Ayme-Gripp syndrome - Disorder Mechanisms

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Mappings

MONDO

MONDO:0010992 Ayme-Gripp syndrome

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Ayme-Gripp syndrome is inherited in an autosomal dominant manner, with most reported individuals representing de novo simplex cases.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:32027476 SUPPORT Human Clinical

"Aymé-Gripp syndrome is inherited in an autosomal dominant manner. Almost all individuals reported to date have been simplex cases (i.e., a single occurrence in a family) resulting from a de novo pathogenic variant."

GeneReviews directly states the inheritance pattern and that most cases arise de novo.

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Pathophysiology

3

Impaired GSK3-mediated MAF phosphorylation

Pathogenic missense variants in the MAF transactivation domain disrupt the conserved GSK3 phosphorylation motifs that normally regulate MAF turnover.

MAF link

protein phosphorylation link ⚠ ABNORMAL

Show evidence (1 reference)

PMID:25865493 SUPPORT Human Clinical

"Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals."

This directly locates the pathogenic variants in the GSK3-regulated phosphorylation motifs of MAF.

Stabilized MAF protein and dysregulated transcriptional programs

Failure of MAF phosphorylation impairs ubiquitination and proteasomal degradation, producing an abnormally persistent transcription factor that perturbs developmental gene-expression programs.

MAF link

Show evidence (2 references)

PMID:25865493 SUPPORT In Vitro

"Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts"

This directly supports defective phosphorylation-dependent turnover and abnormal transcriptional consequences in cell-based systems and primary fibroblasts.

PMID:25865493 SUPPORT Model Organism

"induced neurodevelopmental defects in an in vivo model."

This provides distinct in vivo support that the stabilized mutant protein perturbs neurodevelopment.

Multisystem developmental defects in lens, ear, brain, and growth

Dysregulated MAF activity affects multiple organ systems, producing cataract, hearing loss, abnormal skull growth, developmental impairment, and other ectodermal and skeletal features.

Show evidence (1 reference)

PMID:37186330 SUPPORT Model Organism

"Our murine model exhibited similar phenotypes to those in humans, such as lens abnormalities, short stature, growth retardation, and abnormal skull morphology."

The knock-in mouse model supports a causal developmental link between mutant Maf and the multisystem phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

7

Ear 1

Sensorineural hearing impairment Sensorineural hearing impairment (HP:0000407)

Show evidence (1 reference)

PMID:32027476 SUPPORT Human Clinical

"Hearing loss is often congenital."

This directly supports early sensorineural hearing involvement.

Eye 1

Cataract Cataract (HP:0000518)

Show evidence (1 reference)

PMID:32027476 SUPPORT Human Clinical

"Aymé-Gripp syndrome is classically defined as the triad of bilateral early cataracts, sensorineural hearing loss, and characteristic facial features in combination with neurodevelopmental abnormalities."

GeneReviews identifies bilateral early cataracts as part of the defining diagnostic triad.

Head and Neck 2

Brachycephaly Brachycephaly (HP:0000248)

Show evidence (1 reference)

PMID:32027476 SUPPORT Human Clinical

"The facial features are often described as "Down syndrome-like" and include brachycephaly, flat facial appearance, short nose, long philtrum, narrow mouth, and low-set and posteriorly rotated ears."

GeneReviews explicitly lists brachycephaly among the characteristic facial findings.

Flat facial profile Flat face (HP:0012368)

Show evidence (1 reference)

PMID:32027476 SUPPORT Human Clinical

"The facial features are often described as "Down syndrome-like" and include brachycephaly, flat facial appearance, short nose, long philtrum, narrow mouth, and low-set and posteriorly rotated ears."

This directly supports the characteristic flat facial profile in the syndrome.

Nervous System 2

Global developmental delay Global developmental delay (HP:0001263)

Show evidence (1 reference)

PMID:32027476 SUPPORT Human Clinical

"All affected individuals have had developmental delay, but the degree of cognitive impairment is extremely variable."

GeneReviews directly states that developmental delay is present in all affected individuals.

Seizure Seizure (HP:0001250)

Show evidence (1 reference)

PMID:25865493 SUPPORT Human Clinical

"Seizures and abnormal EEG findings consistent with focal and diffuse abnormal activity were present in all individuals, most often diagnosed in early childhood."

The original case-series abstract explicitly identifies seizures as a frequent early neurologic manifestation.

Growth 1

Growth delay Growth delay (HP:0001510)

Show evidence (1 reference)

PMID:32027476 SUPPORT Human Clinical

"Other features may include postnatal short stature, seizure disorder, nonspecific brain abnormalities on head imaging, skeletal abnormalities, and joint limitations."

GeneReviews documents postnatal short stature as part of the recurring phenotype.

🧬

Genetic Associations

1

MAF (Pathogenic missense variants impairing phosphorylation-dependent turnover)

Show evidence (1 reference)

PMID:25865493 SUPPORT Human Clinical

"Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals."

This establishes the disease-causing variant class and its clustering in the phosphorylation-regulatory domain of MAF.

💊

Treatments

1

Supportive multidisciplinary management

Action: supportive care MAXO:0000950

Management is symptomatic and centers on hearing rehabilitation, cataract surgery and refractive care, developmental therapies, and treatment of seizures and orthopedic or endocrine complications as needed.

Show evidence (1 reference)

PMID:32027476 SUPPORT Human Clinical

"Treatment is symptomatic and ideally involves multidisciplinary care."

GeneReviews directly states that current management is supportive and multidisciplinary.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Ayme-Gripp syndrome:

Stickler syndrome Not Yet Curated MONDO:0019354

Overlapping Features Stickler syndrome overlaps through congenital cataract, hearing impairment, and craniofacial findings, but it is primarily a collagenopathy with vitreoretinopathy and joint disease rather than a MAF-related neurodevelopmental syndrome.

Distinguishing Features

Developmental delay and seizures favor Ayme-Gripp syndrome.
Vitreoretinal degeneration and cleft-related Pierre Robin sequence favor Stickler syndrome.

Marshall syndrome Not Yet Curated MONDO:0007949

Overlapping Features Marshall syndrome can mimic Ayme-Gripp syndrome with cataract, hearing loss, and midface flattening, but is typically driven by collagen-gene defects and lacks the characteristic MAF-related seizure and neurodevelopmental profile.

Distinguishing Features

Congenital cataracts with developmental delay and seizure disorder favor Ayme-Gripp syndrome.
Progressive connective-tissue and ocular collagenopathy features favor Marshall syndrome.

📊

Related Datasets

1

Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies. PMID:25865493

Foundational human clinical-genetic cohort describing eight unrelated individuals with de novo MAF transactivation-domain variants and defining the core Ayme-Gripp syndrome phenotype.

human n=8

Conditions: Ayme-Gripp syndrome de novo MAF pathogenic variants

PMID:25865493

Show evidence (1 reference)

PMID:25865493 SUPPORT Human Clinical

"Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals."

This defines a reusable disease-specific human cohort dataset linking MAF genotype to the canonical Ayme-Gripp phenotype.

{ }

Source YAML

click to show

name: Ayme-Gripp syndrome
creation_date: '2026-04-11T19:38:25Z'
updated_date: '2026-04-11T23:55:00Z'
category: Mendelian
description: >-
  Ayme-Gripp syndrome is an autosomal dominant multisystem developmental
  disorder caused by heterozygous pathogenic variants in MAF. The core phenotype
  combines congenital or early-onset cataracts, sensorineural hearing
  impairment, developmental delay or intellectual disability, seizures, growth
  restriction, and a distinctive flat facial appearance. Disease-causing
  variants cluster in the MAF transactivation domain, where they impair
  GSK3-mediated phosphorylation and proteasomal turnover, leading to abnormal
  persistence of the transcription factor and dysregulation of developmental
  gene-expression programs.
disease_term:
  preferred_term: Ayme-Gripp syndrome
  term:
    id: MONDO:0010992
    label: Ayme-Gripp syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010992
      label: Ayme-Gripp syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- genetic syndrome
- hereditary disease
synonyms:
- Aymé-Gripp syndrome
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Ayme-Gripp syndrome is inherited in an autosomal dominant manner, with most
    reported individuals representing de novo simplex cases.
  evidence:
  - reference: PMID:32027476
    reference_title: "Aymé-Gripp Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aymé-Gripp syndrome is inherited in an autosomal dominant manner. Almost all individuals reported to date have been simplex cases (i.e., a single occurrence in a family) resulting from a de novo pathogenic variant.
    explanation: >-
      GeneReviews directly states the inheritance pattern and that most cases
      arise de novo.
pathophysiology:
- name: Impaired GSK3-mediated MAF phosphorylation
  description: >-
    Pathogenic missense variants in the MAF transactivation domain disrupt the
    conserved GSK3 phosphorylation motifs that normally regulate MAF turnover.
  genes:
  - preferred_term: MAF
    term:
      id: hgnc:6776
      label: MAF
  biological_processes:
  - preferred_term: protein phosphorylation
    modifier: ABNORMAL
    term:
      id: GO:0006468
      label: protein phosphorylation
  evidence:
  - reference: PMID:25865493
    reference_title: "Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals.
    explanation: >-
      This directly locates the pathogenic variants in the GSK3-regulated
      phosphorylation motifs of MAF.
  downstream:
  - target: Stabilized MAF protein and dysregulated transcriptional programs
    description: Loss of normal phosphorylation prevents normal ubiquitination and turnover of MAF
- name: Stabilized MAF protein and dysregulated transcriptional programs
  description: >-
    Failure of MAF phosphorylation impairs ubiquitination and proteasomal
    degradation, producing an abnormally persistent transcription factor that
    perturbs developmental gene-expression programs.
  genes:
  - preferred_term: MAF
    term:
      id: hgnc:6776
      label: MAF
  evidence:
  - reference: PMID:25865493
    reference_title: "Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts
    explanation: >-
      This directly supports defective phosphorylation-dependent turnover and
      abnormal transcriptional consequences in cell-based systems and primary
      fibroblasts.
  - reference: PMID:25865493
    reference_title: "Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: induced neurodevelopmental defects in an in vivo model.
    explanation: >-
      This provides distinct in vivo support that the stabilized mutant protein
      perturbs neurodevelopment.
  downstream:
  - target: Multisystem developmental defects in lens, ear, brain, and growth
    description: Abnormal MAF dosage disrupts multiple developmental programs
- name: Multisystem developmental defects in lens, ear, brain, and growth
  description: >-
    Dysregulated MAF activity affects multiple organ systems, producing cataract,
    hearing loss, abnormal skull growth, developmental impairment, and other
    ectodermal and skeletal features.
  evidence:
  - reference: PMID:37186330
    reference_title: "Generation and mutational analysis of a transgenic murine model of the human MAF mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our murine model exhibited similar phenotypes to those in humans, such as lens abnormalities, short stature, growth retardation, and abnormal skull morphology.
    explanation: >-
      The knock-in mouse model supports a causal developmental link between
      mutant Maf and the multisystem phenotype.
phenotypes:
- name: Cataract
  category: Ophthalmic
  description: >-
    Congenital or early-onset bilateral cataracts are a cardinal feature of
    Ayme-Gripp syndrome.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:32027476
    reference_title: "Aymé-Gripp Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aymé-Gripp syndrome is classically defined as the triad of bilateral early cataracts, sensorineural hearing loss, and characteristic facial features in combination with neurodevelopmental abnormalities.
    explanation: >-
      GeneReviews identifies bilateral early cataracts as part of the defining
      diagnostic triad.
- name: Sensorineural hearing impairment
  category: Otolaryngologic
  description: >-
    Hearing loss is usually congenital or recognized early in life and forms
    part of the classic diagnostic triad.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:32027476
    reference_title: "Aymé-Gripp Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hearing loss is often congenital.
    explanation: >-
      This directly supports early sensorineural hearing involvement.
- name: Global developmental delay
  category: Neurologic
  description: >-
    Developmental delay is universal or near-universal across reported
    individuals, although severity varies.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:32027476
    reference_title: "Aymé-Gripp Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals have had developmental delay, but the degree of cognitive impairment is extremely variable.
    explanation: >-
      GeneReviews directly states that developmental delay is present in all
      affected individuals.
- name: Seizure
  category: Neurologic
  description: >-
    Seizures are a recurrent neurologic feature in Ayme-Gripp syndrome.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:25865493
    reference_title: "Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures and abnormal EEG findings consistent with focal and diffuse abnormal activity were present in all individuals, most often diagnosed in early childhood.
    explanation: >-
      The original case-series abstract explicitly identifies seizures as a
      frequent early neurologic manifestation.
- name: Growth delay
  category: Growth
  description: >-
    Postnatal short stature and poor somatic growth are part of the syndrome's
    multisystem phenotype.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:32027476
    reference_title: "Aymé-Gripp Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other features may include postnatal short stature, seizure disorder, nonspecific brain abnormalities on head imaging, skeletal abnormalities, and joint limitations.
    explanation: >-
      GeneReviews documents postnatal short stature as part of the recurring
      phenotype.
- name: Brachycephaly
  category: Craniofacial
  description: >-
    Brachycephaly is one of the characteristic craniofacial findings in
    Ayme-Gripp syndrome.
  phenotype_term:
    preferred_term: Brachycephaly
    term:
      id: HP:0000248
      label: Brachycephaly
  evidence:
  - reference: PMID:32027476
    reference_title: "Aymé-Gripp Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The facial features are often described as "Down syndrome-like" and include brachycephaly, flat facial appearance, short nose, long philtrum, narrow mouth, and low-set and posteriorly rotated ears.
    explanation: >-
      GeneReviews explicitly lists brachycephaly among the characteristic facial
      findings.
- name: Flat facial profile
  category: Craniofacial
  description: >-
    A flat facial profile is part of the recognizable facial gestalt of
    Ayme-Gripp syndrome.
  phenotype_term:
    preferred_term: Flat face
    term:
      id: HP:0012368
      label: Flat face
  evidence:
  - reference: PMID:32027476
    reference_title: "Aymé-Gripp Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The facial features are often described as "Down syndrome-like" and include brachycephaly, flat facial appearance, short nose, long philtrum, narrow mouth, and low-set and posteriorly rotated ears.
    explanation: >-
      This directly supports the characteristic flat facial profile in the
      syndrome.
genetic:
- name: MAF
  association: Pathogenic missense variants impairing phosphorylation-dependent turnover
  gene_term:
    preferred_term: MAF
    term:
      id: hgnc:6776
      label: MAF
  notes: >-
    Ayme-Gripp syndrome is caused by heterozygous MAF variants affecting the
    GSK3 phosphorylation motifs in the transactivation domain, producing a
    dosage-altering gain-of-stability mechanism rather than simple loss of DNA
    binding.
  evidence:
  - reference: PMID:25865493
    reference_title: "Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals.
    explanation: >-
      This establishes the disease-causing variant class and its clustering in
      the phosphorylation-regulatory domain of MAF.
treatments:
- name: Supportive multidisciplinary management
  description: >-
    Management is symptomatic and centers on hearing rehabilitation, cataract
    surgery and refractive care, developmental therapies, and treatment of
    seizures and orthopedic or endocrine complications as needed.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:32027476
    reference_title: "Aymé-Gripp Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment is symptomatic and ideally involves multidisciplinary care.
    explanation: >-
      GeneReviews directly states that current management is supportive and
      multidisciplinary.
differential_diagnoses:
- name: Stickler syndrome
  disease_term:
    preferred_term: Stickler syndrome
    term:
      id: MONDO:0019354
      label: Stickler syndrome
  description: >-
    Stickler syndrome overlaps through congenital cataract, hearing impairment,
    and craniofacial findings, but it is primarily a collagenopathy with
    vitreoretinopathy and joint disease rather than a MAF-related
    neurodevelopmental syndrome.
  distinguishing_features:
  - Developmental delay and seizures favor Ayme-Gripp syndrome.
  - Vitreoretinal degeneration and cleft-related Pierre Robin sequence favor Stickler syndrome.
- name: Marshall syndrome
  disease_term:
    preferred_term: Marshall syndrome
    term:
      id: MONDO:0007949
      label: Marshall syndrome
  description: >-
    Marshall syndrome can mimic Ayme-Gripp syndrome with cataract, hearing loss,
    and midface flattening, but is typically driven by collagen-gene defects and
    lacks the characteristic MAF-related seizure and neurodevelopmental profile.
  distinguishing_features:
  - Congenital cataracts with developmental delay and seizure disorder favor Ayme-Gripp syndrome.
  - Progressive connective-tissue and ocular collagenopathy features favor Marshall syndrome.
clinical_trials: []
datasets:
- accession: PMID:25865493
  title: Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies.
  description: >-
    Foundational human clinical-genetic cohort describing eight unrelated
    individuals with de novo MAF transactivation-domain variants and defining the
    core Ayme-Gripp syndrome phenotype.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 8
  conditions:
  - Ayme-Gripp syndrome
  - de novo MAF pathogenic variants
  publication: PMID:25865493
  evidence:
  - reference: PMID:25865493
    reference_title: "Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals.
    explanation: >-
      This defines a reusable disease-specific human cohort dataset linking MAF
      genotype to the canonical Ayme-Gripp phenotype.
notes: >-
  Asta deep research was run as requested, but the cached retrieval output was
  partially mismatched across diseases. Final curation relied on directly
  reviewed PubMed and GeneReviews references.