👪

Inheritance

1

X-linked recessive inheritance HP:0001419

Classic Ogden syndrome follows X-linked recessive inheritance and is caused by a recurrent hemizygous NAA10 p.Ser37Pro variant in affected males, while carrier females are typically unaffected because of skewed X-inactivation.

X-linked recessive inheritance

Show evidence (2 references)

PMID:21700266 SUPPORT Human Clinical

"We have identified two families with a previously undescribed lethal X-linked disorder of infancy"

The founding paper establishes Ogden syndrome as a lethal X-linked infantile disorder in the original families.

PMID:34075687 SUPPORT Human Clinical

"Ogden syndrome is a rare lethal X-linked recessive disorder caused by a recurrent missense variant (Ser37Pro) in the NAA10 gene, encoding the catalytic subunit of the N-terminal acetyltransferase A complex (NatA)."

This abstract directly establishes the canonical inheritance pattern and recurrent NAA10 variant underlying classic Ogden syndrome.

⚙

Pathophysiology

3

Impaired NatA catalytic activity and complex assembly

The recurrent NAA10 p.Ser37Pro variant disrupts the catalytic function of the NatA complex and weakens interactions between NAA10 and its binding partners NAA15 and NAA50. Because NatA is the major N-terminal acetyltransferase in human cells, this defect reduces co-translational N-terminal acetylation of selected substrates and establishes the primary molecular lesion in Ogden syndrome. This interpretation is variant-specific: the severe p.Ser37Pro phenotype reflects selective substrate hypoacetylation and NatA complex-assembly defects rather than a nonspecific collapse of all NAA10/NAA15-related acetylation biology.

NAA10 hgnc:18704 ⚠ ABNORMAL

NAA10 hgnc:18704

Protein acetylation GO:0006473

Downstream

Selective NatA substrate hypoacetylation Reduced NatA catalytic activity decreases N-terminal acetylation of selected substrates

Show evidence (2 references)

PMID:25489052 SUPPORT In Vitro

"Biochemical data further demonstrate a reduced catalytic capacity and an impaired interaction between hNaa10 S37P and Naa15 as well as Naa50 (NatE), another interactor of the NatA complex."

Patient-linked biochemical experiments directly show that the Ogden variant impairs NatA catalytic function and complex assembly.

PMID:24408909 SUPPORT Model Organism

"Combined, these data provide strong support for the functional impairment of hNaa10 S37P in vivo and suggest that reduced Nt-acetylation of one or more target substrates contributes to the pathogenesis of the Ogden syndrome."

The yeast complementation model independently confirms in vivo functional impairment of the Ser37Pro NAA10 allele and links reduced Nt-acetylation to pathogenesis.

Selective NatA substrate hypoacetylation

Reduced NatA function in Ogden syndrome causes incomplete N-terminal acetylation of a subset of NatA and NatE substrates rather than a global proteome-wide collapse, defining a selective proteostasis defect downstream of impaired NatA complex activity.

protein acetylation GO:0006473 ↓ DECREASED

Downstream

Fibroblast proliferation and migration defects Selective substrate hypoacetylation perturbs fibroblast cell-cycle and motility programs

Show evidence (1 reference)

PMID:25489052 SUPPORT In Vitro

"N-Terminal acetylome analyses revealed a decreased acetylation of a subset of NatA and NatE substrates in Ogden syndrome cells"

This directly supports selective substrate hypoacetylation in patient-derived Ogden syndrome cells.

Fibroblast proliferation and migration defects

Patient-derived Ogden syndrome fibroblasts show impaired proliferation, abnormal cell-cycle behavior, and defective migration, linking selective NatA substrate hypoacetylation to downstream cellular dysfunction.

fibroblast CL:0000057

cell population proliferation GO:0008283 ⚠ ABNORMAL cell migration GO:0016477 ⚠ ABNORMAL cell cycle GO:0007049 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:25489052 SUPPORT In Vitro

"Furthermore, Ogden syndrome fibroblasts display abnormal cell migration and proliferation capacity, possibly linked to a perturbed retinoblastoma pathway."

Patient fibroblasts show the downstream proliferative and migratory defects that likely connect the molecular acetylation defect to abnormal development.

⬡

Pathograph

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Phenotypes

9

Cardiovascular 2

Structural cardiac anomaly Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:34075687 SUPPORT Human Clinical

"all presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias."

Structural cardiac abnormalities are explicitly part of the recurring clinical phenotype of classic Ogden syndrome.

Arrhythmia Arrhythmia HP:0011675

Classic p.Ser37Pro males have infantile lethality, with published reviews attributing many deaths to cardiac arrhythmia; sex and variant class affect severity in broader NAA10-related disease.

Show evidence (1 reference)

PMID:40293509 SUPPORT Human Clinical

"We found increased incidence of structural and electrophysiologic abnormalities, with particularly high prevalence of QT interval prolongation."

This disease-focused cohort study directly supports arrhythmogenic and electrophysiologic cardiac involvement in Ogden syndrome.

Digestive 1

Feeding difficulties in infancy Feeding difficulties in infancy HP:0008872

Show evidence (1 reference)

PMID:34075687 SUPPORT Human Clinical

"the typical clinical course was characterized by postnatal complications, which required in most of the times neonatal intensive care, particularly for respiratory distress and feeding difficulties."

This directly supports feeding difficulty as part of the classic Ogden infantile clinical course.

Integument 1

Prematurely aged appearance Prematurely aged appearance HP:0007495

Show evidence (2 references)

PMID:21700266 SUPPORT Human Clinical

"the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias."

The original Ogden syndrome paper directly supports the aged appearance and multisystem classic phenotype.

PMID:34075687 SUPPORT Human Clinical

"The prematurely aged appearance with facial wrinkling, reduced subcutaneous adipose tissue and redundant skin is pathognomonic for this syndrome"

The review identifies prematurely aged appearance as a pathognomonic clinical hallmark of classic Ogden syndrome.

Musculoskeletal 1

Hypotonia Hypotonia HP:0001252

Show evidence (1 reference)

PMID:40293509 SUPPORT Human Clinical

"Pathogenic variants within NAA10 cause Ogden Syndrome (OS), which is characterized by varying degrees of intellectual disability, hypotonia, developmental delay, and cardiac abnormalities."

The dedicated cardiovascular cohort abstract lists hypotonia as part of the core syndrome phenotype.

Nervous System 3

Global developmental delay Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:34075687 SUPPORT Human Clinical

"all presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias."

This review directly lists severe global developmental delay as part of the recognizable Ogden syndrome phenotype.

Intellectual disability Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:38747166 SUPPORT Human Clinical

"The condition was initially described in 2011 and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia, and others."

The prospective cohort summary explicitly includes intellectual disability among the defining neurologic manifestations.

Seizures Seizure HP:0001250

Show evidence (1 reference)

PMID:38747166 SUPPORT Human Clinical

"The condition was initially described in 2011 and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia, and others."

The longitudinal cohort abstract explicitly includes seizures in the recognized neurologic phenotype.

Growth 1

Growth delay Growth delay HP:0001510

In classic male p.Ser37Pro Ogden syndrome, postnatal growth failure occurs in the context of an early lethal infantile course; broader NAA10-related syndromes can have longer survival and more variable growth effects.

Show evidence (1 reference)

PMID:34075687 SUPPORT Human Clinical

"all presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias."

This review directly identifies postnatal growth retardation as part of the recurring Ogden syndrome phenotype.

🧬

Genetic Associations

1

NAA10 (Missense mutation)

Show evidence (1 reference)

PMID:34075687 SUPPORT Human Clinical

"Ogden syndrome is a rare lethal X-linked recessive disorder caused by a recurrent missense variant (Ser37Pro) in the NAA10 gene"

This directly establishes NAA10 p.Ser37Pro as the canonical disease variant for classic Ogden syndrome.

💊

Medical Actions

8

Cardiac surveillance with echocardiography and electrocardiographic monitoring

Action: echocardiography MAXO:0010203

Individuals with Ogden syndrome should undergo structured cardiac evaluation, including echocardiography for structural defects and ECG or Holter monitoring for electrophysiologic abnormalities and QT prolongation.

Show evidence (1 reference)

PMID:40293509 SUPPORT Human Clinical

"Our results suggest that an OS diagnosis should be accompanied by full cardiac workup with emphasis on echocardiogram for structural defects and EKG/Holter monitoring for electrophysiologic abnormalities."

This abstract directly recommends structured cardiac surveillance as part of Ogden syndrome management.

Speech therapy

Action: speech therapy MAXO:0000930

Speech therapy is commonly used in Ogden syndrome and showed the clearest signal for benefit among the non-pharmacologic therapies assessed in the prospective cohort.

Show evidence (1 reference)

PMID:38747166 SUPPORT Human Clinical

"A therapy investigation showed speech therapy to be the most commonly used therapy by individuals with NAA10-related neurodevelopmental syndrome"

The prospective cohort identifies speech therapy as the most commonly used intervention and therefore a standard supportive management modality.

Physical therapy

Action: physical therapy MAXO:0000011

Physical therapy is frequently used as supportive management for hypotonia and motor impairment in Ogden syndrome.

Show evidence (1 reference)

PMID:38747166 SUPPORT Human Clinical

"followed by occupational and physical therapy, with more severely affected individuals receiving more types of therapy than their less-severe counterparts."

The prospective cohort shows physical therapy is routinely used as part of supportive multidisciplinary care.

Feeding and nutritional support

Action: feeding therapy MAXO:0001388

Feeding therapy, nutrition monitoring, aspiration-risk assessment, and escalation to nasogastric or gastrostomy feeding when clinically necessary address feeding difficulty, growth failure, and neonatal fragility.

Show evidence (1 reference)

PMID:34075687 SUPPORT Human Clinical

"the typical clinical course was characterized by postnatal complications, which required in most of the times neonatal intensive care, particularly for respiratory distress and feeding difficulties."

This supports feeding and nutrition support as a key management domain.

Seizure management

Action: anticonvulsant agent therapy MAXO:0000167

Evaluate suspected seizures with neurology input and EEG when indicated, and treat recurrent clinical seizures with individualized antiseizure medication.

Show evidence (1 reference)

PMID:38747166 SUPPORT Human Clinical

"In addition, we describe the nature of seizures in this condition in greater detail"

This supports seizure-focused management as part of Ogden syndrome care.

Occupational therapy

Action: occupational therapy MAXO:0001351

Occupational therapy supports adaptive functioning, feeding participation, fine-motor skills, and daily-care needs in individuals with hypotonia and developmental impairment.

Show evidence (1 reference)

PMID:38747166 SUPPORT Human Clinical

"followed by occupational and physical therapy, with more severely affected individuals receiving more types of therapy than their less-severe counterparts."

This cohort documents occupational therapy as part of supportive care.

Ophthalmology and hearing assessment

Action: ophthalmologist evaluation MAXO:0000703

Ophthalmology and audiology screening should be considered when ocular anomalies, microphthalmia-like features, hearing concerns, or broader NAA10-related syndrome features are present.

Show evidence (1 reference)

PMID:34075687 PARTIAL Human Clinical

"While our patient showed persistent pupillary membrane, retinal pigmentary anomalies and an anomalous optic disc, except for a lagophthalmos no other eye anomalies were reported in the other affected boys"

This supports ophthalmology as a variant- and case-specific assessment domain without overstating it as universal.

Genetic counseling

Action: genetic counseling MAXO:0000079

Provide counseling about X-linked inheritance, maternal carrier testing, recurrence risk for male offspring, reproductive options, and the distinction between classic Ogden syndrome and broader NAA10-related disorders.

Show evidence (1 reference)

PMID:21700266 SUPPORT Human Clinical

"We have identified two families with a previously undescribed lethal X-linked disorder of infancy"

The X-linked lethal familial pattern supports genetic counseling and recurrence-risk assessment.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Ogden syndrome:

NAA15-related neurodevelopmental disorder

Overlapping Features Primary pathogenic NAA15 variants cause a distinct autosomal dominant neurodevelopmental disorder with overlapping developmental and cardiac features. This should not be conflated with classic NAA10 p.Ser37Pro Ogden syndrome, even though the NAA15-binding interface is relevant to NatA complex biology and to severity of some NAA10 variants.

Distinguishing Features

Primary NAA15 variants indicate an autosomal dominant NAA15-related neurodevelopmental disorder, not classic X-linked Ogden syndrome.
Classic Ogden syndrome is defined by hemizygous NAA10 p.Ser37Pro in affected males with early lethal progeroid/cardiac disease.

Show evidence (1 reference)

PMID:30054457 SUPPORT Other

"Variants in NAA15 have also been found in patients with congenital heart disease, intellectual disability, and/or autism20,56,57."

This supports NAA15 as an overlapping but distinct NatA-related disease consideration rather than a causal Ogden gene.

NAA10-related syndrome Not Yet Curated MONDO:0100124

Overlapping Features Ogden syndrome represents the severe classic end of the broader NAA10-related syndrome spectrum and must be distinguished from milder NAA10-associated neurodevelopmental phenotypes in females and in individuals with non-Ser37Pro variants.

Distinguishing Features

The recurrent hemizygous NAA10 p.Ser37Pro genotype with early lethality, progeroid appearance, and prominent cardiac disease favors classic Ogden syndrome.
Broader NAA10-related syndrome typically includes more variable and often milder developmental phenotypes across both sexes.

Show evidence (1 reference)

PMID:30054457 SUPPORT Other

"NAA10-related syndrome is an X-linked condition with a broad spectrum of findings ranging from a severe phenotype in males with p.Ser37Pro in NAA10, originally described as Ogden syndrome, to the milder NAA10-related intellectual disability found with different variants in both males and females."

This review explicitly places Ogden syndrome within the broader NAA10-related syndrome spectrum and supports that distinction as a clinically relevant differential diagnosis.

Donohue syndrome Not Yet Curated MONDO:0009517

Overlapping Features Donohue syndrome can resemble Ogden syndrome in infancy through severe failure to thrive, progeroid appearance, and multisystem illness, but is distinguished by extreme insulin resistance rather than NAA10-related developmental disease.

Distinguishing Features

Severe insulin resistance with hyperinsulinemia favors Donohue syndrome.
Congenital heart disease, arrhythmia risk, and a pathogenic NAA10 variant favor Ogden syndrome.

Show evidence (1 reference)

PMID:34075687 SUPPORT Human Clinical

"A diagnosis of Donohue syndrome was considered but insulin levels were normal."

This case report directly documents Donohue syndrome as an initial clinical differential diagnosis for an infant with Ogden syndrome.

{ }

Source YAML

click to show

name: Ogden syndrome
creation_date: '2026-04-11T16:28:32Z'
updated_date: '2026-04-11T18:18:00Z'
category: Mendelian
description: >-
  Ogden syndrome is used here for the classic rare X-linked recessive
  NAA10-related disorder caused by the recurrent hemizygous p.Ser37Pro missense
  variant in NAA10. NAA10 encodes the catalytic subunit of the NatA N-terminal
  acetyltransferase complex. The syndrome is characterized by severe
  developmental impairment, hypotonia, feeding and postnatal growth failure,
  prematurely aged appearance, structural cardiac defects, and cardiac
  arrhythmias with infant male lethality in the classic phenotype. Broader
  NAA10-related syndromes caused by other NAA10 variants and primary
  NAA15-related neurodevelopmental disorder are clinically overlapping but
  distinct disease-boundary considerations.
disease_term:
  preferred_term: Ogden syndrome
  term:
    id: MONDO:0010457
    label: Ogden syndrome
parents:
- NAA10-related syndrome
- X-linked genetic disorder
synonyms:
- OGDNS
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    Classic Ogden syndrome follows X-linked recessive inheritance and is caused
    by a recurrent hemizygous NAA10 p.Ser37Pro variant in affected males, while
    carrier females are typically unaffected because of skewed X-inactivation.
  evidence:
  - reference: PMID:21700266
    reference_title: Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified two families with a previously undescribed lethal
      X-linked disorder of infancy
    explanation: >-
      The founding paper establishes Ogden syndrome as a lethal X-linked infantile
      disorder in the original families.
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ogden syndrome is a rare lethal X-linked recessive disorder caused by a recurrent missense variant (Ser37Pro) in the NAA10 gene, encoding the catalytic subunit of the N-terminal acetyltransferase A complex (NatA).
    explanation: >-
      This abstract directly establishes the canonical inheritance pattern and
      recurrent NAA10 variant underlying classic Ogden syndrome.
prevalence:
- population: Published literature before and including the 2021 confirmatory report
  percentage: Ultra-rare; 9 reported affected males from 3 families
  notes: >-
    No population-based prevalence estimate was identified. The best available
    epidemiology remains case-based and indicates an ultra-rare disorder.
  evidence:
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far eight boys of two different families have been described in the literature, all presenting the distinctive and recognizable phenotype
    explanation: >-
      The 2021 review confirms that only eight affected boys had been reported
      previously; the same paper adds a ninth case, supporting extreme rarity.
pathophysiology:
- name: Impaired NatA catalytic activity and complex assembly
  description: >-
    The recurrent NAA10 p.Ser37Pro variant disrupts the catalytic function of
    the NatA complex and weakens interactions between NAA10 and its binding
    partners NAA15 and NAA50. Because NatA is the major N-terminal
    acetyltransferase in human cells, this defect reduces co-translational
    N-terminal acetylation of selected substrates and establishes the primary
    molecular lesion in Ogden syndrome. This interpretation is variant-specific:
    the severe p.Ser37Pro phenotype reflects selective substrate hypoacetylation
    and NatA complex-assembly defects rather than a nonspecific collapse of all
    NAA10/NAA15-related acetylation biology.
  gene:
    preferred_term: NAA10
    description: Catalytic subunit of the NatA N-terminal acetyltransferase complex.
    modifier: ABNORMAL
    term:
      id: hgnc:18704
      label: NAA10
  genes:
  - preferred_term: NAA10
    term:
      id: hgnc:18704
      label: NAA10
  biological_processes:
  - preferred_term: Protein acetylation
    term:
      id: GO:0006473
      label: protein acetylation
  evidence:
  - reference: PMID:25489052
    reference_title: "Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Biochemical data further demonstrate a reduced catalytic capacity and an impaired interaction between hNaa10 S37P and Naa15 as well as Naa50 (NatE), another interactor of the NatA complex.
    explanation: >-
      Patient-linked biochemical experiments directly show that the Ogden
      variant impairs NatA catalytic function and complex assembly.
  - reference: PMID:24408909
    reference_title: "A Saccharomyces cerevisiae model reveals in vivo functional impairment of the Ogden syndrome N-terminal acetyltransferase NAA10 Ser37Pro mutant."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Combined, these data provide strong support for the functional impairment of hNaa10 S37P in vivo and suggest that reduced Nt-acetylation of one or more target substrates contributes to the pathogenesis of the Ogden syndrome.
    explanation: >-
      The yeast complementation model independently confirms in vivo functional
      impairment of the Ser37Pro NAA10 allele and links reduced Nt-acetylation
      to pathogenesis.
  downstream:
  - target: Selective NatA substrate hypoacetylation
    description: Reduced NatA catalytic activity decreases N-terminal acetylation of selected substrates
- name: Selective NatA substrate hypoacetylation
  description: >-
    Reduced NatA function in Ogden syndrome causes incomplete N-terminal
    acetylation of a subset of NatA and NatE substrates rather than a global
    proteome-wide collapse, defining a selective proteostasis defect downstream
    of impaired NatA complex activity.
  biological_processes:
  - preferred_term: protein acetylation
    modifier: DECREASED
    term:
      id: GO:0006473
      label: protein acetylation
  evidence:
  - reference: PMID:25489052
    reference_title: "Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      N-Terminal acetylome analyses revealed a decreased acetylation of a subset of NatA and NatE substrates in Ogden syndrome cells
    explanation: >-
      This directly supports selective substrate hypoacetylation in
      patient-derived Ogden syndrome cells.
  downstream:
  - target: Fibroblast proliferation and migration defects
    description: Selective substrate hypoacetylation perturbs fibroblast cell-cycle and motility programs
- name: Fibroblast proliferation and migration defects
  description: >-
    Patient-derived Ogden syndrome fibroblasts show impaired proliferation,
    abnormal cell-cycle behavior, and defective migration, linking selective
    NatA substrate hypoacetylation to downstream cellular dysfunction.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: ABNORMAL
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: cell migration
    modifier: ABNORMAL
    term:
      id: GO:0016477
      label: cell migration
  - preferred_term: cell cycle
    modifier: ABNORMAL
    term:
      id: GO:0007049
      label: cell cycle
  evidence:
  - reference: PMID:25489052
    reference_title: "Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, Ogden syndrome fibroblasts display abnormal cell migration and proliferation capacity, possibly linked to a perturbed retinoblastoma pathway.
    explanation: >-
      Patient fibroblasts show the downstream proliferative and migratory defects
      that likely connect the molecular acetylation defect to abnormal
      development.
phenotypes:
- name: Prematurely aged appearance
  category: Craniofacial
  description: >-
    A progeroid or prematurely aged facial and skin appearance with reduced
    subcutaneous adipose tissue is a striking and characteristic feature of
    classic Ogden syndrome.
  phenotype_term:
    preferred_term: Prematurely aged appearance
    term:
      id: HP:0007495
      label: Prematurely aged appearance
  evidence:
  - reference: PMID:21700266
    reference_title: Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the disorder comprises a distinct combination of an aged appearance,
      craniofacial anomalies, hypotonia, global developmental delays,
      cryptorchidism, and cardiac arrhythmias.
    explanation: >-
      The original Ogden syndrome paper directly supports the aged appearance and
      multisystem classic phenotype.
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prematurely aged appearance with facial wrinkling, reduced subcutaneous adipose tissue and redundant skin is pathognomonic for this syndrome
    explanation: >-
      The review identifies prematurely aged appearance as a pathognomonic
      clinical hallmark of classic Ogden syndrome.
- name: Global developmental delay
  category: Neurologic
  description: >-
    Global developmental impairment is a core neurodevelopmental feature of
    Ogden syndrome.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias.
    explanation: >-
      This review directly lists severe global developmental delay as part of
      the recognizable Ogden syndrome phenotype.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Intellectual disability is a common neurodevelopmental manifestation across
    the broader Ogden syndrome cohort.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38747166
    reference_title: "Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition was initially described in 2011 and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia, and others.
    explanation: >-
      The prospective cohort summary explicitly includes intellectual
      disability among the defining neurologic manifestations.
- name: Hypotonia
  category: Neurologic
  description: >-
    Generalized muscular hypotonia is a frequent early feature of Ogden
    syndrome.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:40293509
    reference_title: "The Cardiovascular Manifestations and Management Recommendations for Ogden Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants within NAA10 cause Ogden Syndrome (OS), which is characterized by varying degrees of intellectual disability, hypotonia, developmental delay, and cardiac abnormalities.
    explanation: >-
      The dedicated cardiovascular cohort abstract lists hypotonia as part of
      the core syndrome phenotype.
- name: Growth delay
  category: Growth
  description: >-
    Postnatal growth retardation and poor somatic growth are prominent features
    of classic Ogden syndrome.
  notes: >-
    In classic male p.Ser37Pro Ogden syndrome, postnatal growth failure occurs
    in the context of an early lethal infantile course; broader NAA10-related
    syndromes can have longer survival and more variable growth effects.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias.
    explanation: >-
      This review directly identifies postnatal growth retardation as part of
      the recurring Ogden syndrome phenotype.
- name: Feeding difficulties in infancy
  category: Gastrointestinal
  description: >-
    Classic affected males often require intensive neonatal care, with feeding
    difficulties and respiratory distress contributing to medical fragility.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the typical clinical course was characterized by postnatal complications,
      which required in most of the times neonatal intensive care, particularly
      for respiratory distress and feeding difficulties.
    explanation: >-
      This directly supports feeding difficulty as part of the classic Ogden
      infantile clinical course.
- name: Structural cardiac anomaly
  category: Cardiac
  description: >-
    Congenital structural cardiac abnormalities are a major contributor to
    morbidity in Ogden syndrome.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all presenting the distinctive and recognizable phenotype, which includes mostly postnatal growth retardation, global severe developmental delay, characteristic craniofacial features, and structural cardiac anomalies and/or arrhythmias.
    explanation: >-
      Structural cardiac abnormalities are explicitly part of the recurring
      clinical phenotype of classic Ogden syndrome.
- name: Arrhythmia
  category: Cardiac
  description: >-
    Electrophysiologic cardiac abnormalities, including QT prolongation and
    arrhythmia, are a key life-threatening feature of Ogden syndrome.
  notes: >-
    Classic p.Ser37Pro males have infantile lethality, with published reviews
    attributing many deaths to cardiac arrhythmia; sex and variant class affect
    severity in broader NAA10-related disease.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:40293509
    reference_title: "The Cardiovascular Manifestations and Management Recommendations for Ogden Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found increased incidence of structural and electrophysiologic abnormalities, with particularly high prevalence of QT interval prolongation.
    explanation: >-
      This disease-focused cohort study directly supports arrhythmogenic and
      electrophysiologic cardiac involvement in Ogden syndrome.
- name: Seizures
  category: Neurologic
  description: >-
    Seizures occur in a subset of individuals with Ogden syndrome and are part
    of the recognized neurologic spectrum.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38747166
    reference_title: "Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition was initially described in 2011 and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia, and others.
    explanation: >-
      The longitudinal cohort abstract explicitly includes seizures in the
      recognized neurologic phenotype.
genetic:
- name: NAA10
  association: Missense mutation
  notes: >-
    Classic Ogden syndrome is caused by a recurrent hemizygous NAA10 missense
    variant, p.Ser37Pro, which impairs NatA complex function. Broader
    NAA10-related syndromes caused by other variants can have overlapping but
    more variable phenotypes.
  evidence:
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ogden syndrome is a rare lethal X-linked recessive disorder caused by a recurrent missense variant (Ser37Pro) in the NAA10 gene
    explanation: >-
      This directly establishes NAA10 p.Ser37Pro as the canonical disease
      variant for classic Ogden syndrome.
diagnosis:
- name: NAA10 molecular genetic testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  description: >-
    Sequence analysis of NAA10, with exome/genome sequencing or a
    neurodevelopmental/cardiac panel when the phenotype is less specific,
    establishes the diagnosis and distinguishes classic p.Ser37Pro Ogden syndrome
    from broader NAA10-related presentations.
  results: >-
    A hemizygous NAA10 p.Ser37Pro variant in an affected male establishes classic
    Ogden syndrome; other NAA10 variants should be interpreted within the broader
    NAA10-related syndrome spectrum.
  evidence:
  - reference: PMID:21700266
    reference_title: Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA10, a
      gene encoding the catalytic subunit of the major human N-terminal
      acetyltransferase (NAT).
    explanation: >-
      The founding study supports NAA10 variant detection as the diagnostic
      anchor for classic Ogden syndrome.
  - reference: PMID:30054457
    reference_title: "NAA10-related syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of NAA10-related syndrome is established in a male proband
      with the identification of a disease-contributory hemizygous NAA10 variant
      and in a female proband with the identification of a disease-contributory
      heterozygous NAA10 variant by molecular genetic testing.
    explanation: >-
      This review provides the molecular diagnostic framework for NAA10-related
      disorders.
- name: Cardiac ECG, Holter monitoring, and echocardiography
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: MAXO:0000900
      label: electrocardiography
  description: >-
    Baseline cardiac workup should include ECG, Holter or telemetry monitoring,
    and echocardiography to identify electrophysiologic abnormalities, QT
    prolongation, arrhythmia, and congenital structural defects.
  results: >-
    Structural cardiac disease, QT prolongation, or other arrhythmias identify
    a major risk domain and guide cardiology management.
  evidence:
  - reference: PMID:40293509
    reference_title: "The Cardiovascular Manifestations and Management Recommendations for Ogden Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results suggest that an OS diagnosis should be accompanied by full
      cardiac workup with emphasis on echocardiogram for structural defects and
      EKG/Holter monitoring for electrophysiologic abnormalities.
    explanation: >-
      This directly supports ECG/Holter and echocardiography at diagnosis.
- name: Neurodevelopmental assessment
  diagnosis_term:
    preferred_term: neurodevelopmental assessment
    term:
      id: MAXO:0035041
      label: neurodevelopmental assessment
  description: >-
    Developmental, cognitive, speech/language, adaptive behavior, and motor
    assessments establish baseline function and therapy needs.
  results: >-
    Severe developmental delay, intellectual disability, hypotonia, speech delay,
    or motor impairment supports the neurodevelopmental component and guides
    individualized therapies.
  evidence:
  - reference: PMID:38747166
    reference_title: "Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using Vineland-3 scores, we show decline in cognitive function over time in
      individuals with Ogden syndrome (n = 53).
    explanation: >-
      Longitudinal adaptive-behavior data support structured baseline and
      follow-up neurodevelopmental assessment.
- name: Carrier and variant-specific family testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  description: >-
    Once the familial NAA10 variant is known, test the mother and at-risk
    maternal relatives; consider X-inactivation studies in carrier females when
    phenotype, counseling, or recurrence assessment requires it.
  results: >-
    Carrier detection informs X-linked recurrence risk, prenatal or
    preimplantation options, and interpretation of female carrier phenotype.
  evidence:
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      revealed ~100% skewing in the mother's blood probe.
    explanation: >-
      This supports X-inactivation and carrier evaluation in the context of
      familial p.Ser37Pro Ogden syndrome.
treatments:
- name: Cardiac surveillance with echocardiography and electrocardiographic monitoring
  description: >-
    Individuals with Ogden syndrome should undergo structured cardiac
    evaluation, including echocardiography for structural defects and ECG or
    Holter monitoring for electrophysiologic abnormalities and QT prolongation.
  treatment_term:
    preferred_term: echocardiography
    term:
      id: MAXO:0010203
      label: echocardiography
  evidence:
  - reference: PMID:40293509
    reference_title: "The Cardiovascular Manifestations and Management Recommendations for Ogden Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results suggest that an OS diagnosis should be accompanied by full cardiac workup with emphasis on echocardiogram for structural defects and EKG/Holter monitoring for electrophysiologic abnormalities.
    explanation: >-
      This abstract directly recommends structured cardiac surveillance as part
      of Ogden syndrome management.
- name: Speech therapy
  description: >-
    Speech therapy is commonly used in Ogden syndrome and showed the clearest
    signal for benefit among the non-pharmacologic therapies assessed in the
    prospective cohort.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: MAXO:0000930
      label: speech therapy
  evidence:
  - reference: PMID:38747166
    reference_title: "Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A therapy investigation showed speech therapy to be the most commonly used therapy by individuals with NAA10-related neurodevelopmental syndrome
    explanation: >-
      The prospective cohort identifies speech therapy as the most commonly used
      intervention and therefore a standard supportive management modality.
- name: Physical therapy
  description: >-
    Physical therapy is frequently used as supportive management for hypotonia
    and motor impairment in Ogden syndrome.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:38747166
    reference_title: "Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      followed by occupational and physical therapy, with more severely affected individuals receiving more types of therapy than their less-severe counterparts.
    explanation: >-
      The prospective cohort shows physical therapy is routinely used as part
      of supportive multidisciplinary care.
- name: Feeding and nutritional support
  description: >-
    Feeding therapy, nutrition monitoring, aspiration-risk assessment, and
    escalation to nasogastric or gastrostomy feeding when clinically necessary
    address feeding difficulty, growth failure, and neonatal fragility.
  treatment_term:
    preferred_term: feeding therapy
    term:
      id: MAXO:0001388
      label: feeding therapy
  evidence:
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the typical clinical course was characterized by postnatal complications,
      which required in most of the times neonatal intensive care, particularly
      for respiratory distress and feeding difficulties.
    explanation: >-
      This supports feeding and nutrition support as a key management domain.
- name: Seizure management
  description: >-
    Evaluate suspected seizures with neurology input and EEG when indicated, and
    treat recurrent clinical seizures with individualized antiseizure medication.
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: MAXO:0000167
      label: anticonvulsant agent therapy
  evidence:
  - reference: PMID:38747166
    reference_title: "Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we describe the nature of seizures in this condition in
      greater detail
    explanation: >-
      This supports seizure-focused management as part of Ogden syndrome care.
- name: Occupational therapy
  description: >-
    Occupational therapy supports adaptive functioning, feeding participation,
    fine-motor skills, and daily-care needs in individuals with hypotonia and
    developmental impairment.
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: MAXO:0001351
      label: occupational therapy
  evidence:
  - reference: PMID:38747166
    reference_title: "Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      followed by occupational and physical therapy, with more severely affected
      individuals receiving more types of therapy than their less-severe
      counterparts.
    explanation: >-
      This cohort documents occupational therapy as part of supportive care.
- name: Ophthalmology and hearing assessment
  description: >-
    Ophthalmology and audiology screening should be considered when ocular
    anomalies, microphthalmia-like features, hearing concerns, or broader
    NAA10-related syndrome features are present.
  treatment_term:
    preferred_term: ophthalmologist evaluation
    term:
      id: MAXO:0000703
      label: ophthalmologist evaluation
  notes: >-
    These assessments are especially relevant for broader NAA10-related
    phenotypes and variant-specific presentations; they are included here as
    boundary-aware supportive management rather than as defining classic
    p.Ser37Pro Ogden features.
  evidence:
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While our patient showed persistent pupillary membrane, retinal pigmentary
      anomalies and an anomalous optic disc, except for a lagophthalmos no other
      eye anomalies were reported in the other affected boys
    explanation: >-
      This supports ophthalmology as a variant- and case-specific assessment
      domain without overstating it as universal.
- name: Genetic counseling
  description: >-
    Provide counseling about X-linked inheritance, maternal carrier testing,
    recurrence risk for male offspring, reproductive options, and the distinction
    between classic Ogden syndrome and broader NAA10-related disorders.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:21700266
    reference_title: Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified two families with a previously undescribed lethal
      X-linked disorder of infancy
    explanation: >-
      The X-linked lethal familial pattern supports genetic counseling and
      recurrence-risk assessment.
differential_diagnoses:
- name: NAA15-related neurodevelopmental disorder
  description: >-
    Primary pathogenic NAA15 variants cause a distinct autosomal dominant
    neurodevelopmental disorder with overlapping developmental and cardiac
    features. This should not be conflated with classic NAA10 p.Ser37Pro Ogden
    syndrome, even though the NAA15-binding interface is relevant to NatA complex
    biology and to severity of some NAA10 variants.
  distinguishing_features:
  - Primary NAA15 variants indicate an autosomal dominant NAA15-related neurodevelopmental disorder, not classic X-linked Ogden syndrome.
  - Classic Ogden syndrome is defined by hemizygous NAA10 p.Ser37Pro in affected males with early lethal progeroid/cardiac disease.
  evidence:
  - reference: PMID:30054457
    reference_title: "NAA10-related syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Variants in NAA15 have also been found in patients with congenital heart
      disease, intellectual disability, and/or autism20,56,57.
    explanation: >-
      This supports NAA15 as an overlapping but distinct NatA-related disease
      consideration rather than a causal Ogden gene.
- name: NAA10-related syndrome
  description: >-
    Ogden syndrome represents the severe classic end of the broader
    NAA10-related syndrome spectrum and must be distinguished from milder
    NAA10-associated neurodevelopmental phenotypes in females and in individuals
    with non-Ser37Pro variants.
  distinguishing_features:
  - The recurrent hemizygous NAA10 p.Ser37Pro genotype with early lethality, progeroid appearance, and prominent cardiac disease favors classic Ogden syndrome.
  - Broader NAA10-related syndrome typically includes more variable and often milder developmental phenotypes across both sexes.
  disease_term:
    preferred_term: NAA10-related syndrome
    term:
      id: MONDO:0100124
      label: NAA10-related syndrome
  evidence:
  - reference: PMID:30054457
    reference_title: "NAA10-related syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      NAA10-related syndrome is an X-linked condition with a broad spectrum of findings ranging from a severe phenotype in males with p.Ser37Pro in NAA10, originally described as Ogden syndrome, to the milder NAA10-related intellectual disability found with different variants in both males and females.
    explanation: >-
      This review explicitly places Ogden syndrome within the broader
      NAA10-related syndrome spectrum and supports that distinction as a
      clinically relevant differential diagnosis.
- name: Donohue syndrome
  description: >-
    Donohue syndrome can resemble Ogden syndrome in infancy through severe
    failure to thrive, progeroid appearance, and multisystem illness, but is
    distinguished by extreme insulin resistance rather than NAA10-related
    developmental disease.
  distinguishing_features:
  - Severe insulin resistance with hyperinsulinemia favors Donohue syndrome.
  - Congenital heart disease, arrhythmia risk, and a pathogenic NAA10 variant favor Ogden syndrome.
  disease_term:
    preferred_term: Donohue syndrome
    term:
      id: MONDO:0009517
      label: Donohue syndrome
  evidence:
  - reference: PMID:34075687
    reference_title: "Confirmation of Ogden syndrome as an X-linked recessive fatal disorder due to a recurrent NAA10 variant and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A diagnosis of Donohue syndrome was considered but insulin levels were normal.
    explanation: >-
      This case report directly documents Donohue syndrome as an initial
      clinical differential diagnosis for an infant with Ogden syndrome.
clinical_trials: []
datasets: []
notes: >-
  Scope note: this entry keeps Ogden syndrome restricted to the classic
  NAA10 p.Ser37Pro, X-linked, infant male-lethal presentation. Broader
  NAA10-related syndrome is retained as a parent/differential spectrum, and
  primary NAA15-related neurodevelopmental disorder is treated as a distinct
  differential diagnosis rather than as a causal gene for Ogden syndrome. Asta
  deep research was run as requested, but primary curation relied mainly on
  directly reviewed PubMed sources because the retrieval output was noisy and
  only partially disease-specific.

📚

References & Deep Research

Deep Research

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Ogden syndrome. Core disease mechanisms, molecular and cellular pathways,...

Asta Scientific Corpus Retrieval 20 citations 2026-04-11T12:28:55.461447

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Ogden syndrome. Core disease mechanisms, molecular and cellular pathways,...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.392) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[2] Novel Approaches to Studying SLC13A5 Disease

Authors: Adriana S. Beltran
Year: 2024
Venue: Metabolites
URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
DOI: 10.3390/metabo14020084
PMID: 38392976
PMCID: 10890222
Citations: 2
Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
Evidence snippets:
Snippet 1 (score: 0.384) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[3] New therapeutic targets in rare genetic skeletal diseases

Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
Year: 2015
Venue: Expert Opinion on Orphan Drugs
URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
DOI: 10.1517/21678707.2015.1083853
PMID: 26635999
PMCID: 4643203
Citations: 37
Influential citations: 1
Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
Evidence snippets:
Snippet 1 (score: 0.370) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[4] Drosophila Models Reveal NAT Complex Roles in Heart Development and Enable Functional Validation of Congenital Heart Disease Variants

Authors: Jun-yi Zhu, Hannah Seah, Hangnoh Lee, Hanhan Liu, Z. Han
Year: 2025
Venue: Cells
URL: https://www.semanticscholar.org/paper/bab272a935556bc85d717efea502e424b2349d0e
DOI: 10.3390/cells14201596
PMID: 41148812
PMCID: 12564477
Summary: Human NAA16 completely rescued the cardiac defects in Naa15-16 silenced Drosophila, whereas a CHD-associated variant (NAA16-R70C) failed to do so, providing direct functional evidence of its pathogenicity.
Evidence snippets:
Snippet 1 (score: 0.369) > Ogden syndrome is a rare, X-linked developmental disorder caused by mutations in NAA10, which encodes the catalytic subunit of the NatA complex. Patients with Ogden syndrome exhibit a broad spectrum of clinical manifestations, including severe developmental delay, craniofacial dysmorphisms, hypotonia, and notably, CHDs [16,52,53]. Despite its clinical severity, the molecular mechanisms linking NAA10 dysfunction to cardiac phenotypes remain poorly understood, and no targeted therapies are currently available. > In this study, we showed that Ogden syndrome can be modeled in Drosophila by silencing vnc, the Drosophila homolog of NAA10, specifically in the heart. Loss of vnc in the Drosophila heart led to marked cardiac morphological abnormalities, including disorganization of myocardial actin filaments, reduced muscle fiber density, and excessive Pericardin accumulation, a hallmark of cardiac fibrosis. These phenotypes phenocopy aspects of human cardiac pathology and underscore the importance of NatA-mediated acetylation in maintaining cardiac structure and function. > Our findings provide in vivo support for the pathogenicity of NAA10 dysfunction in cardiac tissue and highlight Drosophila as a powerful model system for studying Ogden syndrome. The mechanistic role of NAA10 in heart development and its involvement in associated diseases requires further investigation. Importantly, Drosophila has previously been recognized as a high-throughput, genetically accessible model for validating candidate heart disease genes [27], as well as for exploring the molecular mechanisms and drug discovery pathways relevant to cardiovascular and other systemic diseases [54][55][56][57]. Future studies can leverage the Drosophila model to conduct small-molecule screens aimed at rescuing vnc-associated cardiac defects and identify the potential treatment for Ogden syndrome. Once promising drugs are identified in the Drosophila model with vnc silencing, further validation in mammalian models will be required. > Taken together, our findings demonstrate that the NatA complex plays a conserved and essential role in heart development. Using Drosophila, we developed a high-throughput platform for validating CHD-associated genes and variants and identified a path forward for modeling and potentially treating heart defects associated with Ogden syndrome.

[5] An overview on cardiac involvement in Inborn Errors of Metabolism: from clinical clues to nutritional management strategies

Authors: C. Montanari, V. Tagi, Martina Tosi, Eliana Stucchi, Eleonora Pisano et al.
Year: 2025
Venue: Frontiers in Cardiovascular Medicine
URL: https://www.semanticscholar.org/paper/53edcd65284033a78e81633fbeb8012f21599561
DOI: 10.3389/fcvm.2025.1648010
PMID: 41425985
PMCID: 12711851
Summary: This review examines nutritional strategies for managing patients affected by IEMs with cardiac involvement, providing clinicians with research-backed guidance to support cardiological care, since specific nutritional strategies have shown promise in reversing or improving cardiac function in specific IEMs.
Evidence snippets:
Snippet 1 (score: 0.367) > Approximately 10% to 30% of the known causes of cardiomyopathy in childhood are attributable to IEMs (10, 130,131). In IEMs, cardiac manifestations can be indicative symptoms discovered during regular multisystem screening. While in disorders like MPS, heart manifestations may dominate the clinical presentation, in others, such as PD, they represent the sole clinical manifestation. Four fundamental mechanisms underlie the pathophysiology of cardiac involvement. First, cardiac symptoms can be linked to a reduction in energy production resulting from genetic mutations in proteins involved in energy homeostasis, molecular transport, or cellular organelles. Second, the intracellular accumulation of intermediates or storage substrates within cardiac myocytes can lead to structural and functional damage of the cardiac tissue. Third, the accumulation of intermediate metabolites may exert toxic effects on cardiac and surrounding tissues, for example, by triggering apoptosis in cardiac myocytes. Fourth, altered cellular functions such as signal transduction, depolarization, and cell adhesion, caused by the absence or alteration of glyconjugates, can compromise tissue integrity and cardiac function. It is important to note that pathogenetic mechanisms, summarized in Figure 3, may often overlap, particularly in later stages of the illness progression (33). In this review, we offered a comprehensive description of the cardiovascular diseases primarily associated with various types of IEMs, to guide cardiologists in the differential diagnosis (Figure 4). Moreover, the diagnosis of an underlying metabolic disorder should rely on the recognition of associated signs and symptoms characteristic of each specific disease. > IEMs have a wide phenotypic spectrum and may be characterized by a late onset or mild organ involvement, remaining misdiagnosed. Following the diagnosis of heart complications, the cardiologist should first conduct a detailed investigation of the patient's and family's medical history, including an assessment of consanguinity and/or the presence of rare inherited disorders. The patient's history should include age of onset of each clinically relevant symptom, the presence of associated pathological conditions and/or symptoms (hypoglycemia, myalgia, neurological issues or liver problems) and the result of neonatal screening.

[6] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
Year: 2023
Venue: Frontiers in Pharmacology
URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
DOI: 10.3389/fphar.2023.1290253
PMID: 38026943
PMCID: 10662320
Citations: 3
Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
Evidence snippets:
Snippet 1 (score: 0.365) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[7] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
Year: 2012
Venue: Croatian Medical Journal
URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
DOI: 10.3325/cmj.2012.53.529
PMID: 23275318
PMCID: 3541579
Citations: 28
Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
Evidence snippets:
Snippet 1 (score: 0.364) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[8] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
Year: 2025
Venue: Frontiers in Endocrinology
URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
DOI: 10.3389/fendo.2025.1501305
PMID: 40070584
PMCID: 11893406
Citations: 11
Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
Evidence snippets:
Snippet 1 (score: 0.362) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

[9] Lateralized and Segmental Overgrowth in Children

Authors: A. Mussa, D. Carli, S. Cardaropoli, G. Ferrero, N. Resta
Year: 2021
Venue: Cancers
URL: https://www.semanticscholar.org/paper/1bf068188ceb52b6d570aedc7fc2b9bdfd8c7ca9
DOI: 10.3390/cancers13246166
PMID: 34944785
PMCID: 8699773
Citations: 19
Summary: Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.
Evidence snippets:
Snippet 1 (score: 0.361) > Simple Summary Congenital lateralized or segmental overgrowth (LO) disorders are conditions characterized by excessive tissue growth of a body region often associated with a predisposition to cancer. LOs are caused by mosaic DNA anomalies, that is, they are present only in a part of the cells making up the body. LOs have an extremely heterogeneous clinical presentation: they widely overlap in presentation, are difficult to frame from a clinical point of view and have a diagnostic complexity representing a challenge for the clinician who approaches them. Here we review the key features of the various LOs, expose their molecular causes, and detail the implications for each of them, such as the need for specific cancer screening or the possibility of treatment. The latter represents a recent scientific achievement in medicine, allowed by the development of precision drugs finely tuning cellular pathways involved in growth and tumorigenesis deranged in LO. Abstract Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue growth and related relevant complications. Recently, next-generation sequencing approaches have increased the knowledge on the molecular defects in LO, allowing classifying them based on the deranged cellular signaling pathway. LO is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Most LOs are classifiable in the Beckwith–Wiedemann spectrum (BWSp), PI3KCA/AKT-related overgrowth spectrum (PROS/AROS), mosaic RASopathies, PTEN Hamartoma Tumor Syndrome, mosaic activating variants in angiogenesis pathways, and isolated LO (ILO). These disorders overlap over common phenotypes, making their appraisal and distinction challenging. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.

[10] Phenotypic drug discovery: a case for thymosin alpha-1

Authors: Enrico Garaci, Maurizio Paci, C. Matteucci, C. Costantini, P. Puccetti et al.
Year: 2024
Venue: Frontiers in Medicine
URL: https://www.semanticscholar.org/paper/84001176cd8c6059e1ee06845db21c61c9fd9d27
DOI: 10.3389/fmed.2024.1388959
PMID: 38903817
PMCID: 11187271
Citations: 4
Summary: The experiences of researchers testing the effect of a thymic peptide hormone, thymosin alpha-1, in preclinical and clinical settings are explored and how its therapeutic utility in the precision medicine era can be accommodated within the PDD framework is discussed.
Evidence snippets:
Snippet 1 (score: 0.361) > This approach focuses on identifying and understanding the specific molecular targets that drugs interact with, and the subsequent biochemical and physiological changes that occur as a result of drug-target interactions.At the molecular level, researchers investigate how drugs bind to specific proteins, receptors, enzymes, or other molecules involved in biological processes.They analyze the structureactivity relationship to determine how the drug's chemical structure influences its interaction with the target, and how this interaction leads to molecular changes.Once the specific target or targets are identified, the reductionistic approach is applied at the cellular level.Researchers examine how the drug affects cellular signaling pathways, gene expression, protein synthesis, or other cellular processes.Understanding these cellular-level interactions helps elucidate how drugs modulate specific cell functions and influence overall physiological responses.At the physiological level, researchers investigate the effects of drugs on organ systems, whole organisms, and clinical outcomes.This includes studying how drugs affect organ function, systemic processes, and the overall disease state.By examining the drug's impact on the entire organism, researchers gain insights into the broader therapeutic effects and potential side effects of the drug.Therefore, the reductionistic approach in mechanisms of action of drugs involves studying drugs at different levels of complexity, from the molecular to the physiological, to understand how they interact with biological systems.Yet, it almost exclusively focuses on modulating specific molecular targets of interest, namely, the qualitative and quantitative description of the drug/receptor interaction (11).As a matter of fact, currently, target-based drug discovery heavily dominates drug discovery approaches in both academia and the pharmaceutical industry.Little emphasis is placed on realistic disease conditions whereby the local tissue microenvironment and/or specific environmental factors might flexibly modulate a patient's response.Indeed, due to the complexity of multifactorial diseases, drug intervention based on single-target drugs with high affinity, high selectivity, and strong potency may not fit well and does not always exhibit satisfactory efficacy with the network-based, inter-balanced regulation mode of the smart biological system (12,13).Many "targetbased" drugs have indeed numerous "off-target" therapeutic mechanisms (14).

[11] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

Authors: Debopam Samanta
Year: 2025
Venue: Children
URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
DOI: 10.3390/children12040481
PMID: 40310132
PMCID: 12025602
Citations: 19
Influential citations: 1
Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
Evidence snippets:
Snippet 1 (score: 0.360) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[12] Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

Authors: E. Courcelles, J. Boissel, J. Massol, I. Klingmann, R. Kahoul et al.
Year: 2022
Venue: Frontiers in Medical Technology
URL: https://www.semanticscholar.org/paper/877d5b1b75599745f704a9c8371f74601ff17e2f
DOI: 10.3389/fmedt.2022.810315
PMID: 35281671
PMCID: 8907708
Citations: 6
Summary: Light is shed on different stakeholder's contributions and needs in the appraisal phase and how mechanistic modeling strategies and reporting can contribute to this effort to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.
Evidence snippets:
Snippet 1 (score: 0.359) > A second limitation in HTA is the fact that currently population (and sometimes stratified) medicine is pursued during clinical Uncertainty not completely addressed in competent authority assessment report Example use of MIDD relevant to address uncertainty potentially also during HTA What is the optimal dosage in the clinical context? > Physiologically based pharmacokinetic models can investigate dosing-regimens relevant for regulatory review and product labels (9) and can also mimic real-life adherence to prescribed treatment regimens (see also below) or pharmacology-relevant characteristics of special populations as well as drug-drug interactions. > What is the duration of the effectiveness, especially with chronic use of a treatment? > Mechanistic models can predict the long-term disease progression by extrapolation of shorter-term findings under the constraints of how the components of the system function (and these constraints convey biological plausibility by design). An example is the use of a mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin, and gliclazide on disease processes underlying Type 2 Diabetes Mellitus (10). Another example is prediction of long-term outcomes by short-term marker data as demonstrated by a semi-mechanistic approach in context of osteoporosis treatment (11). > What is the efficacy for relevant clinical outcomes? > Mechanistic models combined with pharmacometric approaches can translate findings for one outcome to a range of other outcomes. An example of survival modeling on the back of a mechanistic description is the modeling framework for CD19-Specific CAR-T cell immunotherapy using a quantitative systems pharmacology model (12). > What is the size of the clinical effect dependent on patient characteristics and extrinsic factors? > Data-driven modeling techniques can capture correlation within clinical data. Describing the clinical effect of a drug can also be based on mechanistic considerations. Such models either (a) link disease phenotypes to increasingly granular mathematical representations of pathophysiologic processes (top-down approach) or (b) derive functional, computable cellular networks from the molecular building blocks of genes and proteins to elucidate the impact of pathologic or therapeutic alterations on network operating states and hence clinical phenotype (bottom-up) [

[13] Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

Authors: H. Breiteneder, Z. Diamant, T. Eiwegger, W. Fokkens, C. Traidl‐Hoffmann et al.
Year: 2019
Venue: Allergy
URL: https://www.semanticscholar.org/paper/e19b0755c4f4903f68377333676edebf9bd73c89
DOI: 10.1111/all.13851
PMID: 31056763
PMCID: 6973012
Citations: 90
Influential citations: 3
Summary: Recent developments in research and patient care and future trends in the discipline are reviewed and topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen‐specific immunotherapy for airway disease are highlighted.
Evidence snippets:
Snippet 1 (score: 0.358) > The past decades have witnessed extensive progress in unraveling cellular and molecular mechanisms of immune regulation in asthma, allergic diseases, organ transplantation, autoimmune diseases, tumor biology, and chronic infections. 1,2 Consequently, a better understanding of the functions, the reciprocal regulation, and the counterbalance of subsets of immune and inflammatory cells but also structural cells-for example, epithelial and vascular cells, airway smooth muscle cells, neuroendocrine system-that interact via various intercellular messengers will indicate avenues for immune interventions and novel treatment modalities of allergic diseases and immunological disorders. It is generally expected that drug development in the next decades will show a significant shift from chemicals to biologicals. > After more than 20 years without any breakthrough drug becoming available for patients, several disciplines including allergology are now experiencing extraordinary times with the recent licensing of several major biological drugs and novel allergen-specific immunotherapy (AIT) vaccines. Several biological modifiers of the immune response targeting intracellular messengers or their receptors have been developed to date. [3][4][5][6][7][8] In addition, a number of promising small molecule drugs and vaccines are in the development pipeline. [9][10][11] This new era is now calling for the development of biomarkers and phenoand endotyping of diseases for customized patient care, which is termed stratified medicine, precision medicine, or personalized medicine. 4 Distinguishing phenotypes of a complex disease covers the observable clinically relevant properties of the disease but does not show a direct relationship to disease etiology and pathophysiology. In a complex condition, such as asthma, different pathogenetic mechanisms can induce similar clinical manifestations; however, they may require different treatment approaches. 12,13 These pathophysiological mechanisms underlying disease subgroups are addressed by the term "endotype." [12][13][14] Classification of complex diseases based on the concept of endotypes provides advantages for epidemiological, genetic, and drug-related studies. Accurate endotyping by using reliable biomarkers reflects the natural history of the disease and aims to predict the response to (targeted) treatments. 15 Recent studies have focused on better understanding

[14] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

Authors: Hao Xiong, Jinsheng Guo
Year: 2025
Venue: Pharmaceuticals
URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
DOI: 10.3390/ph18040507
PMID: 40283943
PMCID: 12030350
Citations: 8
Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
Evidence snippets:
Snippet 1 (score: 0.357) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[15] The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome

Authors: D. Martinelli, D. Diodato, Emanuela Ponzi, M. Monné, S. Boenzi et al.
Year: 2015
Venue: Orphanet Journal of Rare Diseases
URL: https://www.semanticscholar.org/paper/ed033868ee677da141e5c926bc7c93cac242ea06
DOI: 10.1186/s13023-015-0242-9
PMID: 25874378
PMCID: 4358699
Citations: 92
Influential citations: 5
Summary: The clinical phenotype of HHH syndrome is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.
Evidence snippets:
Snippet 1 (score: 0.356) > Although the disease responds well to treatment with low risk of relapse of hyperammonemia [38], slowly progressive pyramidal signs characterize the chronic course, as also seen in argininemia [89]. However, the mechanism(s) of pyramidal dysfunction in HHH syndrome still remains to be elucidated. Creatine deficiency may contribute to the pathogenetic mechanism of the syndrome, as creatine is relevant for mitochondrial energy metabolism, regulation of glycolysis, proteins synthesis, membrane stabilization and neuromodulation [77,78,85]. This could be in line with the finding of abnormally shaped mitochondria at electron microscopy studies in skin fibroblasts, hepatocytes and muscle biopsy from HHH syndrome patients [11,23,82]. Furthermore, a mitochondrial dysfunction has been recently related to the effects of ornithine and homocitrulline in causing oxidative stress and disturbed mitochondrial homeostasis [79,80]. > A further mechanism that can be involved in the pathophysiology of HHH syndrome is related to polyamines metabolism. Shimizu and colleagues reported increased total and fractional (putrescine, cadaverine, spermine, spermidine) polyamines in one HHH syndrome patient [30]. Indeed, the clinical similarities between HHH syndrome and argininemia, which has been associated to an abnormal polyamine metabolism [91,92], may suggest a common pathogenetic mechanism causing pyramidal dysfunction. > Overall, the pathogenesis of HHH syndrome is complex and not completely understood. It is likely that different mechanisms, including the impact of low mitochondrial ornithine on UC flux, the presence of hyperammonemic crises and the disturbance of other pathways in major organs play a role in determining the heterogeneous clinical presentation of ORC1 deficiency. > In addition, as molecular studies failed to disclose a correlation between type of mutations or ornithine transport capacity and disease severity, an effect of genetic modifiers, such as ORC genes redundancy, seems to be likely, but further studies are certainly needed to clarify this point.

[16] Role of Transcriptomics in Precision Oncology

Authors: Ruby Srivastava
Year: 2024
Venue: Reports of Radiotherapy and Oncology
URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
DOI: 10.5812/rro-142195
Citations: 4
Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
Evidence snippets:
Snippet 1 (score: 0.353) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[17] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

Authors: O. Tsukamoto
Year: 2019
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/07467943fe92ce135b52ded5e5dea2bfc2ddf179
DOI: 10.3390/ijms21010226
PMID: 31905684
PMCID: 6982115
Citations: 16
Summary: The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM, and direct activation of sar COMs modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
Evidence snippets:
Snippet 1 (score: 0.352) > Hereditary DCM can be caused by single point mutations in sarcomere proteins. However, the link between point mutations and clinical phenotypes in DCM is not thoroughly understood in most cases. Recent advances in biochemical, biophysical, stem cell, and gene editing technologies have provided a better understanding of the molecular mechanisms through which the initial insult in DCM (i.e., mutations in a sarcomere protein) induces alterations in cellular organization and contractility, resulting in disease phenotypes. In particular, hiPSC-CMs and genetically modified animals are excellent models because they can capture the initial molecular phenotype that occurs before major compensatory mechanisms mask it.

[18] Aberrant NLRP3 Inflammasome Activation Ignites the Fire of Inflammation in Neuromuscular Diseases

Authors: Christine Péladeau, J. Sandhu
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/763a36db080236fca8cde89b2afcdf056f3584d0
DOI: 10.3390/ijms22116068
PMID: 34199845
PMCID: 8200055
Citations: 17
Influential citations: 1
Summary: Whether therapeutic targeting of the NLRP3 inflammasome components is a viable approach to alleviating the detrimental phenotype of neuromuscular diseases and improving clinical outcomes is examined.
Evidence snippets:
Snippet 1 (score: 0.352) > Despite a large number of mechanisms that have been identified in muscle degeneration and nerve cell loss, none have proven to be the primary cause of the disease. There is much need for a deeper understanding of the biology of the pathogeneses and the molecular mechanisms that are activated early in the diseases in order to identify "druggable" targets and disease-modifying treatments for these devastating diseases. > Human iPSC technologies are emerging as useful platforms for disease modeling to study pathogenic mechanisms and discover novel therapeutics for neuromuscular diseases [211,237]. Indeed, patient-derived iPSCs are being used to create a "patient-in-adish" disease model to derive relevant cell types for testing potential therapeutics, paving the way towards personalized medicine. This approach allows drug screening in a dish prior to administration to patients and "bench-to-bedside" translation of potential therapies. Additionally, iPSCs may also be used to stratify patients with various phenotypes and guide future clinical trials for bringing improved therapies to patients. Since multiple cell types are involved in disease pathogenesis, future research efforts need to be focused on deciphering "disease-specific signatures" at single-cell resolution, and not only in neuronal cells but also in non-neuronal cells. The application of modern technologies, including single-cell RNA sequencing and spatial transcriptomics, to neuromuscular diseases, will allow to ascertain cellular vulnerability and cell-specific mechanisms during various stages of disease progression. > The vital roles of the NLRP3 inflammasome in neuromuscular diseases such as DMD, LGMD and ALS, reveal that targeting this pathway is indeed a promising therapeutic strategy. Dysregulation of the NLRP3 inflammasome in muscle tissues by muscle damage, membrane instability, extracellular ATP and Ca 2+ ions or signals from infiltrating immune cells, clearly impacts the progression of neuromuscular and neurodegenerative disorders. Thus, modulation of these pathways involved with activation and assembly of NLRP3 inflammasome could be truly beneficial.

[19] Differential Tissue Metabolic Signatures in IgG4-Related Ophthalmic Disease and Orbital Mucosa-Associated Lymphoid Tissue Lymphoma

Authors: Hiroyuki Shimizu, Y. Usui, R. Wakita, Yasuko Aita, Atsumi Tomita et al.
Year: 2021
Venue: Investigative Ophthalmology & Visual Science
URL: https://www.semanticscholar.org/paper/566565fe15563034f1302745d5d466be356f2d9e
DOI: 10.1167/iovs.62.1.15
PMID: 33439228
PMCID: 7814356
Citations: 18
Summary: Purpose To identify tissue metabolomic profiles in biopsy specimens with IgG4-related ophthalmic disease (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma and investigate their potential implication in the disease pathogenesis and biomarkers. Methods We conducted a comprehensive analysis of the metabolomes and lipidomes of biopsy-proven IgG4-ROD (n = 22) and orbital MALT lymphoma (n = 21) specimens and matched adjacent microscopically normal adipose tissues using liquid chromat...
Evidence snippets:
Snippet 1 (score: 0.352) > progressing to genetic instabilities with chromosomal abnormalities, causing the transformation of a clone of normal lymphoid cells to MALT lymphoma. 7 However, the pathogenic mechanisms of IgG4-ROD and orbital MALT lymphoma are poorly characterized. Notably, IgG4-ROD occasionally involves regional and/or systemic lymph nodes simultaneously or subsequently and is often clinically and/or histopathologically suspected to be malignant lymphoma. Clinically, IgG4-ROD exhibits similar clinical and imaging (magnetic resonance imaging and computed tomography) features as orbital MALT lymphoma. 8,9 Furthermore, some orbital MALT lymphomas are associated with elevated serum IgG4 levels 9 and infiltration of numerous IgG4positive plasma cells in the affected tissue. 10 Orbital MALT lymphoma can arise from IgG4-ROD 11 and IgG4-producing MALT lymphoma. 12 Elevated serum IgG4 is not sufficiently sensitive or specific for diagnostic purpose. 13,14 Therefore, discriminating IgG4-ROD from orbital MALT lymphoma is sometimes challenging. Moreover, not all patients respond well to treatment, and approximately 50% of patients with IgG4-ROD will develop recurrence or progression after conventional clinical treatment, including with systemic corticosteroids or rituximab. 15,16 Therefore, further elucidation of the underlying molecular mechanisms of IgG4-ROD is required. > Metabolites reflect the integration of upstream processes of genes and proteins. Metabolites function as mediator molecules and comprehensive metabolic analyses may, therefore, provide insights into the features of disease states. Metabolomics, a method for the comprehensive analysis of metabolites, has emerged as a promising tool for the identification of biomarkers, combining advanced analytical chemistry techniques with cheminformatics to characterize thousands of metabolites found in tissues and biofluids. Thus, metabolomics is widely used to characterize disease pathophysiology and metabolic pathways frequently aberrant in inflammatory diseases and cancers. 17,18 Although a recent serum metabolomic study of IgG4-RD has been reported, 19 a comprehensive analysis aiming to reveal the tissue metabolomic

[20] Naa10 in development and disease

Authors: Line M. Myklebust, S. I. Støve, T. Arnesen
Year: 2015
Venue: Oncotarget
URL: https://www.semanticscholar.org/paper/fb6eef2faf1b2d65ce8ea8cc765f5e529e54665e
DOI: 10.18632/oncotarget.5867
PMID: 26431279
PMCID: 4741422
Citations: 14
Influential citations: 1
Summary: The proteomic studies demonstrated a reduced Nt-acetylation level in both B-cells and fibroblasts derived from individuals with Ogden syndrome, while female carriers and wildtype family members had unchanged NT-acetolation levels, supporting that NatA mediated acetylation is specifically perturbed in vivo in Ogden Syndrome males.
Evidence snippets:
Snippet 1 (score: 0.351) > Identification of causative mutations for rare genetic diseases has for long been of interest to medical geneticists. New developments within next generation sequencing have resulted in a huge increase in discovered pathogenic mutations. This is of great importance as it is the first step in the process of understanding the underlying mechanisms of different disorders. In 2011, such a sequencing study led to the identification of a point mutation in the N-terminal acetyltransferase Naa10 as the cause of a previously undescribed lethal disorder called Ogden Syndrome [1]. The NAA10 gene was previously found to be overexpressed in different types of cancer, but its dysfunction had never before been shown to cause disease. > The vast majority of proteins undergo a broad range of chemical modifications either during or after their biosynthesis. These modifications increase the diversity of expressed proteins and are often crucial for their regulation and function. Protein Nα-terminal acetylation (Nt-acetylation) represents one such major modification affecting 80-90% of all soluble human proteins [2]. The N-terminal acetyltransferases (NATs) catalyze this reaction and transfer the acetyl moiety from acetyl-coenzyme A to the Nα-group of proteins' N-termini. In humans, six NAT enzymes (NatA-NatF) exist, acetylating defined sets of substrates [3]. Naa10 constitute the catalytic subunit of the NatA complex, the major NAT acetylating 40% of all cellular proteins [2]. > Ogden syndrome is an X-linked disorder characterized by severe global developmental delays, craniofacial anomalies, hypotonia, cardiac arrhythmia and eventual cardiomyopathy, resulting in mortality during infancy [1]. Our recent study highlights the molecular defects of the Naa10S37P variant causing the Ogden syndrome as well as the downstream cellular implications [4]. The mutant NatA complex displayed both an impaired peptide substrate binding and NAT activity (Figure (Figure1)1) and furthermore, we observed a significantly reduced NatA complex formation. Our proteomic studies demonstrated a reduced Nt-acetylation level in both B-cells and fibroblasts derived from individuals with Ogden syndrome, while female carriers and wildtype family

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[19] Differential Tissue Metabolic Signatures in IgG4-Related Ophthalmic Disease and Orbital Mucosa-Associated Lymphoid Tissue Lymphoma

[20] Naa10 in development and disease

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