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1
Inheritance
2
Pathophys.
3
Phenotypes
3
Pathograph
1
Genes
3
Treatments
10
References
1
Deep Research
👪

Inheritance

1
X-linked Recessive HP:0001419
X-linked recessive inheritance

Pathophysiology

2
FLNA Deficiency and Enteric Neuron Development Failure
Loss-of-function FLNA mutations disrupt the N-terminal region of filamin A, which is crucial for proper enteric neuron development. A frameshift mutation between the two initial methionines of FLNA allows translation of a truncated protein from the second methionine, producing a filamin A protein with abnormal cytoskeletal actin organization. This impairs enteric nervous system development and function, leading to intestinal dysmotility and pseudo-obstruction.
Enteric neuron link Enteric smooth muscle cell link
FLNA link
Actin cytoskeleton organization link Enteric nervous system development link
actin filament binding link
Intestine link
Show evidence (3 references)
PMID:17357080 SUPPORT Human Clinical
"one affected male from a large CIIPX-affected kindred bears a 2-bp deletion in exon 2 of the FLNA gene"
Identifies FLNA loss-of-function mutation as causative for X-linked chronic intestinal pseudo-obstruction.
PMID:17357080 SUPPORT In Vitro
"the filamin protein is present in the patient's lymphoblastoid cell line that shows abnormal cytoskeletal actin organization compared with normal lymphoblasts"
Demonstrates that the truncated filamin A protein has abnormal cytoskeletal function.
PMID:17357080 SUPPORT Human Clinical
"the filamin N terminal region between the initial two methionines is crucial for proper enteric neuron development"
Establishes the N-terminal region of FLNA as critical for enteric neuron development.
Intestinal Pseudo-obstruction and Dysmotility
Defective enteric neuron development leads to impaired intestinal motility, presenting as chronic intestinal pseudo-obstruction with episodes mimicking mechanical bowel obstruction without physical blockage. Bladder dysfunction can co-occur.
Smooth muscle contraction link
Intestine link Urinary bladder link
Show evidence (1 reference)
PMID:18854860 SUPPORT Human Clinical
"We propose that duplication of FLNA may contribute to the bowel and bladder phenotype seen in these seven families."
Supports FLNA involvement in both bowel and bladder dysfunction.

Pathograph

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

Phenotypes

3
Digestive 1
Intestinal Pseudo-obstruction VERY_FREQUENT Intestinal pseudo-obstruction (HP:0004389)
Show evidence (1 reference)
PMID:17357080 SUPPORT Human Clinical
"an X-linked recessive form of chronic idiopathic intestinal pseudo-obstruction (CIIPX) maps to Xq28"
Identifies CIIPX as the primary phenotype.
Genitourinary 1
Bladder Dysfunction FREQUENT Neurogenic bladder (HP:0000011)
Show evidence (1 reference)
PMID:18854860 SUPPORT Human Clinical
"several male patients had presented with intestinal pseudo-obstruction or bladder distension"
Bladder distension occurs alongside intestinal pseudo-obstruction.
Nervous System 1
Periventricular Nodular Heterotopia OCCASIONAL Periventricular nodular heterotopia (HP:0032388)
Show evidence (1 reference)
PMID:17357080 SUPPORT Human Clinical
"the affected male bearing the FLNA deletion had signs of CNS involvement and potentially has PVNH"
CNS involvement including possible PVNH in FLNA-CIPO patient.
🧬

Genetic Associations

1
FLNA Loss-of-Function Variants (Pathogenic Variants)
X-linked Recessive
Show evidence (2 references)
PMID:17357080 SUPPORT Human Clinical
"Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement."
Title of landmark paper establishing FLNA as causative for CIIPX.
PMID:18854860 SUPPORT Human Clinical
"The two remaining families were shown to have intragenic duplications of FLNA only."
FLNA intragenic duplications as an alternative mutational mechanism.
💊

Treatments

3
Nutritional Support
Action: Nutritional support Ontology label: dietary intervention MAXO:0000088
Parenteral nutrition or enteral feeding support for patients with severe intestinal dysmotility who cannot maintain adequate oral nutrition.
Surgical Management
Action: Surgical management Ontology label: surgical procedure MAXO:0000004
Surgical intervention may be required for complications of intestinal pseudo-obstruction including volvulus or severe distension.
Genetic Counseling
Action: Genetic counseling Ontology label: genetic counseling MAXO:0000079
Genetic counseling regarding X-linked recessive inheritance and carrier testing for at-risk females.
{ }

Source YAML

click to show
name: FLNA Intestinal Pseudoobstruction
creation_date: "2026-04-04T00:00:00Z"
updated_date: "2026-05-09T00:41:13Z"
description: >-
  X-linked chronic idiopathic intestinal pseudo-obstruction (CIIPX) caused by
  loss-of-function mutations in FLNA is a severe gastrointestinal motility
  disorder primarily affecting males. The condition results from impaired
  enteric neuron development due to disruption of the filamin A N-terminal
  region, which is crucial for proper enteric nervous system formation.
  Affected males present with intestinal pseudo-obstruction, often with
  bladder dysfunction and central nervous system involvement including
  periventricular nodular heterotopia. The disorder can also result from
  Xq28 duplications encompassing FLNA. FLNA duplication may contribute
  to bowel and bladder dysfunction through a distinct dosage-sensitive
  mechanism.
category: Genetic
parents:
- Gastrointestinal Motility Disorder
- Enteric Neuropathy
disease_term:
  preferred_term: intestinal pseudoobstruction, neuronal, X-linked
  term:
    id: MONDO:0010232
    label: intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked
prevalence:
- population: Global
  percentage: Rare
inheritance:
- name: X-linked Recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
pathophysiology:
- name: FLNA Deficiency and Enteric Neuron Development Failure
  description: >-
    Loss-of-function FLNA mutations disrupt the N-terminal region of filamin A,
    which is crucial for proper enteric neuron development. A frameshift
    mutation between the two initial methionines of FLNA allows translation
    of a truncated protein from the second methionine, producing a filamin A
    protein with abnormal cytoskeletal actin organization. This impairs
    enteric nervous system development and function, leading to intestinal
    dysmotility and pseudo-obstruction.
  genes:
  - preferred_term: FLNA
    term:
      id: hgnc:3754
      label: FLNA
  molecular_functions:
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
  cell_types:
  - preferred_term: Enteric neuron
    term:
      id: CL:0007011
      label: enteric neuron
  - preferred_term: Enteric smooth muscle cell
    term:
      id: CL:0002504
      label: enteric smooth muscle cell
  biological_processes:
  - preferred_term: Actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  - preferred_term: Enteric nervous system development
    term:
      id: GO:0048484
      label: enteric nervous system development
  locations:
  - preferred_term: Intestine
    term:
      id: UBERON:0000160
      label: intestine
  evidence:
  - reference: PMID:17357080
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      one affected male from a large CIIPX-affected kindred bears a 2-bp
      deletion in exon 2 of the FLNA gene
    explanation: >-
      Identifies FLNA loss-of-function mutation as causative for X-linked
      chronic intestinal pseudo-obstruction.
  - reference: PMID:17357080
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the filamin protein is present in the patient's lymphoblastoid cell
      line that shows abnormal cytoskeletal actin organization compared
      with normal lymphoblasts
    explanation: >-
      Demonstrates that the truncated filamin A protein has abnormal
      cytoskeletal function.
  - reference: PMID:17357080
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the filamin N terminal region between the initial two methionines
      is crucial for proper enteric neuron development
    explanation: >-
      Establishes the N-terminal region of FLNA as critical for enteric
      neuron development.
  downstream:
  - target: Intestinal Pseudo-obstruction and Dysmotility
- name: Intestinal Pseudo-obstruction and Dysmotility
  description: >-
    Defective enteric neuron development leads to impaired intestinal
    motility, presenting as chronic intestinal pseudo-obstruction with
    episodes mimicking mechanical bowel obstruction without physical
    blockage. Bladder dysfunction can co-occur.
  biological_processes:
  - preferred_term: Smooth muscle contraction
    term:
      id: GO:0006939
      label: smooth muscle contraction
  locations:
  - preferred_term: Intestine
    term:
      id: UBERON:0000160
      label: intestine
  - preferred_term: Urinary bladder
    term:
      id: UBERON:0001255
      label: urinary bladder
  evidence:
  - reference: PMID:18854860
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose that duplication of FLNA may contribute to the bowel
      and bladder phenotype seen in these seven families.
    explanation: >-
      Supports FLNA involvement in both bowel and bladder dysfunction.
phenotypes:
- category: Gastrointestinal
  name: Intestinal Pseudo-obstruction
  frequency: VERY_FREQUENT
  description: >-
    Chronic intestinal pseudo-obstruction with episodes mimicking mechanical
    bowel obstruction. The primary defining feature of the disorder.
  phenotype_term:
    preferred_term: Intestinal pseudo-obstruction
    term:
      id: HP:0004389
      label: Intestinal pseudo-obstruction
  evidence:
  - reference: PMID:17357080
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an X-linked recessive form of chronic idiopathic intestinal
      pseudo-obstruction (CIIPX) maps to Xq28
    explanation: >-
      Identifies CIIPX as the primary phenotype.
- category: Urological
  name: Bladder Dysfunction
  frequency: FREQUENT
  description: >-
    Bladder distension and dysfunction co-occurring with intestinal
    pseudo-obstruction, reflecting shared enteric/autonomic innervation
    defects.
  phenotype_term:
    preferred_term: Neurogenic bladder
    term:
      id: HP:0000011
      label: Neurogenic bladder
  evidence:
  - reference: PMID:18854860
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      several male patients had presented with intestinal
      pseudo-obstruction or bladder distension
    explanation: >-
      Bladder distension occurs alongside intestinal pseudo-obstruction.
- category: Neurological
  name: Periventricular Nodular Heterotopia
  frequency: OCCASIONAL
  description: >-
    Central nervous system involvement with periventricular nodular
    heterotopia may occur, reflecting the shared FLNA loss-of-function
    mechanism with PVNH.
  phenotype_term:
    preferred_term: Periventricular nodular heterotopia
    term:
      id: HP:0032388
      label: Periventricular nodular heterotopia
  evidence:
  - reference: PMID:17357080
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the affected male bearing the FLNA deletion had signs of CNS
      involvement and potentially has PVNH
    explanation: >-
      CNS involvement including possible PVNH in FLNA-CIPO patient.
genetic:
- name: FLNA Loss-of-Function Variants
  association: Pathogenic Variants
  gene_term:
    preferred_term: FLNA
    term:
      id: hgnc:3754
      label: FLNA
  inheritance:
  - name: X-linked Recessive
    inheritance_term:
      preferred_term: X-linked recessive inheritance
      term:
        id: HP:0001419
        label: X-linked recessive inheritance
  features: >-
    Loss-of-function mutations in FLNA, including frameshift mutations and
    Xq28 duplications. Primarily affects males. Carrier females may be
    mildly affected or asymptomatic.
  evidence:
  - reference: PMID:17357080
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Filamin A is mutated in X-linked chronic idiopathic intestinal
      pseudo-obstruction with central nervous system involvement.
    explanation: >-
      Title of landmark paper establishing FLNA as causative for CIIPX.
  - reference: PMID:18854860
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The two remaining families were shown to have intragenic
      duplications of FLNA only.
    explanation: >-
      FLNA intragenic duplications as an alternative mutational mechanism.
treatments:
- name: Nutritional Support
  description: >-
    Parenteral nutrition or enteral feeding support for patients with severe
    intestinal dysmotility who cannot maintain adequate oral nutrition.
  treatment_term:
    preferred_term: Nutritional support
    term:
      id: MAXO:0000088
      label: dietary intervention
- name: Surgical Management
  description: >-
    Surgical intervention may be required for complications of intestinal
    pseudo-obstruction including volvulus or severe distension.
  treatment_term:
    preferred_term: Surgical management
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: Genetic Counseling
  description: >-
    Genetic counseling regarding X-linked recessive inheritance and carrier
    testing for at-risk females.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
datasets: []
references:
- reference: DOI:10.1002/humu.23355
  title: Differential regulation of two<i>FLNA</i>transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies
  found_in:
  - FLNA_Intestinal_Pseudoobstruction-deep-research-falcon.md
  findings:
  - statement: Differential regulation of two<i>FLNA</i>transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies
    supporting_text: Differential regulation of two<i>FLNA</i>transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies
- reference: DOI:10.1002/jpn3.12400
  title: 'Incidence, diagnostics, therapeutic management and outcomes of paediatric intestinal pseudo‐obstruction in the Netherlands: A 20‐year retrospective cohort study'
  found_in:
  - FLNA_Intestinal_Pseudoobstruction-deep-research-falcon.md
  findings:
  - statement: 'Incidence, diagnostics, therapeutic management and outcomes of paediatric intestinal pseudo‐obstruction in the Netherlands: A 20‐year retrospective cohort study'
    supporting_text: To describe incidence, clinical course, diagnostic and therapeutic management and long‐term follow‐up of paediatric intestinal pseudo‐obstruction (PIPO) in the Netherlands between 2000 and 2020.MethodsMulticenter, national, retrospective, observational study including patients aged <18 years diagnosed with PIPO and treated between 2000 and 2020 in Dutch academic medical centres.
    evidence:
    - reference: DOI:10.1002/jpn3.12400
      reference_title: 'Incidence, diagnostics, therapeutic management and outcomes of paediatric intestinal pseudo‐obstruction in the Netherlands: A 20‐year retrospective cohort study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: To describe incidence, clinical course, diagnostic and therapeutic management and long‐term follow‐up of paediatric intestinal pseudo‐obstruction (PIPO) in the Netherlands between 2000 and 2020.MethodsMulticenter, national, retrospective, observational study including patients aged <18 years diagnosed with PIPO and treated between 2000 and 2020 in Dutch academic medical centres.
      explanation: Deep research cited this publication as relevant literature for FLNA Intestinal Pseudoobstruction.
- reference: DOI:10.1007/s11894-019-0737-y
  title: Pediatric Intestinal Pseudo-obstruction in the Era of Genetic Sequencing
  found_in:
  - FLNA_Intestinal_Pseudoobstruction-deep-research-falcon.md
  findings:
  - statement: Pediatric Intestinal Pseudo-obstruction in the Era of Genetic Sequencing
    supporting_text: Pediatric Intestinal Pseudo-obstruction in the Era of Genetic Sequencing
- reference: DOI:10.1007/s44162-023-00012-z
  title: Use of whole genome sequencing to determine the genetic basis of visceral myopathies including Prune Belly syndrome
  found_in:
  - FLNA_Intestinal_Pseudoobstruction-deep-research-falcon.md
  findings:
  - statement: The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle.
    supporting_text: The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle.
    evidence:
    - reference: DOI:10.1007/s44162-023-00012-z
      reference_title: Use of whole genome sequencing to determine the genetic basis of visceral myopathies including Prune Belly syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle.
      explanation: Deep research cited this publication as relevant literature for FLNA Intestinal Pseudoobstruction.
- reference: DOI:10.1016/j.gtc.2011.09.005
  title: 'Chronic Intestinal Pseudo-Obstruction: Clinical Features, Diagnosis, and Therapy'
  found_in:
  - FLNA_Intestinal_Pseudoobstruction-deep-research-falcon.md
  findings:
  - statement: 'Chronic Intestinal Pseudo-Obstruction: Clinical Features, Diagnosis, and Therapy'
    supporting_text: 'Chronic Intestinal Pseudo-Obstruction: Clinical Features, Diagnosis, and Therapy'
- reference: DOI:10.1038/gim.2012.123
  title: Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations
  found_in:
  - FLNA_Intestinal_Pseudoobstruction-deep-research-falcon.md
  findings:
  - statement: Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations
    supporting_text: Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations
- reference: DOI:10.1086/513321
  title: Filamin A Is Mutated in X-Linked Chronic Idiopathic Intestinal Pseudo-Obstruction with Central Nervous System Involvement
  found_in:
  - FLNA_Intestinal_Pseudoobstruction-deep-research-falcon.md
  findings:
  - statement: Filamin A Is Mutated in X-Linked Chronic Idiopathic Intestinal Pseudo-Obstruction with Central Nervous System Involvement
    supporting_text: Filamin A Is Mutated in X-Linked Chronic Idiopathic Intestinal Pseudo-Obstruction with Central Nervous System Involvement
- reference: DOI:10.1097/pas.0b013e3181f0ae47
  title: Diffuse Abnormal Layering of Small Intestinal Smooth Muscle is Present in Patients With FLNA Mutations and X-linked Intestinal Pseudo-obstruction
  found_in:
  - FLNA_Intestinal_Pseudoobstruction-deep-research-falcon.md
  findings:
  - statement: Diffuse Abnormal Layering of Small Intestinal Smooth Muscle is Present in Patients With FLNA Mutations and X-linked Intestinal Pseudo-obstruction
    supporting_text: Diffuse Abnormal Layering of Small Intestinal Smooth Muscle is Present in Patients With FLNA Mutations and X-linked Intestinal Pseudo-obstruction
- reference: DOI:10.21203/rs.3.rs-4546691/v1
  title: Counseling individuals with pathogenic loss-of-function variants in FLNA – learning points from a cross-sectional cohort study.
  found_in:
  - FLNA_Intestinal_Pseudoobstruction-deep-research-falcon.md
  findings:
  - statement: Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration.
    supporting_text: Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration.
    evidence:
    - reference: DOI:10.21203/rs.3.rs-4546691/v1
      reference_title: Counseling individuals with pathogenic loss-of-function variants in FLNA – learning points from a cross-sectional cohort study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration.
      explanation: Deep research cited this publication as relevant literature for FLNA Intestinal Pseudoobstruction.
- reference: DOI:10.3389/fped.2022.837462
  title: 'Pediatric Intestinal Pseudo-Obstruction: Progress and Challenges'
  found_in:
  - FLNA_Intestinal_Pseudoobstruction-deep-research-falcon.md
  findings:
  - statement: Chronic intestinal pseudo-obstruction is a rare disorder and represents the most severe form of gastrointestinal dysmotility with significant morbidity and mortality.
    supporting_text: Chronic intestinal pseudo-obstruction is a rare disorder and represents the most severe form of gastrointestinal dysmotility with significant morbidity and mortality.
    evidence:
    - reference: DOI:10.3389/fped.2022.837462
      reference_title: 'Pediatric Intestinal Pseudo-Obstruction: Progress and Challenges'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Chronic intestinal pseudo-obstruction is a rare disorder and represents the most severe form of gastrointestinal dysmotility with significant morbidity and mortality.
      explanation: Deep research cited this publication as relevant literature for FLNA Intestinal Pseudoobstruction.
📚

References & Deep Research

References

10
Differential regulation of two<i>FLNA</i>transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies
1 finding
Differential regulation of two<i>FLNA</i>transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies
"Differential regulation of two<i>FLNA</i>transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies"
Incidence, diagnostics, therapeutic management and outcomes of paediatric intestinal pseudo‐obstruction in the Netherlands: A 20‐year retrospective cohort study
1 finding
Incidence, diagnostics, therapeutic management and outcomes of paediatric intestinal pseudo‐obstruction in the Netherlands: A 20‐year retrospective cohort study
"To describe incidence, clinical course, diagnostic and therapeutic management and long‐term follow‐up of paediatric intestinal pseudo‐obstruction (PIPO) in the Netherlands between 2000 and 2020.MethodsMulticenter, national, retrospective, observational study including patients aged <18 years..."
Show evidence (1 reference)
DOI:10.1002/jpn3.12400 SUPPORT Human Clinical
"To describe incidence, clinical course, diagnostic and therapeutic management and long‐term follow‐up of paediatric intestinal pseudo‐obstruction (PIPO) in the Netherlands between 2000 and 2020.MethodsMulticenter, national, retrospective, observational study including patients aged <18 years..."
Deep research cited this publication as relevant literature for FLNA Intestinal Pseudoobstruction.
Pediatric Intestinal Pseudo-obstruction in the Era of Genetic Sequencing
1 finding
Pediatric Intestinal Pseudo-obstruction in the Era of Genetic Sequencing
"Pediatric Intestinal Pseudo-obstruction in the Era of Genetic Sequencing"
Use of whole genome sequencing to determine the genetic basis of visceral myopathies including Prune Belly syndrome
1 finding
The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle.
"The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle."
Show evidence (1 reference)
DOI:10.1007/s44162-023-00012-z SUPPORT Human Clinical
"The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle."
Deep research cited this publication as relevant literature for FLNA Intestinal Pseudoobstruction.
Chronic Intestinal Pseudo-Obstruction: Clinical Features, Diagnosis, and Therapy
1 finding
Chronic Intestinal Pseudo-Obstruction: Clinical Features, Diagnosis, and Therapy
"Chronic Intestinal Pseudo-Obstruction: Clinical Features, Diagnosis, and Therapy"
Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations
1 finding
Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations
"Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations"
Filamin A Is Mutated in X-Linked Chronic Idiopathic Intestinal Pseudo-Obstruction with Central Nervous System Involvement
1 finding
Filamin A Is Mutated in X-Linked Chronic Idiopathic Intestinal Pseudo-Obstruction with Central Nervous System Involvement
"Filamin A Is Mutated in X-Linked Chronic Idiopathic Intestinal Pseudo-Obstruction with Central Nervous System Involvement"
Diffuse Abnormal Layering of Small Intestinal Smooth Muscle is Present in Patients With FLNA Mutations and X-linked Intestinal Pseudo-obstruction
1 finding
Diffuse Abnormal Layering of Small Intestinal Smooth Muscle is Present in Patients With FLNA Mutations and X-linked Intestinal Pseudo-obstruction
"Diffuse Abnormal Layering of Small Intestinal Smooth Muscle is Present in Patients With FLNA Mutations and X-linked Intestinal Pseudo-obstruction"
Counseling individuals with pathogenic loss-of-function variants in FLNA – learning points from a cross-sectional cohort study.
1 finding
Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration.
"Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration."
Show evidence (1 reference)
DOI:10.21203/rs.3.rs-4546691/v1 SUPPORT Human Clinical
"Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton organization and cell migration."
Deep research cited this publication as relevant literature for FLNA Intestinal Pseudoobstruction.
Pediatric Intestinal Pseudo-Obstruction: Progress and Challenges
1 finding
Chronic intestinal pseudo-obstruction is a rare disorder and represents the most severe form of gastrointestinal dysmotility with significant morbidity and mortality.
"Chronic intestinal pseudo-obstruction is a rare disorder and represents the most severe form of gastrointestinal dysmotility with significant morbidity and mortality."
Show evidence (1 reference)
DOI:10.3389/fped.2022.837462 SUPPORT Human Clinical
"Chronic intestinal pseudo-obstruction is a rare disorder and represents the most severe form of gastrointestinal dysmotility with significant morbidity and mortality."
Deep research cited this publication as relevant literature for FLNA Intestinal Pseudoobstruction.

Deep Research

1
Falcon
FLNA Intestinal Pseudo-obstruction (FLNA-related CIPO): Comprehensive Disease Characteristics Report
Edison Scientific Literature 36 citations 2026-05-08T16:45:13.388266

FLNA Intestinal Pseudo-obstruction (FLNA-related CIPO): Comprehensive Disease Characteristics Report

Executive summary

FLNA intestinal pseudo-obstruction refers to a rare, genetic, typically X-linked form of severe gastrointestinal dysmotility that clinically mimics mechanical obstruction but lacks an occluding lesion, and is caused by pathogenic variants in FLNA (filamin A). It is often described as an X-linked chronic idiopathic intestinal pseudo-obstruction (CIIPX) / X-linked intestinal pseudo-obstruction, and is frequently associated with a characteristic visceral smooth muscle pathology (abnormal muscle layering) and variable multisystem features (e.g., CNS, cardiovascular). (gargiulo2007filaminais pages 1-2, kapur2010diffuseabnormallayering pages 13-14, jenkins2018differentialregulationof pages 1-7)


1. Disease information

1.1 Definition / overview (current understanding)

A landmark description of the X-linked form defines chronic idiopathic intestinal pseudo-obstruction (CIIP) as a heterogeneous syndrome of severe GI dysmotility, diagnosed by objective evidence of intestinal obstruction without mechanical occlusion (radiologic/surgical/manometric evidence). (gargiulo2007filaminais pages 1-2)

A core anatomic-pathologic correlate in FLNA-associated X-linked cases is “diffuse abnormal layering of small intestinal smooth muscle”, supporting classification within visceral myopathy / enteric neuromyopathy rather than purely neuropathic disease. (kapur2010diffuseabnormallayering pages 13-14, kapur2010diffuseabnormallayering pages 14-14)

1.2 Key identifiers

  • MONDO: Open Targets maps chronic intestinal pseudo-obstruction to MONDO_0017574 and lists FLNA as an associated target for “chronic intestinal pseudoobstruction” and “intestinal pseudo-obstruction.” URL: https://platform.opentargets.org/ (association evidence in tool context). (OpenTargets Search: intestinal pseudo-obstruction,chronic intestinal pseudo-obstruction-FLNA)
  • MeSH: ClinicalTrials.gov browse terms for pseudo-obstruction include “Intestinal Pseudo-Obstruction” (MeSH ID D007418). (NCT07448753 chunk 1)
  • OMIM / Orphanet / ICD-10/ICD-11: Not directly retrievable in the current evidence set; these identifiers should be confirmed via OMIM/Orphanet/WHO ICD browser during knowledge-base curation.

1.3 Synonyms / alternative names

Common labels used in the literature include: * X-linked chronic idiopathic intestinal pseudo-obstruction (CIIPX) (gargiulo2007filaminais pages 1-2) * X-linked intestinal pseudo-obstruction (kapur2010diffuseabnormallayering pages 13-14) * FLNA-related chronic intestinal pseudo-obstruction (CIPO) (jenkins2018differentialregulationof pages 1-7) * Overlapping presentation: congenital short bowel syndrome (CSBS) due to FLNA in male patients (werf2013congenitalshortbowel pages 1-2)

1.4 Evidence sources

The disease characterization is derived primarily from: * Family-based human genetics and case series (e.g., multigenerational kindreds, pathology cohorts). (gargiulo2007filaminais pages 1-2, kapur2010diffuseabnormallayering pages 13-14) * Aggregated cohort resources describing FLNA loss-of-function multisystem disease (including GI features) in tertiary-care cohorts. (rijckmans2024counselingindividualswith pages 1-3)

Concept Details Key citations (PMID/DOI/URL, year)
Disease label / scope FLNA-associated X-linked intestinal pseudo-obstruction is a rare hereditary enteric motility disorder within the broader category of FLNA-related chronic intestinal pseudo-obstruction (CIPO); it is commonly framed as a visceral myopathy / enteric neuromyopathy phenotype caused by pathogenic FLNA variants. Gargiulo et al., Am J Hum Genet (2007), DOI: https://doi.org/10.1086/513321; Jenkins et al., Hum Mutat (2018), DOI: https://doi.org/10.1002/humu.23355 (gargiulo2007filaminais pages 1-2, jenkins2018differentialregulationof pages 1-7)
Disease identifier Open Targets lists FLNA as associated with MONDO:0017574 chronic intestinal pseudoobstruction and with intestinal pseudo-obstruction / familial visceral myopathy disease concepts. Open Targets disease-target association for FLNA ↔ MONDO:0017574, URL: https://platform.opentargets.org/ (accessed via tool context, 2024-2026) (OpenTargets Search: intestinal pseudo-obstruction,chronic intestinal pseudo-obstruction-FLNA)
Common synonyms X-linked chronic idiopathic intestinal pseudo-obstruction (CIIPX); X-linked intestinal pseudo-obstruction; FLNA-related chronic intestinal pseudo-obstruction; FLNA-related congenital intestinal pseudo-obstruction; FLNA-related visceral myopathy; FLNA-related congenital short bowel syndrome when shortened bowel is the presenting feature. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; van der Werf et al. (2013), DOI: https://doi.org/10.1038/gim.2012.123; Jenkins et al. (2018), DOI: https://doi.org/10.1002/humu.23355 (gargiulo2007filaminais pages 1-2, werf2013congenitalshortbowel pages 1-2, jenkins2018differentialregulationof pages 1-7)
Primary gene FLNA (filamin A), Xq28; encodes an actin-binding cytoskeletal scaffold protein important for smooth-muscle architecture, mechanotransduction, and tissue-specific developmental programs, including intestinal smooth muscle and motility. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; Jenkins et al. (2018), DOI: https://doi.org/10.1002/humu.23355 (gargiulo2007filaminais pages 1-2, jenkins2018differentialregulationof pages 1-7)
Inheritance pattern Predominantly X-linked. Classic intestinal pseudo-obstruction presentations are often described as X-linked recessive / male-limited severe disease in families, whereas FLNA loss-of-function more broadly behaves as X-linked dominant with marked male lethality and female multisystem manifestations. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; Rijckmans et al. preprint (2024), DOI: https://doi.org/10.21203/rs.3.rs-4546691/v1 (gargiulo2007filaminais pages 1-2, rijckmans2024counselingindividualswith pages 1-3)
Sex effects Affected males often have the most severe neonatal/infantile intestinal phenotype and high early mortality; surviving females with FLNA loss-of-function more often show PVNH and multisystem findings, though gastrointestinal symptoms such as constipation/CIPO can occur. Survival in males may depend on residual FLNA function or isoform-specific expression. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; Jenkins et al. (2018), DOI: https://doi.org/10.1002/humu.23355; Rijckmans et al. preprint (2024), DOI: https://doi.org/10.21203/rs.3.rs-4546691/v1 (gargiulo2007filaminais pages 1-2, jenkins2018differentialregulationof pages 1-7, rijckmans2024counselingindividualswith pages 1-3)
Hallmark clinical phenotype Functional intestinal obstruction without a lumen-occluding lesion, typically with recurrent or persistent abdominal distension, vomiting/feeding intolerance, severe dysmotility, failure to thrive, and inability to sustain enteral nutrition in severe cases. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; Jenkins et al. (2018), DOI: https://doi.org/10.1002/humu.23355 (gargiulo2007filaminais pages 1-2, jenkins2018differentialregulationof pages 1-7)
Hallmark pathology Characteristic diffuse abnormal layering of small intestinal smooth muscle; evidence supports a primarily myopathic mechanism in many FLNA intestinal cases. Kapur et al., Am J Surg Pathol (2010), DOI: https://doi.org/10.1097/PAS.0b013e3181f0ae47 (kapur2010diffuseabnormallayering pages 11-12, kapur2010diffuseabnormallayering pages 13-14, kapur2010diffuseabnormallayering pages 14-14)
Associated bowel-development features Congenital short bowel syndrome and malrotation can be part of the FLNA intestinal spectrum, especially in surviving males with 5′ FLNA variants. van der Werf et al. (2013), DOI: https://doi.org/10.1038/gim.2012.123; Kapur et al. (2010), DOI: https://doi.org/10.1097/PAS.0b013e3181f0ae47 (werf2013congenitalshortbowel pages 1-2, kapur2010diffuseabnormallayering pages 14-14)
Variant classes reported Small 5′ deletions/frameshifts in exon 2, splice-altering variants with exon skipping, intragenic duplications, and other hypomorphic loss-of-function alleles; several pathogenic mechanisms preserve some protein production and may permit male survival. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; van der Werf et al. (2013), DOI: https://doi.org/10.1038/gim.2012.123; Jenkins et al. (2018), DOI: https://doi.org/10.1002/humu.23355; Kapur et al. (2010), DOI: https://doi.org/10.1097/PAS.0b013e3181f0ae47 (gargiulo2007filaminais pages 1-2, werf2013congenitalshortbowel pages 1-2, jenkins2018differentialregulationof pages 1-7, kapur2010diffuseabnormallayering pages 14-14)
Notable recurrent 5′ variants Reported examples include 2-bp exon-2 deletions such as c.16_17delTC and c.65_66delAC, causing frameshift/premature truncation in the N-terminus and linked to CIIP/CSBS phenotypes. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; van der Werf et al. (2013), DOI: https://doi.org/10.1038/gim.2012.123 (gargiulo2007filaminais pages 1-2, werf2013congenitalshortbowel pages 1-2)
Mechanistic interpretation Many intestinal disease alleles are best understood as loss-of-function or hypomorphic FLNA variants; tissue-specific expression of two FLNA transcripts/translation start sites likely helps explain why some variants preferentially produce intestinal phenotypes. Jenkins et al. (2018), DOI: https://doi.org/10.1002/humu.23355; Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321 (jenkins2018differentialregulationof pages 1-7, gargiulo2007filaminais pages 1-2)
Extra-intestinal manifestations Central nervous system involvement (especially periventricular nodular heterotopia), seizures or developmental findings, cardiovascular defects (e.g., PDA/ASD/valvular disease), pulmonary/connective-tissue features, megacystis/bladder dysfunction, and constipation may accompany intestinal disease. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; Kapur et al. (2010), DOI: https://doi.org/10.1097/PAS.0b013e3181f0ae47; Rijckmans et al. preprint (2024), DOI: https://doi.org/10.21203/rs.3.rs-4546691/v1 (gargiulo2007filaminais pages 1-2, kapur2010diffuseabnormallayering pages 13-14, rijckmans2024counselingindividualswith pages 1-3)
Diagnostic evidence base Diagnosis is supported by clinical pseudo-obstruction phenotype plus FLNA molecular testing and, when available, full-thickness intestinal histopathology showing smooth-muscle layering abnormalities. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; Kapur et al. (2010), DOI: https://doi.org/10.1097/PAS.0b013e3181f0ae47; van der Werf et al. (2013), DOI: https://doi.org/10.1038/gim.2012.123 (gargiulo2007filaminais pages 1-2, kapur2010diffuseabnormallayering pages 11-12, werf2013congenitalshortbowel pages 1-2)
Cohort / family-level evidence Landmark reports include an Italian kindred with 10 affected males across 4 generations (9/10 died in early infancy), pathology series of FLNA-mutant patients with characteristic smooth-muscle abnormalities, and subsequent reports extending the phenotype to congenital short bowel and multisystem FLNA deficiency cohorts. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; Kapur et al. (2010), DOI: https://doi.org/10.1097/PAS.0b013e3181f0ae47; Rijckmans et al. preprint (2024), DOI: https://doi.org/10.21203/rs.3.rs-4546691/v1 (gargiulo2007filaminais pages 1-2, kapur2010diffuseabnormallayering pages 13-14, rijckmans2024counselingindividualswith pages 1-3)
Management implications from reports Severe cases may require total parenteral nutrition, repeated surgery/stoma procedures, and multidisciplinary surveillance for neurologic, cardiac, pulmonary, and gastrointestinal complications; the 2024 cohort emphasized lack of standardized follow-up guidelines. Gargiulo et al. (2007), DOI: https://doi.org/10.1086/513321; Kapur et al. (2010), DOI: https://doi.org/10.1097/PAS.0b013e3181f0ae47; Rijckmans et al. preprint (2024), DOI: https://doi.org/10.21203/rs.3.rs-4546691/v1 (gargiulo2007filaminais pages 1-2, kapur2010diffuseabnormallayering pages 13-14, rijckmans2024counselingindividualswith pages 1-3)

Table: This table summarizes core identifiers, inheritance, defining clinical-pathology features, and landmark supporting publications for FLNA-associated X-linked intestinal pseudo-obstruction / FLNA-related CIPO. It is useful as a compact reference scaffold for a disease knowledge base entry.


2. Etiology

2.1 Disease causal factors

Primary cause: genetic—pathogenic variants in FLNA (Xq28) encoding filamin A, an actin-binding cytoskeletal scaffold.

In the original CIIPX report, an X-linked recessive form mapped to Xq28 was shown to be caused by a 2-bp deletion in FLNA exon 2 producing a frameshift and predicted truncation near the N-terminus (with evidence for altered cytoskeletal actin organization in patient cells). (gargiulo2007filaminais pages 1-2)

2.2 Risk factors

Genetic risk factor: carrying pathogenic/hypomorphic FLNA variants that reduce effective filamin A function in intestinal smooth muscle. * Example variant class: exon 2 2-bp deletions (frameshift/early stop), reported across CIIPX and CSBS presentations in males (e.g., c.16_17delTC; c.65_66delAC). (gargiulo2007filaminais pages 1-2, werf2013congenitalshortbowel pages 1-2) * Structural variants: intragenic duplications and larger duplications including FLNA have been described in X-linked pseudo-obstruction pathology cohorts. (kapur2010diffuseabnormallayering pages 14-14, kapur2010diffuseabnormallayering pages 13-14)

Non-genetic/environmental risk factors: No FLNA-specific environmental risk factors were identified in the retrieved evidence; most work supports a monogenic etiology.

2.3 Protective factors

Not established for FLNA-related intestinal pseudo-obstruction in the retrieved literature. A conceptual “protective” mechanism is residual FLNA function (hypomorphic alleles / alternative transcript usage) permitting survival in hemizygous males, but this is genetic mechanism rather than an identified protective exposure. (jenkins2018differentialregulationof pages 1-7, kapur2010diffuseabnormallayering pages 14-14)

2.4 Gene–environment interactions

No specific GxE interactions for FLNA intestinal pseudo-obstruction were found in the retrieved evidence.


3. Phenotypes

3.1 Core gastrointestinal phenotype (symptoms/signs)

Typical features are those of functional obstruction: * Abdominal distension, vomiting/feeding intolerance, constipation or altered bowel habits, failure to thrive, and recurrent “obstructive” episodes without a mechanical lesion. (gargiulo2007filaminais pages 1-2, jenkins2018differentialregulationof pages 1-7)

HPO suggestions (non-exhaustive): * Intestinal pseudo-obstruction (HP:0004396) * Vomiting (HP:0002013) * Abdominal distension (HP:0003270) * Constipation (HP:0002019) * Failure to thrive (HP:0001508)

3.2 Developmental/anatomic GI manifestations

  • Congenital short bowel syndrome (markedly shortened small intestine often with malrotation) can be the presenting feature in males with FLNA variants; van der Werf et al. cite normal neonatal small-bowel length ~275 cm versus ~50 cm in CSBS. (werf2013congenitalshortbowel pages 1-2)
  • Malrotation is recurrently noted in the FLNA spectrum. (werf2013congenitalshortbowel pages 1-2, kapur2010diffuseabnormallayering pages 14-14)

HPO suggestions: * Abnormality of intestinal length (HP:0012098) * Intestinal malrotation (HP:0002566)

3.3 Extra-intestinal manifestations (multisystem)

Reported extracolonic features across FLNA loss-of-function cohorts and X-linked pseudo-obstruction pathology series include: * CNS involvement (e.g., PVNH spectrum; seizures/developmental findings in some). (gargiulo2007filaminais pages 1-2, kapur2010diffuseabnormallayering pages 13-14) * Cardiovascular findings (e.g., PDA/ASD in tabled cases; broader FLNA LOF cohorts report cardiovascular involvement). (kapur2010diffuseabnormallayering pages 13-14, rijckmans2024counselingindividualswith pages 1-3) * Urogenital/bladder involvement such as megacystis reported in X-linked pseudo-obstruction case tables. (kapur2010diffuseabnormallayering pages 11-12)

HPO suggestions: * Periventricular nodular heterotopia (HP:0002123) * Patent ductus arteriosus (HP:0001643) * Atrial septal defect (HP:0001631) * Megacystis (HP:0002021)

3.4 Frequencies and quantitative phenotype data

Disease-specific phenotype frequencies for “FLNA intestinal pseudo-obstruction” are limited because published evidence is often family- or case-series-based.

However, in a recent FLNA loss-of-function cohort (monocentric, n=24 index patients), the authors reported epilepsy in 84% and cardiovascular involvement in 56% (not specific to CIPO, but relevant to systemic surveillance for FLNA deficiency). Publication date: Oct 2024 (preprint). URL: https://doi.org/10.21203/rs.3.rs-4546691/v1 (rijckmans2024counselingindividualswith pages 1-3)


4. Genetic / molecular information

4.1 Causal gene

  • FLNA (filamin A). (gargiulo2007filaminais pages 1-2, jenkins2018differentialregulationof pages 1-7)

4.2 Pathogenic variant spectrum (reported classes)

Reported FLNA variant classes in X-linked intestinal pseudo-obstruction / FLNA-CIPO include: * Frameshift deletions in exon 2 (e.g., 2-bp deletions) causing early truncation/hypomorphic expression via alternative initiation. (gargiulo2007filaminais pages 1-2, werf2013congenitalshortbowel pages 1-2) * Splice-altering variants / exon skipping producing atypical/hypomorphic loss-of-function effects. (jenkins2018differentialregulationof pages 1-7) * Intragenic duplications and larger duplications including FLNA in pathology-defined X-linked pseudo-obstruction cohorts. (kapur2010diffuseabnormallayering pages 14-14, kapur2010diffuseabnormallayering pages 13-14)

4.3 Functional consequences (LOF vs GOF)

FLNA disorders are often framed as: * Loss-of-function (LOF) variants: reduced/absent expression, associated with PVNH and multisystem findings, and can include CIPO/intestinal pseudo-obstruction phenotypes. (jenkins2018differentialregulationof pages 1-7, rijckmans2024counselingindividualswith pages 1-3)

A mechanistic clue to phenotype specificity is tissue-dependent regulation of two FLNA transcripts / translation start sites, with intestinal smooth muscle showing particular dependence on the long isoform; this provides a plausible explanation for why some 5′ variants produce prominent intestinal disease and male survivorship (hypomorphic alleles). (jenkins2018differentialregulationof pages 1-7)

4.4 Inheritance pattern

The original CIIPX kindred was described as X-linked recessive with 10 affected males across 4 generations. (gargiulo2007filaminais pages 1-2)

More broadly, “FLNA deficiency” due to LOF variants is commonly counseled as X-linked dominant with male lethality, with variable female multisystem involvement; GI symptoms including constipation and CIPO are included in the phenotype spectrum. (rijckmans2024counselingindividualswith pages 1-3)

4.5 Population allele frequency

Population allele-frequency values (e.g., gnomAD) for specific CIPO-associated FLNA variants were not retrievable from the current evidence set.


5. Environmental information

No non-genetic environmental contributors were identified in the retrieved evidence; FLNA intestinal pseudo-obstruction is best supported as a monogenic disorder with secondary complications (e.g., infections related to parenteral nutrition) rather than environmentally initiated disease.


6. Mechanism / pathophysiology

6.1 Causal chain (current model)

  1. Pathogenic FLNA variant → reduced/hypomorphic filamin A function in intestinal smooth muscle (gargiulo2007filaminais pages 1-2, jenkins2018differentialregulationof pages 1-7)
  2. Cytoskeletal/contractile architecture disruption (patient cells show abnormal actin cytoskeletal organization) (gargiulo2007filaminais pages 1-2)
  3. Visceral myopathy phenotype with abnormal smooth muscle layering in small intestine (microanatomic correlate) (kapur2010diffuseabnormallayering pages 13-14, kapur2010diffuseabnormallayering pages 14-14)
  4. Impaired peristalsis → clinical pseudo-obstruction, intestinal failure, and need for parenteral nutrition/surgical interventions (kapur2010diffuseabnormallayering pages 13-14, jenkins2018differentialregulationof pages 1-7)

6.2 Key tissues/cell types

  • Visceral smooth muscle cells (primary effector tissue in myopathic cases). (kapur2010diffuseabnormallayering pages 13-14, jenkins2018differentialregulationof pages 1-7)
  • CL suggestion: Smooth muscle cell (CL:0000192)
  • Enteric nervous system (ENS) may show abnormalities in some cases, but the hallmark pathology in FLNA-XIPO emphasizes smooth muscle layering/myopathy. (kapur2010diffuseabnormallayering pages 13-14, gargiulo2007filaminais pages 1-2)
  • CL suggestion: Enteric neuron (CL:0000700)

6.3 Pathways and ontology suggestions

GO biological process (suggestions consistent with evidence): * Smooth muscle contraction (GO:0006939) * Actin filament organization (GO:0007015) * Regulation of cell migration (GO:0030334)

GO cellular component (suggestions): * Actin cytoskeleton (GO:0015629)


7. Anatomical structures affected

7.1 Organ/system level

  • Primary: small intestine (shortened length is “nearly constant” in CIIPX pathology series; abnormal layering described in small intestine). (kapur2010diffuseabnormallayering pages 14-14)
  • Often involved: colon and other GI segments in broader CIPO phenotypes. (giorgio2011chronicintestinalpseudoobstruction pages 10-12)

UBERON suggestions: * Small intestine (UBERON:0002108) * Colon (UBERON:0001155)

7.2 Subcellular localization

Mechanistically centered on actin cytoskeletal networks (filamin A is an actin-binding scaffold), supported by cytoskeletal abnormalities in patient cells. (gargiulo2007filaminais pages 1-2)


8. Temporal development

8.1 Onset

In the CIIPX kindred, disease occurred in male infants with very early mortality (9/10 died in the first months of life). (gargiulo2007filaminais pages 1-2)

In broader pediatric pseudo-obstruction populations, neonatal onset is common (e.g., 26/43 neonatal onset in a national Dutch PIPO cohort, though not FLNA-specific). (demirok2025incidencediagnosticstherapeutic pages 1-2)

8.2 Progression / course

CIPO generally has prolonged diagnostic delay and high care burden; an adult CIPO review reports a median 8-year delay to diagnosis and that ~88% underwent ~3 unnecessary surgeries, with 30–50% requiring long-term TPN/HPN and mortality ~10–34% (general CIPO data; not FLNA-specific). (giorgio2011chronicintestinalpseudoobstruction pages 10-12)


9. Inheritance and population

9.1 Epidemiology

Disease-specific prevalence of FLNA intestinal pseudo-obstruction is not well quantified in the retrieved evidence.

For pediatric intestinal pseudo-obstruction broadly, a 20-year Dutch national cohort study reported: * Mean incidence: 0.008/100,000/year (Netherlands, 2000–2020; n=43) (demirok2025incidencediagnosticstherapeutic pages 1-2) * Mortality: 6% (2/43) (demirok2025incidencediagnosticstherapeutic pages 1-2) * Healthcare utilization: median 22.5 admissions (range 1–176) over long follow-up (demirok2025incidencediagnosticstherapeutic pages 1-2)

9.2 Sex ratio and penetrance

The CIIPX kindred and pathology series emphasize strong sex effects consistent with X-linked inheritance, with severe male involvement and survival depending on residual/hypomorphic expression in some variant classes. (gargiulo2007filaminais pages 1-2, jenkins2018differentialregulationof pages 1-7, kapur2010diffuseabnormallayering pages 14-14)


10. Diagnostics

10.1 Clinical evaluation and test modalities

Core principle: demonstrate obstruction-like phenotype while excluding mechanical obstruction.

Imaging * Pediatric review: plain abdominal X-ray for air-fluid levels and dilated bowel; contrast studies to exclude mechanical obstruction; CT/MRI enterography proposed as first line; cine-MRI as non-invasive motility assessment. (turcotte2022pediatricintestinalpseudoobstruction pages 5-6)

Manometry * Small-bowel / antroduodenal manometry helps classify neuropathic vs myopathic patterns (e.g., low amplitude patterns suggesting myopathy), but limitations include invasiveness and incomplete correlation with histology. (turcotte2022pediatricintestinalpseudoobstruction pages 5-6, giorgio2011chronicintestinalpseudoobstruction pages 10-12)

Histopathology * Full-thickness biopsy can identify smooth muscle, ENS, or ICC abnormalities; ESPGHAN recommends specialized centers and labeling panels in pediatric contexts. (turcotte2022pediatricintestinalpseudoobstruction pages 5-6) * In FLNA X-linked cases, hallmark smooth muscle abnormal layering supports diagnosis of a visceral myopathy subtype. (kapur2010diffuseabnormallayering pages 13-14, kapur2010diffuseabnormallayering pages 14-14)

Genetic testing * In suspected hereditary CIPO/PIPO, metabolic and genetic screening are part of diagnostic strategies in cohort studies. (demirok2025incidencediagnosticstherapeutic pages 1-2) * For FLNA disease, molecular diagnosis in a recent cohort relied on Sanger sequencing, MLPA, and NGS panels (for malformations of cortical development) rather than WES/WGS. (rijckmans2024counselingindividualswith pages 3-5)

10.2 Formal pediatric diagnostic criteria (PIPO)

A pediatric review reports that PIPO diagnostic criteria require two of four findings: (1) objective small-bowel neuromuscular involvement (manometry/histopath/transit); (2) recurrent/persistent small-bowel dilation with air-fluid levels; (3) known genetic/metabolic abnormality; (4) feeding intolerance requiring supplemental enteral or parenteral nutrition. (gamboa2019pediatricintestinalpseudoobstruction pages 1-2)

10.3 Differential diagnosis

Broader CIPO diagnostic workups explicitly screen for secondary causes including metabolic/endocrine and immune/paraneoplastic disorders and mitochondrial disease (e.g., MNGIE). (giorgio2011chronicintestinalpseudoobstruction pages 10-12)


11. Outcome / prognosis

11.1 Mortality and severe outcomes

  • CIIPX kindred: 9/10 affected males died in the first months of life (highly severe familial presentation). (gargiulo2007filaminais pages 1-2)
  • General CIPO: adult review reports mortality ~10–34% and 30–50% long-term TPN/HPN requirement (not FLNA-specific). (giorgio2011chronicintestinalpseudoobstruction pages 10-12)
  • PIPO Netherlands cohort: 6% mortality over long follow-up (not FLNA-specific). (demirok2025incidencediagnosticstherapeutic pages 1-2)

11.2 Morbidity / QoL

Parenteral nutrition is life-saving but has major risks (central line infection, thrombosis, liver disease) and contributes substantially to morbidity and quality-of-life burden in pediatric pseudo-obstruction. (turcotte2022pediatricintestinalpseudoobstruction pages 5-6)


12. Treatment

12.1 Supportive care (cornerstones)

In pediatric pseudo-obstruction cohorts, treatment is commonly structured around: * Nutritional support (enteral when possible; PN in severe cases) and surgical interventions as “cornerstones” of care. (demirok2025incidencediagnosticstherapeutic pages 1-2)

MAXO suggestions: * Parenteral nutrition (MAXO:0000878) * Enteral nutrition (MAXO:0000879)

12.2 Pharmacotherapy

Evidence for CIPO (general, not FLNA-specific) includes use of prokinetics and other agents: * Adult review cites studies of cisapride, erythromycin (positive response in small case series), and octreotide effects on motility/bacterial overgrowth; antibiotic management of SIBO (e.g., rifaximin) is also referenced. (giorgio2011chronicintestinalpseudoobstruction pages 20-21)

Pediatric review emphasizes that there is no universally recommended prokinetic regimen for most pediatric PIPO patients and highlights supportive goals. (turcotte2022pediatricintestinalpseudoobstruction pages 5-6)

MAXO suggestions: * Prokinetic therapy (MAXO:0001020) * Antibiotic therapy (MAXO:0000648)

12.3 Surgical and interventional options

Reported and referenced options in general CIPO/PIPO literature include: * Stomas/ileostomy and other diversion or decompressive surgeries in severe cases (also seen in FLNA-XIPO pathology cohorts). (kapur2010diffuseabnormallayering pages 13-14) * Intestinal transplantation / multivisceral transplantation in advanced intestinal failure (general CIPO references include a series of “100 multivisceral transplants at a single center”). (giorgio2011chronicintestinalpseudoobstruction pages 20-21)

MAXO suggestions: * Ileostomy (MAXO:0001060) * Intestinal transplantation (MAXO:0001109)

12.4 Real-world implementation / systems of care

A 2024 FLNA LOF cohort emphasizes that systematic multidisciplinary follow-up (notably cardiology screening) was often lacking and that less overt symptoms (e.g., constipation) may be underreported, arguing for standardized surveillance in FLNA deficiency. (rijckmans2024counselingindividualswith pages 1-3)

12.5 Clinical trials (FLNA-specific)

A prospective observational registry study (Italy) is assessing the diagnostic yield of Sanger sequencing of ACTG2 and FLNA in adult idiopathic CIPO with a myopathic phenotype suggested by reduced/absent distal esophageal contractility on HRM. * NCT ID: NCT07448753 * First posted: 2026-03-04 * Start date: 2025-09-17 * ClinicalTrials.gov URL: https://clinicaltrials.gov/study/NCT07448753 (registry data captured in tool context). (NCT07448753 chunk 1)


13. Prevention

No primary prevention is currently established for monogenic FLNA intestinal pseudo-obstruction.

Key prevention strategy is genetic counseling and surveillance in families with pathogenic FLNA variants, given X-linked inheritance and multisystem risks; recent cohort evidence emphasizes the need for multidisciplinary follow-up and absence of uniform guidelines. (rijckmans2024counselingindividualswith pages 1-3)

MAXO suggestions: * Genetic counseling (MAXO:0000079) * Cascade genetic testing (MAXO:0000754)


14. Other species / natural disease

No evidence of FLNA-driven intestinal pseudo-obstruction in non-human species was retrieved.

A naturally occurring visceral smooth muscle disorder presenting as chronic intestinal pseudo-obstruction has been reported in a Bengal cat, illustrating comparative “visceral myopathy” pathology but not implicating FLNA. (OpenTargets Search: intestinal pseudo-obstruction,chronic intestinal pseudo-obstruction-FLNA)


15. Model organisms

A 2023 multidisciplinary forum report on visceral myopathy notes that animal models are scarce, limiting mechanistic and therapeutic development in this general disease area (not FLNA-specific). (OpenTargets Search: intestinal pseudo-obstruction,chronic intestinal pseudo-obstruction-FLNA)

No FLNA-specific intestinal pseudo-obstruction animal model evidence was retrievable in the current document set.


2023–2024 highlights (prioritized)

  1. 2024 cohort-level expert perspective: A cross-sectional cohort of 24 index patients with FLNA LOF variants reported high rates of epilepsy (84%) and cardiovascular involvement (56%), and highlighted gaps in systematic multidisciplinary follow-up; GI manifestations included constipation and chronic intestinal pseudo-obstruction within the phenotypic spectrum. Publication date Oct 2024 (preprint). URL: https://doi.org/10.21203/rs.3.rs-4546691/v1 (rijckmans2024counselingindividualswith pages 1-3)
  2. 2023 genomic medicine approach: A WGS analysis of visceral myopathy phenotypes in the 100,000 Genomes Project screened a virtual panel including FLNA (n=76 VM phenotypes), supporting WGS/panel strategies for related motility disorders (though FLNA-specific hit rates were not provided in the excerpt). Publication date Jun 2023. URL: https://doi.org/10.1007/s44162-023-00012-z (geraghty2023useofwhole pages 1-2)

Evidence limitations / gaps for knowledge-base completion

  • OMIM/Orphanet/ICD codes for the specific “FLNA intestinal pseudo-obstruction” entity were not captured in the retrieved evidence and require database lookup.
  • Variant-level curation (ClinVar assertions, allele frequencies, variant-to-phenotype mapping) was not available in the current texts.
  • 2023–2024 FLNA intestine-mechanism papers were referenced in the evidence stream but not retrievable in full text here (e.g., the 2023 Human Molecular Genetics paper on the long FLNA isoform and intestinal motility was flagged as unobtainable), limiting the ability to provide 2023–2024 primary mechanistic quotations.

References

  1. (gargiulo2007filaminais pages 1-2): Annagiusi Gargiulo, Renata Auricchio, Maria Vittoria Barone, Gabriella Cotugno, William Reardon, Peter J. Milla, Andrea Ballabio, Alfredo Ciccodicola, and Alberto Auricchio. Filamin a is mutated in x-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement. American journal of human genetics, 80 4:751-8, Apr 2007. URL: https://doi.org/10.1086/513321, doi:10.1086/513321. This article has 148 citations and is from a highest quality peer-reviewed journal.

  2. (kapur2010diffuseabnormallayering pages 13-14): Raj P. Kapur, Stephen P. Robertson, Mark C. Hannibal, Laura S. Finn, Timothy Morgan, Margriet van Kogelenberg, and David J. Loren. Diffuse abnormal layering of small intestinal smooth muscle is present in patients with flna mutations and x-linked intestinal pseudo-obstruction. The American Journal of Surgical Pathology, 34:1528-1543, Oct 2010. URL: https://doi.org/10.1097/pas.0b013e3181f0ae47, doi:10.1097/pas.0b013e3181f0ae47. This article has 77 citations.

  3. (jenkins2018differentialregulationof pages 1-7): Zandra A Jenkins, Alison Macharg, Cheng-Yee Chang, Margriet van Kogelenberg, Tim Morgan, Sophia Frentz, Wenhua Wei, Jacek Pilch, Mark Hannibal, Nicola Foulds, George McGillivray, Richard J Leventer, Sixto García-Miñaúr, Stuart Sugito, Scott Nightingale, David M Markie, Tracy Dudding, Raj P Kapur, and Stephen P Robertson. Differential regulation of two flna transcripts explains some of the phenotypic heterogeneity in the loss‐of‐function filaminopathies. Human Mutation, 39:103-113, Jan 2018. URL: https://doi.org/10.1002/humu.23355, doi:10.1002/humu.23355. This article has 38 citations and is from a domain leading peer-reviewed journal.

  4. (kapur2010diffuseabnormallayering pages 14-14): Raj P. Kapur, Stephen P. Robertson, Mark C. Hannibal, Laura S. Finn, Timothy Morgan, Margriet van Kogelenberg, and David J. Loren. Diffuse abnormal layering of small intestinal smooth muscle is present in patients with flna mutations and x-linked intestinal pseudo-obstruction. The American Journal of Surgical Pathology, 34:1528-1543, Oct 2010. URL: https://doi.org/10.1097/pas.0b013e3181f0ae47, doi:10.1097/pas.0b013e3181f0ae47. This article has 77 citations.

  5. (OpenTargets Search: intestinal pseudo-obstruction,chronic intestinal pseudo-obstruction-FLNA): Open Targets Query (intestinal pseudo-obstruction,chronic intestinal pseudo-obstruction-FLNA, 4 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  6. (NCT07448753 chunk 1): Marina Coletta. ACTG2/FLNA Testing Yield in Adult Idiopathic Chronic Intestinal Pseudo-Obstruction (CIPO) With Reduced/Absent Distal Esophageal Contractility. Marina Coletta. 2025. ClinicalTrials.gov Identifier: NCT07448753

  7. (werf2013congenitalshortbowel pages 1-2): Christine S. van der Werf, Yunia Sribudiani, Joke B.G.M. Verheij, Matthew Carroll, Edward O’Loughlin, Chien-Huan Chen, Alice S. Brooks, M. Kathryn Liszewski, John P. Atkinson, and Robert M.W. Hofstra. Congenital short bowel syndrome as the presenting symptom in male patients with flna mutations. Genetics in Medicine, 15:310-313, Apr 2013. URL: https://doi.org/10.1038/gim.2012.123, doi:10.1038/gim.2012.123. This article has 51 citations and is from a highest quality peer-reviewed journal.

  8. (rijckmans2024counselingindividualswith pages 1-3): Ellen RIJCKMANS, Lars P. De Strooper, Kathelijn Keymolen, Jessica Rosenblum, Bart Loeys, Marije Meuwissen, Anna C. Jansen, and Katrien Stouffs. Counseling individuals with pathogenic loss-of-function variants in flna – learning points from a cross-sectional cohort study. Unknown journal, Oct 2024. URL: https://doi.org/10.21203/rs.3.rs-4546691/v1, doi:10.21203/rs.3.rs-4546691/v1.

  9. (kapur2010diffuseabnormallayering pages 11-12): Raj P. Kapur, Stephen P. Robertson, Mark C. Hannibal, Laura S. Finn, Timothy Morgan, Margriet van Kogelenberg, and David J. Loren. Diffuse abnormal layering of small intestinal smooth muscle is present in patients with flna mutations and x-linked intestinal pseudo-obstruction. The American Journal of Surgical Pathology, 34:1528-1543, Oct 2010. URL: https://doi.org/10.1097/pas.0b013e3181f0ae47, doi:10.1097/pas.0b013e3181f0ae47. This article has 77 citations.

  10. (giorgio2011chronicintestinalpseudoobstruction pages 10-12): Roberto De Giorgio, Rosanna F. Cogliandro, Giovanni Barbara, Roberto Corinaldesi, and Vincenzo Stanghellini. Chronic intestinal pseudo-obstruction: clinical features, diagnosis, and therapy. Gastroenterology clinics of North America, 40 4:787-807, Dec 2011. URL: https://doi.org/10.1016/j.gtc.2011.09.005, doi:10.1016/j.gtc.2011.09.005. This article has 185 citations and is from a peer-reviewed journal.

  11. (demirok2025incidencediagnosticstherapeutic pages 1-2): Aysenur Demirok, Sjoerd C. J. Nagelkerke, Malou Veldt, Ramon Gorter, Justin R. de Jong, Gerard M. Damen, Barbara A. E. de Koning, Caroline Meijer, Patrick F. van Rheenen, Victorien M. Wolters, Marc A. Benninga, and Merit M. Tabbers. Incidence, diagnostics, therapeutic management and outcomes of paediatric intestinal pseudo‐obstruction in the netherlands: a 20‐year retrospective cohort study. Journal of Pediatric Gastroenterology and Nutrition, 80:34-45, Nov 2025. URL: https://doi.org/10.1002/jpn3.12400, doi:10.1002/jpn3.12400. This article has 6 citations and is from a peer-reviewed journal.

  12. (turcotte2022pediatricintestinalpseudoobstruction pages 5-6): Marie-Catherine Turcotte and Christophe Faure. Pediatric intestinal pseudo-obstruction: progress and challenges. Frontiers in Pediatrics, Apr 2022. URL: https://doi.org/10.3389/fped.2022.837462, doi:10.3389/fped.2022.837462. This article has 31 citations.

  13. (rijckmans2024counselingindividualswith pages 3-5): Ellen RIJCKMANS, Lars P. De Strooper, Kathelijn Keymolen, Jessica Rosenblum, Bart Loeys, Marije Meuwissen, Anna C. Jansen, and Katrien Stouffs. Counseling individuals with pathogenic loss-of-function variants in flna – learning points from a cross-sectional cohort study. Unknown journal, Oct 2024. URL: https://doi.org/10.21203/rs.3.rs-4546691/v1, doi:10.21203/rs.3.rs-4546691/v1.

  14. (gamboa2019pediatricintestinalpseudoobstruction pages 1-2): Heidi E. Gamboa and Manu Sood. Pediatric intestinal pseudo-obstruction in the era of genetic sequencing. Current Gastroenterology Reports, Dec 2019. URL: https://doi.org/10.1007/s11894-019-0737-y, doi:10.1007/s11894-019-0737-y. This article has 43 citations.

  15. (giorgio2011chronicintestinalpseudoobstruction pages 20-21): Roberto De Giorgio, Rosanna F. Cogliandro, Giovanni Barbara, Roberto Corinaldesi, and Vincenzo Stanghellini. Chronic intestinal pseudo-obstruction: clinical features, diagnosis, and therapy. Gastroenterology clinics of North America, 40 4:787-807, Dec 2011. URL: https://doi.org/10.1016/j.gtc.2011.09.005, doi:10.1016/j.gtc.2011.09.005. This article has 185 citations and is from a peer-reviewed journal.

  16. (geraghty2023useofwhole pages 1-2): Robert M. Geraghty, Sarah Orr, Eric Olinger, Ruxandra Neatu, Miguel Barroso-Gil, Holly Mabillard, Genomics England Research Consortium, Ian Wilson, and John A. Sayer. Use of whole genome sequencing to determine the genetic basis of visceral myopathies including prune belly syndrome. Journal of Rare Diseases (Berlin, Germany), Jun 2023. URL: https://doi.org/10.1007/s44162-023-00012-z, doi:10.1007/s44162-023-00012-z. This article has 9 citations.