome.
Intellectual Disability VERY_FREQUENT Intellectual disability (HP:0001249)
Show evidence (1 reference)
PMID:30940925 SUPPORT
"All the patients have hypotonia (N = 13/13), and either intellectual disability (N = 12/13) or developmental delay"
Intellectual disability is present in 12 of 13 patients.
Epilepsy FREQUENT Seizure (HP:0001250)
Show evidence (1 reference)
PMID:30940925 SUPPORT
"the common presenting features include strabismus (N = 11/13, 85%), epilepsy (N = 10/13, 77%), and central or obstructive sleep apnea"
Epilepsy is present in 77% of HIDEA patients.
Dysautonomia FREQUENT Abnormality of the autonomic nervous system (HP:0002270)
Show evidence (1 reference)
PMID:30940925 SUPPORT
"Some patients also show dysautonomia, including constipation (N = 6/13, 46%), recurrent hypothermia or hyperthermia (N = 4/13, 31%), and reduced sweating (N = 2/13, 15%)"
Dysautonomia features including temperature dysregulation and constipation are present in subsets of HIDEA patients.
Gait Disturbance FREQUENT Gait disturbance (HP:0001288)
Respiratory 1
Central Hypoventilation VERY_FREQUENT Central hypoventilation (HP:0007110)
Show evidence (1 reference)
PMID:30940925 SUPPORT
"the common presenting features include strabismus (N = 11/13, 85%), epilepsy (N = 10/13, 77%), and central or obstructive sleep apnea"
Central or obstructive sleep apnea occurs in most HIDEA patients.
Growth 1
Obesity OCCASIONAL Obesity (HP:0001513)
Show evidence (1 reference)
PMID:30940925 SUPPORT
"Six patients (N = 6/13, 46%) have a body mass index (BMI) over 25 kg/m2"
Some HIDEA patients have elevated BMI/obesity.
🧬

Genetic Associations

1
P4HTM (Causative)
Autosomal recessive
Show evidence (2 references)
PMID:30940925 SUPPORT
"Variant characterization demonstrates that the variants affect protein folding by yielding an insoluble protein product."
The study demonstrated that P4HTM variants cause loss of function through protein misfolding.
PMID:25078763 SUPPORT
"Whole-genome sequencing of one affected individual pinpointed three genes with potentially protein damaging homozygous sequence changes within the predisposition locus transketolase (TKT), prolyl 4-hydroxylase transmembrane (P4HTM), and ubiquitin specific peptidase 4 (USP4)."
Initial identification of P4HTM as a candidate gene for HIDEA syndrome in a Finnish kindred.
💊

Treatments

4
Respiratory Support
Action: Respiratory support Ontology label: supportive care MAXO:0000950
Non-invasive ventilation such as BiPAP may be required for management of hypoventilation, particularly during sleep or respiratory infections.
Anticonvulsant Therapy
Action: Anticonvulsant therapy Ontology label: Pharmacotherapy NCIT:C15986
Seizures are generally responsive to standard anticonvulsant medications. Valproate has been noted as potentially beneficial due to its HIF-1 alpha inhibiting properties.
Physical Therapy
Action: Physical therapy Ontology label: physical therapy MAXO:0000011
Rehabilitation to address hypotonia, motor delays, and gait abnormalities.
Ophthalmologic Management
Action: Ophthalmologic management Ontology label: supportive care MAXO:0000950
Regular ophthalmologic evaluation and management of visual impairments including corrective lenses and treatment of strabismus.
{ }

Source YAML

click to show 
name: HIDEA_Syndrome
creation_date: '2025-12-10T21:01:43Z'
updated_date: '2026-02-17T21:53:14Z'
description: HIDEA syndrome (Hypotonia, Hypoventilation, Impaired Intellectual
  Development, Dysautonomia, Epilepsy, and Eye Abnormalities) is a severe
  autosomal recessive neurodevelopmental disorder caused by biallelic
  loss-of-function variants in P4HTM, encoding the endoplasmic reticulum
  transmembrane prolyl 4-hydroxylase P4H-TM. The enzyme localizes to the ER
  membrane with its catalytic domain in the ER lumen and contains a unique
  EF-hand domain suggesting calcium regulation of enzymatic activity. Loss of
  P4H-TM leads to dysregulated HIF-1 signaling and calcium dynamics in
  astrocytes, affecting gliotransmission and central respiratory control
  circuits.
category: Genetic
parents:
- Neurologic Disorder
- Developmental Disorder
- Epileptic Encephalopathy
prevalence:
- population: Global
  percentage: Rare
progression:
- phase: Onset
  age_range: Infancy
pathophysiology:
- name: P4HTM Gene Loss-of-Function
  description: Biallelic loss-of-function variants in P4HTM result in loss of
    ER-resident transmembrane prolyl 4-hydroxylase activity. The enzyme contains
    an EF-hand domain that allows calcium-dependent regulation of its catalytic
    activity, linking the genetic defect to both HIF signaling and calcium
    homeostasis pathways.
  genes:
  - preferred_term: P4HTM
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: Biallelic loss-of-function P4HTM gene variants cause hypotonia,
      hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye
      abnormalities (HIDEA).
    explanation: The foundational paper establishing that biallelic P4HTM
      mutations cause HIDEA syndrome.
- name: Dysregulated Astrocyte Calcium Signaling
  description: P4H-TM is a regulator of calcium dynamics and gliotransmission in
    astrocytes via a HIF-1-dependent mechanism. Loss of P4H-TM impairs
    receptor-operated and store-operated calcium entry (ROCE/SOCE), reduces
    mitochondrial calcium uptake and ATP production, and attenuates
    gliotransmission.
  cell_types:
  - preferred_term: Astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: Calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
  - preferred_term: Gliotransmitter secretion
    term:
      id: GO:0007269
      label: neurotransmitter secretion
- name: Central Respiratory Control Dysfunction
  description: Loss of P4H-TM leads to impaired central respiratory control,
    with hypoventilation and blunted responses to hypoxia. Patients may require
    BiPAP support and are at risk for respiratory distress during infections.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Regulation of respiratory system process
    term:
      id: GO:0044065
      label: regulation of respiratory system process
  - preferred_term: Response to hypoxia
    term:
      id: GO:0001666
      label: response to hypoxia
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: Hypoventilation, obstructive and central sleep apnea, and
      dysautonomia were identified as novel features associated with the
      phenotype.
    explanation: The foundational HIDEA paper identified hypoventilation and
      central sleep apnea as core features.
- name: Mitochondrial Dysfunction
  description: A subset of HIDEA patients show mitochondrial respiratory chain
    complex deficiency in muscle biopsies, suggesting that P4H-TM loss can
    affect mitochondrial function.
  biological_processes:
  - preferred_term: Oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: The muscle biopsy of patient 1 showed low activity of mitochondrial
      respiratory chain complex III. In addition, the muscle biopsy of patient 2
      was suggestive of a mitochondrial, neurometabolic disease.
    explanation: Evidence from muscle biopsies showing mitochondrial respiratory
      chain deficiency in some HIDEA patients.
phenotypes:
- category: Neurologic
  name: Generalized Hypotonia
  description: Decreased muscle tone present from infancy, contributing to motor
    delays.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: All the patients have hypotonia (N = 13/13), and either
      intellectual disability (N = 12/13) or developmental delay
    explanation: Hypotonia is present in 100% of HIDEA patients.
- category: Respiratory
  name: Central Hypoventilation
  description: Reduced ventilation due to impaired central respiratory control,
    with blunted responses to hypoxia and hypercapnia. May require BiPAP
    support.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Central hypoventilation
    term:
      id: HP:0007110
      label: Central hypoventilation
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: the common presenting features include strabismus (N = 11/13, 85%),
      epilepsy (N = 10/13, 77%), and central or obstructive sleep apnea
    explanation: Central or obstructive sleep apnea occurs in most HIDEA
      patients.
- category: Developmental
  name: Global Developmental Delay
  description: Significant delays in motor, speech, and cognitive development
    beginning in infancy.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: All the patients have hypotonia (N = 13/13), and either
      intellectual disability (N = 12/13) or developmental delay
    explanation: Global developmental delay is a core feature of the syndrome.
- category: Cognitive
  name: Intellectual Disability
  description: Cognitive impairment ranging from severe to profound, often with
    absent or severely limited speech.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: All the patients have hypotonia (N = 13/13), and either
      intellectual disability (N = 12/13) or developmental delay
    explanation: Intellectual disability is present in 12 of 13 patients.
- category: Neurologic
  name: Epilepsy
  description: Seizures in most patients, often beginning in infancy, with EEG
    showing multifocal spikes. Multiple seizure types may occur but are often
    relatively well-controlled with anticonvulsants.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: the common presenting features include strabismus (N = 11/13, 85%),
      epilepsy (N = 10/13, 77%), and central or obstructive sleep apnea
    explanation: Epilepsy is present in 77% of HIDEA patients.
- category: Autonomic
  name: Dysautonomia
  description: Autonomic dysfunction including temperature dysregulation and
    constipation. Some patients show ROHHAD-like features including rapid weight
    gain.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Abnormality of the autonomic nervous system
    term:
      id: HP:0002270
      label: Abnormality of the autonomic nervous system
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: Some patients also show dysautonomia, including constipation (N =
      6/13, 46%), recurrent hypothermia or hyperthermia (N = 4/13, 31%), and
      reduced sweating (N = 2/13, 15%)
    explanation: Dysautonomia features including temperature dysregulation and
      constipation are present in subsets of HIDEA patients.
- category: Ophthalmologic
  name: Abnormal Eye Movements
  description: Eye movement abnormalities including rotary nystagmus, exotropia,
    and strabismus.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: the common presenting features include strabismus (N = 11/13, 85%),
      epilepsy (N = 10/13, 77%)
    explanation: Strabismus is a common feature of HIDEA syndrome.
- category: Ophthalmologic
  name: Visual Impairment
  description: Visual problems including myopia, hyperopia, astigmatism, optic
    atrophy, cortical blindness, or achromic fundi.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: All the patients with P4HTM gene variants have developmental delay
      or intellectual disability and visual abnormalities—such as strabismus,
      rotating eye movements, nystagmus, or cortical blindness
    explanation: Visual abnormalities are part of the eye phenotype in HIDEA.
- category: Motor
  name: Gait Disturbance
  description: Delayed walking or inability to walk, with unsteady wide-based
    gait in those who achieve ambulation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
- category: Respiratory
  name: Recurrent Respiratory Infections
  description: Recurrent pneumonia and respiratory distress, likely related to
    hypoventilation and aspiration risk.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
- category: Skeletal
  name: Scoliosis
  description: Spinal curvature abnormality developing in some patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
- category: Metabolic
  name: Obesity
  description: Tendency toward obesity, sometimes with rapid weight gain similar
    to ROHHAD syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: Six patients (N = 6/13, 46%) have a body mass index (BMI) over 25
      kg/m2
    explanation: Some HIDEA patients have elevated BMI/obesity.
- category: Craniofacial
  name: Coarse Facial Features
  description: Some patients develop coarse facial features.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
genetic:
- name: P4HTM
  association: Causative
  inheritance:
  - name: Autosomal recessive
  notes: Biallelic loss-of-function mutations including missense, nonsense, and
    frameshift variants. The gene encodes prolyl 4-hydroxylase transmembrane
    (P4H-TM), an ER membrane enzyme with roles in hypoxia signaling and calcium
    regulation.
  evidence:
  - reference: PMID:30940925
    reference_title: "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)."
    supports: SUPPORT
    snippet: Variant characterization demonstrates that the variants affect
      protein folding by yielding an insoluble protein product.
    explanation: The study demonstrated that P4HTM variants cause loss of
      function through protein misfolding.
  - reference: PMID:25078763
    reference_title: "Clinical characterization, genetic mapping and whole-genome sequence analysis of a novel autosomal recessive intellectual disability syndrome."
    supports: SUPPORT
    snippet: Whole-genome sequencing of one affected individual pinpointed three
      genes with potentially protein damaging homozygous sequence changes within
      the predisposition locus transketolase (TKT), prolyl 4-hydroxylase
      transmembrane (P4HTM), and ubiquitin specific peptidase 4 (USP4).
    explanation: Initial identification of P4HTM as a candidate gene for HIDEA
      syndrome in a Finnish kindred.
treatments:
- name: Respiratory Support
  description: Non-invasive ventilation such as BiPAP may be required for
    management of hypoventilation, particularly during sleep or respiratory
    infections.
  treatment_term:
    preferred_term: Respiratory support
    term:
      id: MAXO:0000950
      label: supportive care
- name: Anticonvulsant Therapy
  description: Seizures are generally responsive to standard anticonvulsant
    medications. Valproate has been noted as potentially beneficial due to its
    HIF-1 alpha inhibiting properties.
  treatment_term:
    preferred_term: Anticonvulsant therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Physical Therapy
  description: Rehabilitation to address hypotonia, motor delays, and gait
    abnormalities.
  treatment_term:
    preferred_term: Physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
- name: Ophthalmologic Management
  description: Regular ophthalmologic evaluation and management of visual
    impairments including corrective lenses and treatment of strabismus.
  treatment_term:
    preferred_term: Ophthalmologic management
    term:
      id: MAXO:0000950
      label: supportive care
disease_term:
  preferred_term: HIDEA syndrome
  term:
    id: MONDO:0032780
    label: hypotonia, hypoventilation, impaired intellectual development,
      dysautonomia, epilepsy, and eye abnormalities
references:
- reference: DOI:10.1007/s00424-024-02920-5
  title: Metabolic characteristics of transmembrane prolyl 4-hydroxylase
    (P4H-TM) deficient mice
  findings: []
- reference: DOI:10.1038/s41431-021-00932-8
  title: Biallelic P4HTM variants associated with HIDEA syndrome and
    mitochondrial respiratory chain complex I deficiency
  findings: []
- reference: DOI:10.1038/s41436-019-0503-4
  title: Biallelic loss-of-function P4HTM gene variants cause hypotonia,
    hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye
    abnormalities (HIDEA syndrome)
  findings: []
- reference: DOI:10.1523/eneuro.0253-20.2020
  title: Transmembrane Prolyl 4-Hydroxylase is a Novel Regulator of Calcium
    Signaling in Astrocytes
  findings: []
- reference: DOI:10.3389/fgene.2023.1137767
  title: 'HIDEA syndrome: A new case report highlighting similarities with ROHHAD
    syndrome'
  findings: []
- reference: DOI:10.3389/fneur.2024.1428076
  title: 'Clinical characteristics of patients with P4HTM variant-associated epilepsy
    and therapeutic exploration: a case report and literature review'
  findings: []
📚

References & Deep Research

References

6
DOI:10.1007/s00424-024-02920-5
Metabolic characteristics of transmembrane prolyl 4-hydroxylase (P4H-TM) deficient mice
No top-level findings curated for this source.
DOI:10.1038/s41431-021-00932-8
Biallelic P4HTM variants associated with HIDEA syndrome and mitochondrial respiratory chain complex I deficiency
No top-level findings curated for this source.
DOI:10.1038/s41436-019-0503-4
Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome)
No top-level findings curated for this source.
DOI:10.1523/eneuro.0253-20.2020
Transmembrane Prolyl 4-Hydroxylase is a Novel Regulator of Calcium Signaling in Astrocytes
No top-level findings curated for this source.
DOI:10.3389/fgene.2023.1137767
HIDEA syndrome: A new case report highlighting similarities with ROHHAD syndrome
No top-level findings curated for this source.
DOI:10.3389/fneur.2024.1428076
Clinical characteristics of patients with P4HTM variant-associated epilepsy and therapeutic exploration: a case report and literature review
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: HIDEA_Syndrome
  • Category: Genetic
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 20

Key Pathophysiology Nodes

  • P4HTM Gene Loss-of-Function
  • Dysregulated Astrocyte Calcium Signaling
  • Central Respiratory Control Dysfunction
  • Mitochondrial Dysfunction
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s00424-024-02920-5
  • DOI:10.1038/s41431-021-00932-8
  • DOI:10.1038/s41436-019-0503-4
  • DOI:10.1523/eneuro.0253-20.2020
  • DOI:10.3389/fgene.2023.1137767
  • DOI:10.3389/fneur.2024.1428076
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 24 citations 2025-12-09T13:03:13.642272

Disease Pathophysiology Research Report

Target Disease

  • Disease Name: HIDEA Syndrome
  • MONDO ID: [not established in sources retrieved]
  • Category: Genetic (autosomal recessive)

Pathophysiology Description (Narrative)

HIDEA syndrome is a severe, autosomal recessive neurodevelopmental disorder caused by biallelic loss-of-function variants in P4HTM, encoding the endoplasmic reticulum (ER) transmembrane prolyl 4-hydroxylase P4H‑TM. Foundational clinical genetics established that “biallelic loss‑of‑function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA)” (Genetics in Medicine, Oct 2019; https://doi.org/10.1038/s41436-019-0503-4). Mechanistically, P4H‑TM localizes to the ER membrane with its catalytic domain in the ER lumen and includes a unique EF‑hand domain, suggesting Ca2+ regulation of enzymatic activity and a tight link to ER–calcium signaling. Recent experimental work demonstrated that P4H‑TM is a regulator of astrocyte Ca2+ signaling and gliotransmission via a HIF‑1–dependent mechanism, implicating dysregulated hypoxia signaling in CNS networks that govern respiration and autonomic function (eNeuro, Dec 2021; https://doi.org/10.1523/eneuro.0253-20.2020) (alanisula2024metaboliccharacteristicsof pages 3-6). Complementary in vivo evidence from global P4h‑tm−/− mice shows alterations in whole‑body energy metabolism, neuromuscular weakness, and, critically, a reduced respiratory rate with blunted ventilatory responses to hypoxia and hypercapnia, leading to respiratory acidosis; the authors conclude that these changes “appear to be neurological and controlled by the brain and central nervous system circuits,” recapitulating key human HIDEA features (Pflügers Archiv, Feb 2024; https://doi.org/10.1007/s00424-024-02920-5) (alanisula2024metaboliccharacteristicsof pages 1-2, alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 7-9, alanisula2024metaboliccharacteristicsof pages 3-6, alanisula2024metaboliccharacteristicsof pages 9-11).

A subset of HIDEA patients show mitochondrial respiratory chain complex I deficiency in muscle biopsies, suggesting that P4H‑TM loss can intersect with mitochondrial function and integrated stress response pathways (e.g., ATF4), potentially downstream of altered HIF signaling and ER–mitochondria Ca2+ crosstalk (Eur J Hum Genet, Jul 2021; https://doi.org/10.1038/s41431-021-00932-8) (wang2024clinicalcharacteristicsof pages 6-7). Clinically, HIDEA overlaps with ROHHAD-like presentations (rapid-onset obesity, hypoventilation, dysautonomia), leading experts to recommend P4HTM sequencing in ROHHAD-suspected cases that also exhibit abnormal neurodevelopment or eye findings (Front Genet, Mar 2023; https://doi.org/10.3389/fgene.2023.1137767) (harvengt2023hideasyndromea pages 5-6).

Category Key finding or quote Molecular/Cellular process implicated Species / Context Source (authors, year) Journal URL / DOI Publication date
Foundational description "Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA)" (diagnostic/phenotypic definition) (harvengt2023hideasyndromea pages 5-6) Genetic loss-of-function in P4HTM → syndromic neurodevelopmental disorder Human patients / clinical genetics Rahikkala et al., 2019 Genetics in Medicine https://doi.org/10.1038/s41436-019-0503-4 Oct 2019
Clinical case / phenotype overlap Case report: clinical similarity between HIDEA and ROHHAD; recommends testing P4HTM in ROHHAD-like cases (harvengt2023hideasyndromea pages 5-6) Hypothalamic/dysautonomia features; central hypoventilation Human clinical case series / diagnostic recommendation Harvengt et al., 2023 Frontiers in Genetics https://doi.org/10.3389/fgene.2023.1137767 Mar 2023
Cellular mechanism (astrocytes) "P4H-TM is a novel regulator of calcium dynamics and gliotransmission" (HIF1 mediates effect on calcium signaling) (alanisula2024metaboliccharacteristicsof pages 3-6) Disrupted receptor-/store-operated Ca2+ entry (ROCE/SOCE), mitochondrial Ca2+ uptake, altered ATP; HIF-1α–dependent pathway Mouse primary astrocytes / cortex (cellular assays) Byts et al., 2021 eNeuro https://doi.org/10.1523/eneuro.0253-20.2020 Dec 2021
Mitochondrial involvement Reports of mitochondrial respiratory chain complex I deficiency in some HIDEA patients; ATF4/ISR proposed link (alanisula2024metaboliccharacteristicsof pages 3-6) Mitochondrial respiratory chain dysfunction, integrated stress response (ATF4) Human muscle biopsy / clinical case Hay et al., 2021 European Journal of Human Genetics https://doi.org/10.1038/s41431-021-00932-8 Jul 2021
Mouse model — systemic phenotypes P4h-tm−/− mice show altered 24-h energy expenditure, lower respiratory rate, blunted hypoxia/hypercapnia responses, neuromuscular weakness — "recapitulates some symptoms of HIDEA" (alanisula2024metaboliccharacteristicsof pages 12-13, alanisula2024metaboliccharacteristicsof pages 11-12) Altered whole-body energy metabolism, respiratory control, neuromuscular function; CNS-origin hypothesis Global knockout mouse (P4h-tm−/−) — physiological, metabolic, respiratory assays Ala‑Nisula et al., 2024 Pflugers Archiv https://doi.org/10.1007/s00424-024-02920-5 Feb 2024
Therapeutics / clinical management Seizures in P4HTM-associated patients often start in infancy and are relatively controllable; valproate (a HIF‑1α inhibitor) proposed as promising (wang2024clinicalcharacteristicsof pages 6-7) Pharmacologic HIF‑1α modulation considered (valproate cited) Human case report + literature review (epilepsy focus) Wang et al., 2024 Frontiers in Neurology https://doi.org/10.3389/fneur.2024.1428076 Nov 2024
Subcellular localization P4H-TM is an endoplasmic reticulum (ER) transmembrane prolyl 4‑hydroxylase with its catalytic domain in the ER lumen (alanisula2024metaboliccharacteristicsof pages 1-2) ER membrane localization → lumenal catalytic activity; potential ER‑related substrates/processes Biochemical/structural annotation from mouse/human studies (Ala‑Nisula summary of prior work), 2024 (summarized in Pflugers Archiv) https://doi.org/10.1007/s00424-024-02920-5 Feb 2024
EF‑hand / Ca2+ regulation "its catalytic activity may be regulated by Ca2+"; P4H‑TM contains a unique EF‑hand adjacent to the dioxygenase domain (alanisula2024metaboliccharacteristicsof pages 1-2) EF‑hand calcium‑binding domain → Ca2+ modulation of enzymatic activity; links to calcium signaling defects Structural/functional inference (protein domain and mouse/cell data) (Ala‑Nisula summary of structural data), 2024 (summarized in Pflugers Archiv) https://doi.org/10.1007/s00424-024-02920-5 Feb 2024

Table: Concise, citation-linked summary of mechanistic, clinical, model, localization, and therapeutic evidence for HIDEA syndrome (P4HTM/P4H‑TM) from prioritized 2019–2024 literature; useful as an evidence-annotated quick reference for disease knowledge base entries.

1. Core Pathophysiology

  • Primary mechanisms:
  • Loss of ER-resident transmembrane prolyl 4-hydroxylase (P4H‑TM) activity with EF‑hand–mediated Ca2+ modulation, disturbing ER–calcium signaling and HIF‑linked pathways in neural cells (astrocytes) (alanisula2024metaboliccharacteristicsof pages 1-2, alanisula2024metaboliccharacteristicsof pages 3-6).
  • HIF‑1–dependent perturbation of receptor‑operated and store‑operated Ca2+ entry (ROCE/SOCE), impaired mitochondrial Ca2+ uptake, reduced ATP, and attenuated gliotransmission in P4h‑tm−/− astrocytes (eNeuro 2021) (alanisula2024metaboliccharacteristicsof pages 3-6).
  • CNS‑origin respiratory control dysfunction, evidenced by reduced respiratory rate, blunted hypoxia/hypercapnia responses, and respiratory acidosis in P4h‑tm−/− mice, mechanistically linking astroglial/neuronal signaling defects to ventilatory control (Pflügers Archiv 2024) (alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 7-9, alanisula2024metaboliccharacteristicsof pages 9-11).

  • In some patients, mitochondrial complex I deficiency suggests secondary mitochondrial dysfunction and activation of integrated stress response nodes (e.g., ATF4) (EJHG 2021) (wang2024clinicalcharacteristicsof pages 6-7).

  • Dysregulated molecular pathways:

  • Hypoxia signaling (HIF‑1 axis) and calcium signaling pathways in glia (astrocytes) (alanisula2024metaboliccharacteristicsof pages 3-6).

  • Potential ER stress/integrated stress response convergence (ATF4) in patient tissues with mitochondrial involvement (wang2024clinicalcharacteristicsof pages 6-7).

  • Affected cellular processes:

  • Calcium homeostasis (ROCE, SOCE), mitochondrial Ca2+ uptake, gliotransmission, and cellular energy metabolism (alanisula2024metaboliccharacteristicsof pages 3-6).
  • Central control of respiration and autonomic function; whole‑body energy balance and glycogenolysis (alanisula2024metaboliccharacteristicsof pages 1-2, alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 7-9, alanisula2024metaboliccharacteristicsof pages 9-11).

2. Key Molecular Players

  • Genes/Proteins (HGNC):
  • P4HTM (HGNC:20070): ER transmembrane prolyl 4‑hydroxylase; causal gene for HIDEA (Genet Med 2019; https://doi.org/10.1038/s41436-019-0503-4) (harvengt2023hideasyndromea pages 5-6).
  • HIF1A (HGNC:4910): Effector of hypoxia signaling implicated in P4H‑TM–dependent astrocyte Ca2+ regulation (eNeuro 2021) (alanisula2024metaboliccharacteristicsof pages 3-6).

  • ATF4 (HGNC:785): Integrated stress response factor hypothesized to be involved in patient mitochondrial phenotype (EJHG 2021) (wang2024clinicalcharacteristicsof pages 6-7).

  • Chemical entities (CHEBI) and relevant metabolites/drugs:

  • Calcium ion (CHEBI:29108): EF‑hand regulation; Ca2+ signaling defects (alanisula2024metaboliccharacteristicsof pages 3-6).
  • Lactate (CHEBI:24996): Elevated in sedated P4h‑tm−/− mice, consistent with tissue hypoxia and glycolytic shift (Pflügers Archiv 2024) (alanisula2024metaboliccharacteristicsof pages 9-11).
  • Insulin (CHEBI:5931): Altered responses in mice; >50% loss of consciousness after insulin injection under certain conditions (Pflügers Archiv 2024) (alanisula2024metaboliccharacteristicsof pages 9-11).

  • Valproate (CHEBI:39867): Proposed for seizure control; noted HIF‑1α‑inhibiting properties in review context (Front Neurol 2024) (wang2024clinicalcharacteristicsof pages 6-7).

  • Cell types (CL):

  • Astrocytes (CL:0000127): Primary cell type with demonstrated P4H‑TM–dependent Ca2+ signaling and gliotransmission defects (alanisula2024metaboliccharacteristicsof pages 3-6).

  • Neurons (CL:0000540): Implicated in central respiratory/autonomic control (inferred from CNS-origin in mouse phenotype) (alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 9-11).

  • Anatomical locations (UBERON):

  • Endoplasmic reticulum (GO/Cellular Component but anatomical context within cells): ER membrane localization of P4H‑TM (alanisula2024metaboliccharacteristicsof pages 1-2).
  • Brain/central nervous system (UBERON:0000955), including respiratory centers (medulla/pons; UBERON:0001898, UBERON:0000988) (alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 9-11).
  • Eye (UBERON:0000970): HIDEA includes eye abnormalities; retinal involvement reported in some patients (harvengt2023hideasyndromea pages 5-6, wang2024clinicalcharacteristicsof pages 6-7).
  • Liver (UBERON:0002107): Altered glycogenolysis in P4h‑tm−/− mice (alanisula2024metaboliccharacteristicsof pages 7-9).

3. Biological Processes (GO) Disrupted

  • Calcium ion transmembrane transport; receptor‑operated and store‑operated Ca2+ entry (GO:0070588; GO:0007204; GO:0005245 context) (alanisula2024metaboliccharacteristicsof pages 3-6).
  • Gliotransmission and regulation of synaptic signaling by glia (GO:0099177; GO:0099154) (alanisula2024metaboliccharacteristicsof pages 3-6).
  • Response to hypoxia and HIF‑1 signaling (GO:0001666; GO:0071456) (alanisula2024metaboliccharacteristicsof pages 3-6).
  • Regulation of respiratory system process and ventilatory response to hypoxia/hypercapnia (GO:0003016; GO:0061419) (mouse phenotype mapping to GO context) (alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 7-9, alanisula2024metaboliccharacteristicsof pages 9-11).
  • Glycogen catabolic process and glucose homeostasis (GO:0005980; GO:0042593) (alanisula2024metaboliccharacteristicsof pages 7-9).
  • Mitochondrial electron transport, NADH to ubiquinone (complex I) (GO:0006120) in subset of patients (wang2024clinicalcharacteristicsof pages 6-7).

4. Cellular Components

  • Endoplasmic reticulum membrane and lumen (GO:0005789; GO:0005788): P4H‑TM localization; catalytic domain in ER lumen (alanisula2024metaboliccharacteristicsof pages 1-2).
  • Mitochondrion (GO:0005739): Altered Ca2+ uptake and complex I deficiency in some patients; astrocyte mitochondrial redistribution in vitro (alanisula2024metaboliccharacteristicsof pages 3-6, wang2024clinicalcharacteristicsof pages 6-7).
  • Synapse and astrocyte processes (GO:0045202; GO:0097449): Attenuated calcium agonist–induced gliotransmission (alanisula2024metaboliccharacteristicsof pages 3-6).

5. Disease Progression (Proposed Sequence)

  • Genetic trigger: biallelic P4HTM loss-of-function variants (harvengt2023hideasyndromea pages 5-6).
  • Cellular dysfunction: loss of P4H‑TM activity in ER with EF‑hand Ca2+ regulation → HIF‑1–linked dysregulation of astrocyte ROCE/SOCE, reduced mitochondrial Ca2+ uptake and ATP, attenuated gliotransmission (alanisula2024metaboliccharacteristicsof pages 3-6).
  • Network-level impact: impaired astrocyte–neuron signaling within brainstem/hypothalamic circuits → disordered autonomic and ventilatory control (alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 9-11).
  • Systemic manifestations: hypoventilation with blunted response to hypoxia/hypercapnia and respiratory acidosis; altered energy balance, accelerated hepatic glycogenolysis, shifts toward glycolysis (in mice) (alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 7-9, alanisula2024metaboliccharacteristicsof pages 9-11).
  • Clinical phenotypes: hypotonia, intellectual disability, dysautonomia, epilepsy, eye abnormalities; occasional mitochondrial complex I deficiency consistent with bioenergetic stress (harvengt2023hideasyndromea pages 5-6, wang2024clinicalcharacteristicsof pages 6-7).

6. Phenotypic Manifestations (HPO) and Mechanistic Links

  • Generalized hypotonia (HP:0001252): neuromuscular weakness in mice and clinical hypotonia in patients (harvengt2023hideasyndromea pages 5-6, alanisula2024metaboliccharacteristicsof pages 3-6, alanisula2024metaboliccharacteristicsof pages 9-11).
  • Central hypoventilation (HP:0002875) and sleep-related hypoventilation (HP:0002871): reduced respiratory rate, blunted ventilatory responses, respiratory acidosis in mice; clinical hypoventilation in HIDEA (alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 7-9, alanisula2024metaboliccharacteristicsof pages 9-11, harvengt2023hideasyndromea pages 5-6).
  • Intellectual disability (HP:0001249) (harvengt2023hideasyndromea pages 5-6).
  • Dysautonomia (HP:0002279): overlapping ROHHAD-like dysautonomia and rapid weight gain reported in case; hypothalamic features suggested (harvengt2023hideasyndromea pages 5-6).
  • Epilepsy (HP:0001250): variable seizures; 2024 review notes early onset and relative treatment responsiveness; valproate proposed (wang2024clinicalcharacteristicsof pages 6-7).
  • Eye abnormalities: strabismus (HP:0000486), ocular motor abnormalities, retinal hypopigmentation (HP:0007736) in some cases (harvengt2023hideasyndromea pages 5-6, wang2024clinicalcharacteristicsof pages 6-7).
  • Metabolic alterations: increased lactate under sedation, altered glycogenolysis, insulin responses (mouse) (not direct HPO but mechanistically relevant) (alanisula2024metaboliccharacteristicsof pages 7-9, alanisula2024metaboliccharacteristicsof pages 9-11).

Recent Developments and Latest Research (2023–2024 priority)

  • 2024 P4h‑tm−/− physiology study provided quantitative evidence for central ventilatory control defects and systemic metabolic changes: conscious male mutants had ~20% lower respiratory rate; under fentanyl–midazolam, further ~25% reduction with lower arterial pO2, higher pCO2, and lower pH; hypercapnic ventilatory response: WT +31% vs mutants +13%; fasting hepatic glycogen decreased to ~18% in mutants vs ~33% WT (male) (Pflügers Archiv, Feb 2024; https://doi.org/10.1007/s00424-024-02920-5) (alanisula2024metaboliccharacteristicsof pages 7-9, alanisula2024metaboliccharacteristicsof pages 11-12).
  • 2024 clinical epilepsy report and review: seizures often begin in infancy, multiple types, relatively well controlled; “Valproate, which has HIF‑1α inhibiting properties, may be a promising treatment avenue” (Front Neurol, Nov 2024; https://doi.org/10.3389/fneur.2024.1428076) (wang2024clinicalcharacteristicsof pages 6-7).
  • 2023 case report highlighted clinical overlap with ROHHAD and suggested P4HTM testing in ROHHAD-like phenotypes with neurodevelopmental or ocular abnormalities (Front Genet, Mar 2023; https://doi.org/10.3389/fgene.2023.1137767) (harvengt2023hideasyndromea pages 5-6).

Current Applications and Real-World Implementations

  • Diagnostics: Gene sequencing of P4HTM in patients with hypotonia–hypoventilation–dysautonomia–eye abnormalities and in ROHHAD-like cases with atypical neurodevelopment/eye findings, as recommended by recent clinical reports (Front Genet 2023; https://doi.org/10.3389/fgene.2023.1137767) (harvengt2023hideasyndromea pages 5-6).
  • Model systems: Global P4h‑tm−/− mice as a translational model recapitulating respiratory and neuromuscular features for preclinical evaluation of ventilatory support or pharmacologic modulation of HIF/Ca2+ pathways (Pflügers Archiv 2024; https://doi.org/10.1007/s00424-024-02920-5) (alanisula2024metaboliccharacteristicsof pages 1-2, alanisula2024metaboliccharacteristicsof pages 9-11).
  • Therapeutics: Seizure management generally responsive to standard agents; valproate suggested as potentially beneficial through HIF‑1α inhibition, though controlled trials are lacking (Front Neurol 2024; https://doi.org/10.3389/fneur.2024.1428076) (wang2024clinicalcharacteristicsof pages 6-7).

Expert Opinions and Authoritative Analyses (selected quotes)

  • “P4H‑TM is a novel regulator of calcium dynamics and gliotransmission.” (eNeuro, Dec 2021; https://doi.org/10.1523/eneuro.0253-20.2020) (alanisula2024metaboliccharacteristicsof pages 3-6).
  • Mouse in vivo conclusion: respiratory/metabolic/neuromuscular changes “appear to be neurological and controlled by the brain and central nervous system circuits.” (Pflügers Archiv, Feb 2024; https://doi.org/10.1007/s00424-024-02920-5) (alanisula2024metaboliccharacteristicsof pages 11-12).
  • Clinical genetics definition: “Biallelic loss‑of‑function P4HTM gene variants cause… (HIDEA)” (Genet Med, Oct 2019; https://doi.org/10.1038/s41436-019-0503-4) (harvengt2023hideasyndromea pages 5-6).

Relevant Statistics and Data (recent studies)

  • Respiratory physiology in P4h‑tm−/− mice: ~20% lower respiratory rate in conscious males; further ~25% reduction under sedation; blunted hypercapnia response (+13% vs WT +31%); arterial blood gases consistent with respiratory acidosis (Pflügers Archiv, Feb 2024; https://doi.org/10.1007/s00424-024-02920-5) (alanisula2024metaboliccharacteristicsof pages 7-9, alanisula2024metaboliccharacteristicsof pages 11-12).
  • Hepatic glycogen during fasting: male mutants ~18% vs WT ~33% remaining (P=0.024) (Pflügers Archiv, Feb 2024) (alanisula2024metaboliccharacteristicsof pages 7-9).
  • Metabolic effects under sedation: improved glucose tolerance, lower fasting insulin, higher blood lactate, lower serum FFA in mutants; >50% lost consciousness ~30 min post‑insulin injection (Pflügers Archiv, Feb 2024) (alanisula2024metaboliccharacteristicsof pages 9-11).
  • Clinical epilepsy course: early-onset seizures, multiple types, relatively controlled; valproate effectiveness noted in a case report (Front Neurol, Nov 2024) (wang2024clinicalcharacteristicsof pages 6-7).

Gene/Protein Annotations and Ontology Mappings

  • HGNC:
  • P4HTM (HGNC:20070) (harvengt2023hideasyndromea pages 5-6)
  • HIF1A (HGNC:4910) (alanisula2024metaboliccharacteristicsof pages 3-6)

  • ATF4 (HGNC:785) (wang2024clinicalcharacteristicsof pages 6-7)

  • GO Biological Processes: calcium ion transmembrane transport; receptor‑operated Ca2+ entry; store‑operated Ca2+ entry; regulation of gliotransmission; response to hypoxia (HIF‑1 signaling); ventilatory response to hypoxia/hypercapnia; glycogen catabolism; mitochondrial electron transport (complex I) (alanisula2024metaboliccharacteristicsof pages 3-6, alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 7-9, wang2024clinicalcharacteristicsof pages 6-7).

  • GO Cellular Components: ER membrane/lumen; mitochondrion; synapse; astrocyte processes (alanisula2024metaboliccharacteristicsof pages 1-2, alanisula2024metaboliccharacteristicsof pages 3-6).

  • CL (Cell types): Astrocytes (CL:0000127); Neurons (CL:0000540) (alanisula2024metaboliccharacteristicsof pages 3-6, alanisula2024metaboliccharacteristicsof pages 11-12).

  • UBERON (Anatomy): Brain/CNS (UBERON:0000955); medulla (UBERON:0001898); pons (UBERON:0000988); eye (UBERON:0000970); liver (UBERON:0002107) (alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 7-9, harvengt2023hideasyndromea pages 5-6).

  • CHEBI (Chemicals): Calcium (CHEBI:29108); Lactate (CHEBI:24996); Insulin (CHEBI:5931); Valproate (CHEBI:39867) (alanisula2024metaboliccharacteristicsof pages 9-11, wang2024clinicalcharacteristicsof pages 6-7, alanisula2024metaboliccharacteristicsof pages 3-6).

  • HPO (Phenotypes): Hypotonia (HP:0001252); Central hypoventilation (HP:0002875); Intellectual disability (HP:0001249); Dysautonomia (HP:0002279); Epilepsy (HP:0001250); Strabismus (HP:0000486); Retinal hypopigmentation (HP:0007736) (harvengt2023hideasyndromea pages 5-6, wang2024clinicalcharacteristicsof pages 6-7).

Evidence Items with PMIDs/DOIs, URLs, Dates

  • Rahikkala et al., 2019. Genetics in Medicine. DOI: 10.1038/s41436-019-0503-4. URL: https://doi.org/10.1038/s41436-019-0503-4. Publication date: Oct 2019. (harvengt2023hideasyndromea pages 5-6)
  • Harvengt et al., 2023. Frontiers in Genetics. DOI: 10.3389/fgene.2023.1137767. URL: https://doi.org/10.3389/fgene.2023.1137767. Publication date: Mar 2023. (harvengt2023hideasyndromea pages 5-6)
  • Byts et al., 2021. eNeuro. DOI: 10.1523/eneuro.0253-20.2020. URL: https://doi.org/10.1523/eneuro.0253-20.2020. Publication date: Dec 2021. (alanisula2024metaboliccharacteristicsof pages 3-6)
  • Hay et al., 2021. European Journal of Human Genetics. DOI: 10.1038/s41431-021-00932-8. URL: https://doi.org/10.1038/s41431-021-00932-8. Publication date: Jul 2021. (wang2024clinicalcharacteristicsof pages 6-7)
  • Ala‑Nisula et al., 2024. Pflügers Archiv. DOI: 10.1007/s00424-024-02920-5. URL: https://doi.org/10.1007/s00424-024-02920-5. Publication date: Feb 2024. (alanisula2024metaboliccharacteristicsof pages 1-2, alanisula2024metaboliccharacteristicsof pages 11-12, alanisula2024metaboliccharacteristicsof pages 7-9, alanisula2024metaboliccharacteristicsof pages 3-6, alanisula2024metaboliccharacteristicsof pages 9-11)
  • Wang et al., 2024. Frontiers in Neurology. DOI: 10.3389/fneur.2024.1428076. URL: https://doi.org/10.3389/fneur.2024.1428076. Publication date: Nov 2024. (wang2024clinicalcharacteristicsof pages 6-7)

Notes on Open Questions

  • The primary physiological substrate(s) of P4H‑TM in vivo remain uncertain; although HIF‑α hydroxylation can be observed in vitro and HIF‑1–dependent effects are demonstrated in astrocytes, multiple studies emphasize that HIFα may not be the primary substrate across all contexts, leaving room for discovery of additional ER‑luminal target(s) relevant to CNS circuits and mitochondria–ER crosstalk (Pflügers Archiv 2024) (alanisula2024metaboliccharacteristicsof pages 1-2).

References

  1. (alanisula2024metaboliccharacteristicsof pages 3-6): Tuulia Ala-Nisula, Riikka Halmetoja, Henri Leinonen, Margareta Kurkela, Henna-Riikka Lipponen, Samuli Sakko, Mikko Karpale, Antti M. Salo, Niina Sissala, Tapio Röning, Ghulam S. Raza, Kari A. Mäkelä, Jérôme Thevenot, Karl-Heinz Herzig, Raisa Serpi, Johanna Myllyharju, Heikki Tanila, Peppi Koivunen, and Elitsa Y. Dimova. Metabolic characteristics of transmembrane prolyl 4-hydroxylase (p4h-tm) deficient mice. Pflugers Archiv, 476:1339-1351, Feb 2024. URL: https://doi.org/10.1007/s00424-024-02920-5, doi:10.1007/s00424-024-02920-5. This article has 5 citations.

  2. (alanisula2024metaboliccharacteristicsof pages 1-2): Tuulia Ala-Nisula, Riikka Halmetoja, Henri Leinonen, Margareta Kurkela, Henna-Riikka Lipponen, Samuli Sakko, Mikko Karpale, Antti M. Salo, Niina Sissala, Tapio Röning, Ghulam S. Raza, Kari A. Mäkelä, Jérôme Thevenot, Karl-Heinz Herzig, Raisa Serpi, Johanna Myllyharju, Heikki Tanila, Peppi Koivunen, and Elitsa Y. Dimova. Metabolic characteristics of transmembrane prolyl 4-hydroxylase (p4h-tm) deficient mice. Pflugers Archiv, 476:1339-1351, Feb 2024. URL: https://doi.org/10.1007/s00424-024-02920-5, doi:10.1007/s00424-024-02920-5. This article has 5 citations.

  3. (alanisula2024metaboliccharacteristicsof pages 11-12): Tuulia Ala-Nisula, Riikka Halmetoja, Henri Leinonen, Margareta Kurkela, Henna-Riikka Lipponen, Samuli Sakko, Mikko Karpale, Antti M. Salo, Niina Sissala, Tapio Röning, Ghulam S. Raza, Kari A. Mäkelä, Jérôme Thevenot, Karl-Heinz Herzig, Raisa Serpi, Johanna Myllyharju, Heikki Tanila, Peppi Koivunen, and Elitsa Y. Dimova. Metabolic characteristics of transmembrane prolyl 4-hydroxylase (p4h-tm) deficient mice. Pflugers Archiv, 476:1339-1351, Feb 2024. URL: https://doi.org/10.1007/s00424-024-02920-5, doi:10.1007/s00424-024-02920-5. This article has 5 citations.

  4. (alanisula2024metaboliccharacteristicsof pages 7-9): Tuulia Ala-Nisula, Riikka Halmetoja, Henri Leinonen, Margareta Kurkela, Henna-Riikka Lipponen, Samuli Sakko, Mikko Karpale, Antti M. Salo, Niina Sissala, Tapio Röning, Ghulam S. Raza, Kari A. Mäkelä, Jérôme Thevenot, Karl-Heinz Herzig, Raisa Serpi, Johanna Myllyharju, Heikki Tanila, Peppi Koivunen, and Elitsa Y. Dimova. Metabolic characteristics of transmembrane prolyl 4-hydroxylase (p4h-tm) deficient mice. Pflugers Archiv, 476:1339-1351, Feb 2024. URL: https://doi.org/10.1007/s00424-024-02920-5, doi:10.1007/s00424-024-02920-5. This article has 5 citations.

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