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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name: HIDEA_Syndrome
creation_date: '2025-12-10T21:01:43Z'
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
prevalence_class: RARE
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
term:
id: hgnc:28858
label: 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.
downstream:
- target: Coarse Facial Features
- target: Obesity
- 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
downstream:
- target: Generalized Hypotonia
- target: Global Developmental Delay
- target: Intellectual Disability
- target: Epilepsy
- target: Dysautonomia
- target: Abnormal Eye Movements
- target: Visual Impairment
- target: Gait Disturbance
- target: Scoliosis
- name: Central Respiratory Control Dysfunction
conforms_to: "sleep_disordered_breathing_intermittent_hypoxia#Ventilatory Control Instability or Chemoreflex Failure"
notes: >-
Conformance is declared at the module's control-arm trigger, and specifically
at its HYPORESPONSIVE rather than unstable branch: the chemoreflex here fails
to respond (hypoventilation with blunted responses to hypoxia) rather than
oscillating with high loop gain, which is the same branch congenital central
hypoventilation syndrome enters through. As there, conformance is NOT
declared at the module's central node
(#Chronic Intermittent Hypoxia and Reoxygenation): the gas-exchange lesion is
sustained hypoventilation, not the cyclical desaturation-reoxygenation that
drives that node's oxidative-inflammatory arm. Note that obstructive sleep
apnea is also reported in this syndrome, so an individual patient may
additionally have disease entering through the module's anatomic arm; that is
a separate lesion and is not claimed by this node.
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.
downstream:
- target: Central Hypoventilation
- target: Recurrent Respiratory Infections
- 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
gene_term:
preferred_term: P4HTM
term:
id: hgnc:28858
label: 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: NCIT:C15747
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.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Physical therapy
term:
id: NCIT:C15302
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: NCIT:C15747
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: []
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.
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:
Potential ER stress/integrated stress response convergence (ATF4) in patient tissues with mitochondrial involvement (wang2024clinicalcharacteristicsof pages 6-7).
Affected cellular processes:
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:
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):
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):
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).
References
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