Spondyloepimetaphyseal Dysplasia Bieganski Type

Mendelian MONDO:0010275 Pathograph 7 Spondyloepimetaphyseal Dysplasia mitochondrial disease

Spondyloepimetaphyseal dysplasia, Bieganski type is a rare X-linked AIFM1-associated mitochondrial disorder combining spondyloepimetaphyseal skeletal dysplasia with progressive neurodegeneration, hypomyelinating leukodystrophy, growth failure, visual and auditory involvement, and developmental impairment. The reported molecular mechanism implicates the AIFM1 p.Asp237Gly variant and additional exon 7-region variants, linking mitochondrial apoptosis-inducing factor dysfunction to both neurologic and skeletal phenotypes. Falcon deep research noted that MBTPS1-related spondyloepiphyseal dysplasia, Kondo-Fu type is sometimes discussed with overlapping SEMD terminology, but it is a distinct autosomal recessive condition and is not modeled as the causal entity for this MONDO:0010275 page.

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1
Inheritance
3
Pathophys.
13
Phenotypes
7
Pathograph
2
Genes
1
Differentials
1
Deep Research
👪

Inheritance

1
X-linked recessive inheritance HP:0001419
The disorder was originally described with probable X-linked recessive inheritance, and later molecular work showed segregation of an AIFM1 Xq26.1 variant with disease in two families.
X-linked recessive inheritance
Show evidence (2 references)
PMID:27102849 SUPPORT Human Clinical
"In 1999, based on a single family, spondyloepimetaphyseal dysplasia (SEMD) with mental retardation (MR) was described as a novel syndrome with probably X-linked recessive inheritance and unknown molecular defect (MIM 300232)."
The original family history supported X-linked recessive inheritance before the causative AIFM1 variant was identified.
PMID:27102849 SUPPORT Human Clinical
"The p.Asp237Gly segregated with disease as indicated by linkage analysis [maximum logarithm of odds score (LOD) score at theta 0 for the two families was 3.359]."
Segregation of the X-linked AIFM1 variant in two families supports the inherited disease mechanism.
⚙

Pathophysiology

3
AIFM1 Variant-Associated Mitochondrial Dysfunction
AIFM1 encodes a mitochondria-associated apoptosis-inducing factor. In Bieganski-type spondyloepimetaphyseal dysplasia, the AIFM1 p.Asp237Gly variant segregates with disease and is predicted pathogenic. Later AIFM1-associated SMD-H reports implicate variants at or near exon 7, including splice-altering variants, placing this skeletal-neurologic syndrome within the AIFM1-related mitochondrial disease spectrum.
AIFM1 link
Mitochondrion Organization link Apoptotic Process link RNA Splicing link ⚠ ABNORMAL
Downstream
Hypomyelination and Neurodegeneration
Spondyloepimetaphyseal Skeletal Dysplasia
Show evidence (3 references)
PMID:27102849 SUPPORT Human Clinical
"Whole exome sequencing performed in two subjects showed a single plausible candidate - the p.Asp237Gly variant in AIFM1 (chr. Xq26.1)."
Exome sequencing identified AIFM1 p.Asp237Gly as the single plausible candidate variant in affected subjects.
PMID:27102849 SUPPORT Human Clinical
"AIFM1 encodes mitochondria associated apoptosis-inducing factor."
This supports annotation of the mechanism as mitochondrial and apoptosis-related.
PMID:33439541 SUPPORT Human Clinical
"Recently, SMD-H has been associated with variants confined to a specific intra-genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination."
The 2021 case expansion links AIFM1 exon 7-region variants to the combined bone-development and cerebral-myelination phenotype.
Hypomyelination and Neurodegeneration
Affected individuals show early developmental delay and progressive central and peripheral neurologic involvement, with brain MRI evidence of diffuse hypomyelination in reported cases.
Oligodendrocyte link
Myelination link
Downstream
Developmental Delay
Gait Ataxia
Show evidence (3 references)
PMID:27102849 SUPPORT Human Clinical
"All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia."
The AIFM1-linked families had progressive central and peripheral neurodegeneration.
PMID:23239615 SUPPORT Human Clinical
"His brain MRI revealed diffuse hypomyelination."
This case report documents diffuse cerebral hypomyelination in a patient with spondylo-epi-metaphyseal dysplasia.
PMID:33439541 SUPPORT Human Clinical
"Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy."
The abstract directly defines the AIFM1-associated phenotype as a combination of skeletal dysplasia and hypomyelinating leukodystrophy.
Spondyloepimetaphyseal Skeletal Dysplasia
The skeletal disease includes spondyloepimetaphyseal dysplasia, severe growth retardation, and generalized skeletal abnormalities, indicating that the AIFM1-associated mitochondrial disorder affects skeletal development as well as the nervous system.
Chondrocyte link
Bone Development link
Show evidence (3 references)
PMID:27102849 SUPPORT Human Clinical
"Our results place SEMD as the third instance of a skeletal phenotype associated with a mitochondrial disease (the others being EVEN-PLUS syndrome caused by mutations of HSPA9 and CODAS syndrome due to LONP1 mutations)."
This directly links the Bieganski-type SEMD phenotype to mitochondrial disease.
PMID:23239615 SUPPORT Human Clinical
"The patient had severe growth retardation and general skeletal dysplasia compatible with spondylo-epi-metaphyseal dysplasia; however the mutation of discoidin domain receptor (DDR) 2 gene was absent."
The case report supports severe growth retardation and skeletal dysplasia compatible with SEMD.
PMID:33439541 SUPPORT Human Clinical
"Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1."
Additional affected boys with AIFM1 exon 7-region variants support the skeletal-dysplasia disease mechanism.
⬡

Pathograph

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

Phenotypes

13
Ear 1
Sensorineural Hearing Impairment Sensorineural hearing impairment (HP:0000407)
Show evidence (1 reference)
PMID:36136119 SUPPORT Human Clinical
"Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual..."
The abstract identifies sensorineural hearing loss as a characteristic feature.
Eye 1
Nystagmus Nystagmus (HP:0000639)
Show evidence (1 reference)
PMID:23239615 SUPPORT Human Clinical
"The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age."
Nystagmus was reported as an early clinical manifestation.
Head and Neck 1
Microcephaly Microcephaly (HP:0000252)
Show evidence (1 reference)
PMID:36136119 SUPPORT Human Clinical
"Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual..."
The abstract lists microcephaly as a characteristic feature of the syndrome.
Musculoskeletal 2
Skeletal Dysplasia Skeletal dysplasia (HP:0002652)
Show evidence (1 reference)
PMID:27102849 SUPPORT Human Clinical
"All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia."
This establishes skeletal dysplasia as a shared feature among affected patients.
Joint Hypermobility Joint hypermobility (HP:0001382)
Show evidence (1 reference)
PMID:36136119 SUPPORT Human Clinical
"Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual..."
The abstract lists joint laxity among characteristic features; OAK showed HP:0001388 is obsolete and HP:0001382 has exact synonym "Joint laxity".
Nervous System 4
Progressive Neurologic Deterioration Progressive neurologic deterioration (HP:0002344)
Show evidence (1 reference)
PMID:27102849 SUPPORT Human Clinical
"All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia."
This directly supports progressive neurologic deterioration in the AIFM1-linked families.
Developmental Delay Global developmental delay (HP:0001263)
Show evidence (1 reference)
PMID:23239615 SUPPORT Human Clinical
"The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age."
The case report identifies developmental delay as an early clinical manifestation.
Intellectual Disability Intellectual disability (HP:0001249)
Show evidence (1 reference)
PMID:36136119 SUPPORT Human Clinical
"Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual..."
The abstract lists intellectual disability as part of the reported phenotype.
Gait Ataxia Gait ataxia (HP:0002066)
Show evidence (1 reference)
PMID:23239615 SUPPORT Human Clinical
"The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age."
Ataxia was one of the earliest observed neurologic signs.
Growth 1
Short Stature Short stature (HP:0004322)
Show evidence (1 reference)
PMID:36136119 SUPPORT Human Clinical
"Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual..."
The abstract lists short stature among characteristic features of Liberfarb syndrome.
Other 3
Spondylometaphyseal Dysplasia Spondylometaphyseal dysplasia (HP:0002657)
Show evidence (1 reference)
PMID:33439541 SUPPORT Human Clinical
"Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy."
The paper defines SMD-H as a distinctive spondylometaphyseal dysplasia phenotype with cerebral hypomyelination.
Delayed CNS Myelination Delayed CNS myelination (HP:0002188)
Show evidence (2 references)
PMID:23239615 SUPPORT Human Clinical
"His brain MRI revealed diffuse hypomyelination."
Diffuse hypomyelination on MRI supports the delayed CNS myelination phenotype.
PMID:33439541 SUPPORT Human Clinical
"Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy."
The abstract directly supports cerebral hypomyelination as a defining feature.
Retinal Degeneration Retinal degeneration (HP:0000546)
Show evidence (1 reference)
PMID:36136119 SUPPORT Human Clinical
"Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual..."
The abstract identifies early-onset retinal degeneration as a characteristic feature.
🧬

Genetic Associations

2
AIFM1 p.Asp237Gly (Causal X-linked missense variant)
X-linked recessive inheritance
Show evidence (1 reference)
PMID:27102849 SUPPORT Human Clinical
"This variant had not been previously reported and it was predicted to be pathogenic by Polyphen2, SIFT, MutationTaster and Mutation Assessor."
The authors report rarity and multiple pathogenicity predictions for AIFM1 p.Asp237Gly.
AIFM1 exon 7-region variants (Causal X-linked exon 7-region variants)
X-linked recessive inheritance
Show evidence (1 reference)
PMID:33439541 SUPPORT Human Clinical
"Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1."
This supports additional AIFM1 exon 7-region variants and exon 7 skipping as part of the disease's genetic mechanism.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Spondyloepimetaphyseal Dysplasia Bieganski Type:

Spondyloepiphyseal dysplasia, Kondo-Fu type
Overlapping Features MBTPS1-related spondyloepiphyseal dysplasia, Kondo-Fu type can be discussed with overlapping SEMD terminology, but Falcon deep research found it is a distinct autosomal recessive entity characterized by elevated plasma lysosomal enzymes and cataracts rather than the X-linked AIFM1 hypomyelination syndrome modeled here.
Show evidence (1 reference)
PMID:32420688 SUPPORT Human Clinical
"Here, we report the second individual with this newly described autosomal recessive spondyloepiphyseal dysplasia (OMIM #618392), presenting severe growth retardation, cataract and dysmorphic features, mainly retromicrognathia."
This supports Kondo-Fu/MBTPS1 disease as an autosomal recessive spondyloepiphyseal dysplasia with cataract and dysmorphic features, distinct from the AIFM1 X-linked hypomyelination syndrome.
{ }

Source YAML

click to show 
name: Spondyloepimetaphyseal Dysplasia Bieganski Type
creation_date: "2026-05-08T16:20:35Z"
updated_date: "2026-05-08T16:20:35Z"
category: Mendelian
description: >-
  Spondyloepimetaphyseal dysplasia, Bieganski type is a rare X-linked
  AIFM1-associated mitochondrial disorder combining spondyloepimetaphyseal
  skeletal dysplasia with progressive neurodegeneration, hypomyelinating
  leukodystrophy, growth failure, visual and auditory involvement, and
  developmental impairment. The reported molecular mechanism implicates the
  AIFM1 p.Asp237Gly variant and additional exon 7-region variants, linking
  mitochondrial apoptosis-inducing factor dysfunction to both neurologic and
  skeletal phenotypes. Falcon deep research noted that MBTPS1-related
  spondyloepiphyseal dysplasia, Kondo-Fu type is sometimes discussed with
  overlapping SEMD terminology, but it is a distinct autosomal recessive
  condition and is not modeled as the causal entity for this MONDO:0010275 page.
disease_term:
  preferred_term: spondyloepimetaphyseal dysplasia, Bieganski type
  term:
    id: MONDO:0010275
    label: spondyloepimetaphyseal dysplasia, Bieganski type
parents:
- Spondyloepimetaphyseal Dysplasia
- mitochondrial disease
synonyms:
- hypomyelination-spondyloepimetaphyseal dysplasia syndrome
- leukoencephalopathy-SEMD syndrome
- leukoencephalopathy-metaphyseal chondrodysplasia syndrome
- Liberfarb syndrome
- X-linked spondylometaphyseal dysplasia with cerebral hypomyelination
- spondylometaphyseal dysplasia with cerebral hypomyelination
- SMD-H
inheritance:
- name: X-linked recessive inheritance
  description: >-
    The disorder was originally described with probable X-linked recessive
    inheritance, and later molecular work showed segregation of an AIFM1
    Xq26.1 variant with disease in two families.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:27102849
    reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 1999, based on a single family, spondyloepimetaphyseal dysplasia (SEMD) with mental retardation (MR) was described as a novel syndrome with probably X-linked recessive inheritance and unknown molecular defect (MIM 300232).
    explanation: >-
      The original family history supported X-linked recessive inheritance before the causative AIFM1 variant was identified.
  - reference: PMID:27102849
    reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The p.Asp237Gly segregated with disease as indicated by linkage analysis [maximum logarithm of odds score (LOD) score at theta 0 for the two families was 3.359].
    explanation: >-
      Segregation of the X-linked AIFM1 variant in two families supports the inherited disease mechanism.
pathophysiology:
- name: AIFM1 Variant-Associated Mitochondrial Dysfunction
  description: >-
    AIFM1 encodes a mitochondria-associated apoptosis-inducing factor. In
    Bieganski-type spondyloepimetaphyseal dysplasia, the AIFM1 p.Asp237Gly
    variant segregates with disease and is predicted pathogenic. Later
    AIFM1-associated SMD-H reports implicate variants at or near exon 7,
    including splice-altering variants, placing this skeletal-neurologic
    syndrome within the AIFM1-related mitochondrial disease spectrum.
  genes:
  - preferred_term: AIFM1
    term:
      id: hgnc:8768
      label: AIFM1
  biological_processes:
  - preferred_term: Mitochondrion Organization
    term:
      id: GO:0007005
      label: mitochondrion organization
  - preferred_term: Apoptotic Process
    term:
      id: GO:0006915
      label: apoptotic process
  - preferred_term: RNA Splicing
    term:
      id: GO:0008380
      label: RNA splicing
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27102849
    reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing performed in two subjects showed a single plausible candidate - the p.Asp237Gly variant in AIFM1 (chr. Xq26.1).
    explanation: >-
      Exome sequencing identified AIFM1 p.Asp237Gly as the single plausible candidate variant in affected subjects.
  - reference: PMID:27102849
    reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AIFM1 encodes mitochondria associated apoptosis-inducing factor.
    explanation: >-
      This supports annotation of the mechanism as mitochondrial and apoptosis-related.
  - reference: PMID:33439541
    reference_title: "AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, SMD-H has been associated with variants confined to a specific intra-genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination.
    explanation: >-
      The 2021 case expansion links AIFM1 exon 7-region variants to the combined bone-development and cerebral-myelination phenotype.
  downstream:
  - target: Hypomyelination and Neurodegeneration
    evidence:
    - reference: PMID:33439541
      reference_title: "AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recently, SMD-H has been associated with variants confined to a specific intra-genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination.
      explanation: >-
        This supports the causal edge from AIFM1 exon 7-region variation to cerebral myelination defects.
  - target: Spondyloepimetaphyseal Skeletal Dysplasia
    evidence:
    - reference: PMID:33439541
      reference_title: "AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Recently, SMD-H has been associated with variants confined to a specific intra-genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination.
      explanation: >-
        This supports the causal edge from AIFM1 exon 7-region variation to abnormal bone development and metabolism.
- name: Hypomyelination and Neurodegeneration
  description: >-
    Affected individuals show early developmental delay and progressive central
    and peripheral neurologic involvement, with brain MRI evidence of diffuse
    hypomyelination in reported cases.
  biological_processes:
  - preferred_term: Myelination
    term:
      id: GO:0042552
      label: myelination
  cell_types:
  - preferred_term: Oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  evidence:
  - reference: PMID:27102849
    reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia.
    explanation: >-
      The AIFM1-linked families had progressive central and peripheral neurodegeneration.
  - reference: PMID:23239615
    reference_title: "A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His brain MRI revealed diffuse hypomyelination.
    explanation: >-
      This case report documents diffuse cerebral hypomyelination in a patient with spondylo-epi-metaphyseal dysplasia.
  - reference: PMID:33439541
    reference_title: "AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy.
    explanation: >-
      The abstract directly defines the AIFM1-associated phenotype as a combination of skeletal dysplasia and hypomyelinating leukodystrophy.
  downstream:
  - target: Developmental Delay
    evidence:
    - reference: PMID:23239615
      reference_title: "A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age.
      explanation: >-
        This supports developmental delay as a downstream clinical manifestation of the hypomyelination-neurodegeneration phenotype.
  - target: Gait Ataxia
    evidence:
    - reference: PMID:23239615
      reference_title: "A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age.
      explanation: >-
        This supports gait ataxia as a downstream clinical manifestation of the hypomyelination-neurodegeneration phenotype.
- name: Spondyloepimetaphyseal Skeletal Dysplasia
  description: >-
    The skeletal disease includes spondyloepimetaphyseal dysplasia, severe
    growth retardation, and generalized skeletal abnormalities, indicating that
    the AIFM1-associated mitochondrial disorder affects skeletal development as
    well as the nervous system.
  biological_processes:
  - preferred_term: Bone Development
    term:
      id: GO:0060348
      label: bone development
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:27102849
    reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results place SEMD as the third instance of a skeletal phenotype associated with a mitochondrial disease (the others being EVEN-PLUS syndrome caused by mutations of HSPA9 and CODAS syndrome due to LONP1 mutations).
    explanation: >-
      This directly links the Bieganski-type SEMD phenotype to mitochondrial disease.
  - reference: PMID:23239615
    reference_title: "A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient had severe growth retardation and general skeletal dysplasia compatible with spondylo-epi-metaphyseal dysplasia; however the mutation of discoidin domain receptor (DDR) 2 gene was absent.
    explanation: >-
      The case report supports severe growth retardation and skeletal dysplasia compatible with SEMD.
  - reference: PMID:33439541
    reference_title: "AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1.
    explanation: >-
      Additional affected boys with AIFM1 exon 7-region variants support the skeletal-dysplasia disease mechanism.
phenotypes:
- name: Skeletal Dysplasia
  description: >-
    Generalized skeletal dysplasia with spondyloepimetaphyseal involvement is a
    defining clinical feature.
  phenotype_term:
    preferred_term: Skeletal dysplasia
    term:
      id: HP:0002652
      label: Skeletal dysplasia
  evidence:
  - reference: PMID:27102849
    reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia.
    explanation: >-
      This establishes skeletal dysplasia as a shared feature among affected patients.
- name: Spondylometaphyseal Dysplasia
  description: >-
    Later AIFM1 literature describes the Bieganski-type phenotype as
    spondylometaphyseal dysplasia with cerebral hypomyelination.
  phenotype_term:
    preferred_term: Spondylometaphyseal dysplasia
    term:
      id: HP:0002657
      label: Spondylometaphyseal dysplasia
  evidence:
  - reference: PMID:33439541
    reference_title: "AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy.
    explanation: >-
      The paper defines SMD-H as a distinctive spondylometaphyseal dysplasia phenotype with cerebral hypomyelination.
- name: Short Stature
  description: >-
    Short stature and severe growth retardation are reported in the
    hypomyelination-SEMD phenotype.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:36136119
    reference_title: "Brain imaging findings in Liberfarb syndrome: hypomyelination and optic nerve and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual disability, but clinical variability has been observed.
    explanation: >-
      The abstract lists short stature among characteristic features of Liberfarb syndrome.
- name: Joint Hypermobility
  description: >-
    Joint laxity is reported as part of the broader Liberfarb syndrome
    phenotype; this is mapped to the current HPO term for joint hypermobility.
  phenotype_term:
    preferred_term: Joint laxity
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:36136119
    reference_title: "Brain imaging findings in Liberfarb syndrome: hypomyelination and optic nerve and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual disability, but clinical variability has been observed.
    explanation: >-
      The abstract lists joint laxity among characteristic features; OAK showed HP:0001388 is obsolete and HP:0001382 has exact synonym "Joint laxity".
- name: Delayed CNS Myelination
  description: >-
    Brain MRI findings include diffuse hypomyelination and delayed CNS
    myelination.
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: PMID:23239615
    reference_title: "A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His brain MRI revealed diffuse hypomyelination.
    explanation: >-
      Diffuse hypomyelination on MRI supports the delayed CNS myelination phenotype.
  - reference: PMID:33439541
    reference_title: "AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy.
    explanation: >-
      The abstract directly supports cerebral hypomyelination as a defining feature.
- name: Progressive Neurologic Deterioration
  description: >-
    Affected patients show slowly progressive central and peripheral neurologic
    decline.
  phenotype_term:
    preferred_term: Progressive neurologic deterioration
    term:
      id: HP:0002344
      label: Progressive neurologic deterioration
  evidence:
  - reference: PMID:27102849
    reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia.
    explanation: >-
      This directly supports progressive neurologic deterioration in the AIFM1-linked families.
- name: Developmental Delay
  description: >-
    Developmental delay may be the presenting feature in infancy or early
    childhood.
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:23239615
    reference_title: "A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age.
    explanation: >-
      The case report identifies developmental delay as an early clinical manifestation.
- name: Microcephaly
  description: >-
    Microcephaly is reported as part of the multisystem Liberfarb syndrome
    phenotype.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:36136119
    reference_title: "Brain imaging findings in Liberfarb syndrome: hypomyelination and optic nerve and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual disability, but clinical variability has been observed.
    explanation: >-
      The abstract lists microcephaly as a characteristic feature of the syndrome.
- name: Intellectual Disability
  description: >-
    Intellectual disability is reported in the multisystem phenotype, with
    clinical variability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36136119
    reference_title: "Brain imaging findings in Liberfarb syndrome: hypomyelination and optic nerve and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual disability, but clinical variability has been observed.
    explanation: >-
      The abstract lists intellectual disability as part of the reported phenotype.
- name: Gait Ataxia
  description: >-
    Ataxia accompanies the hypomyelinating neurodegenerative component.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  evidence:
  - reference: PMID:23239615
    reference_title: "A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age.
    explanation: >-
      Ataxia was one of the earliest observed neurologic signs.
- name: Nystagmus
  description: >-
    Ocular motor abnormalities are reported in early childhood.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:23239615
    reference_title: "A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The condition was first noticed as a developmental delay, nystagmus and ataxia at 1 year of age.
    explanation: >-
      Nystagmus was reported as an early clinical manifestation.
- name: Sensorineural Hearing Impairment
  description: >-
    Sensorineural hearing loss is described as part of the broader Liberfarb
    syndrome phenotype.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:36136119
    reference_title: "Brain imaging findings in Liberfarb syndrome: hypomyelination and optic nerve and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual disability, but clinical variability has been observed.
    explanation: >-
      The abstract identifies sensorineural hearing loss as a characteristic feature.
- name: Retinal Degeneration
  description: >-
    Retinal degeneration is part of the multisystem AIFM1-associated phenotype.
  phenotype_term:
    preferred_term: Retinal degeneration
    term:
      id: HP:0000546
      label: Retinal degeneration
  evidence:
  - reference: PMID:36136119
    reference_title: "Brain imaging findings in Liberfarb syndrome: hypomyelination and optic nerve and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual disability, but clinical variability has been observed.
    explanation: >-
      The abstract identifies early-onset retinal degeneration as a characteristic feature.
genetic:
- name: AIFM1 p.Asp237Gly
  association: Causal X-linked missense variant
  gene_term:
    preferred_term: AIFM1
    term:
      id: hgnc:8768
      label: AIFM1
  notes: >-
    The recurrent AIFM1 p.Asp237Gly variant on Xq26.1 segregated with disease in
    two families and was predicted pathogenic by multiple in silico tools.
  inheritance:
  - name: X-linked recessive inheritance
    inheritance_term:
      preferred_term: X-linked recessive inheritance
      term:
        id: HP:0001419
        label: X-linked recessive inheritance
    evidence:
    - reference: PMID:27102849
      reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The p.Asp237Gly segregated with disease as indicated by linkage analysis [maximum logarithm of odds score (LOD) score at theta 0 for the two families was 3.359].
      explanation: >-
        Segregation of the AIFM1 variant with disease supports the X-linked inherited genetic association.
  evidence:
  - reference: PMID:27102849
    reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant had not been previously reported and it was predicted to be pathogenic by Polyphen2, SIFT, MutationTaster and Mutation Assessor.
    explanation: >-
      The authors report rarity and multiple pathogenicity predictions for AIFM1 p.Asp237Gly.
- name: AIFM1 exon 7-region variants
  association: Causal X-linked exon 7-region variants
  gene_term:
    preferred_term: AIFM1
    term:
      id: hgnc:8768
      label: AIFM1
  notes: >-
    Later SMD-H reports identify intronic and synonymous AIFM1 exon 7-region
    variants, including variants associated with exon 7 skipping.
  inheritance:
  - name: X-linked recessive inheritance
    inheritance_term:
      preferred_term: X-linked recessive inheritance
      term:
        id: HP:0001419
        label: X-linked recessive inheritance
    evidence:
    - reference: PMID:27102849
      reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The p.Asp237Gly segregated with disease as indicated by linkage analysis [maximum logarithm of odds score (LOD) score at theta 0 for the two families was 3.359].
      explanation: >-
        Segregation of an AIFM1 variant with disease supports the X-linked inherited genetic association.
  evidence:
  - reference: PMID:33439541
    reference_title: "AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1.
    explanation: >-
      This supports additional AIFM1 exon 7-region variants and exon 7 skipping as part of the disease's genetic mechanism.
diagnosis:
- name: Brain MRI
  description: >-
    Brain MRI can demonstrate diffuse cerebral hypomyelination in affected
    individuals.
  evidence:
  - reference: PMID:23239615
    reference_title: "A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 4 years of age, he was diagnosed as hypomyelination with skeletal abnormalities from clinical features, brain magnetic resonance imaging (MRI) and skeletal X-rays.
    explanation: >-
      The abstract identifies MRI and skeletal X-rays as part of the diagnostic workup.
- name: Skeletal X-ray
  description: >-
    Skeletal X-rays can demonstrate skeletal abnormalities compatible with
    spondylo-epi-metaphyseal dysplasia.
  evidence:
  - reference: PMID:23239615
    reference_title: "A case of cerebral hypomyelination with spondylo-epi-metaphyseal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 4 years of age, he was diagnosed as hypomyelination with skeletal abnormalities from clinical features, brain magnetic resonance imaging (MRI) and skeletal X-rays.
    explanation: >-
      The abstract identifies skeletal X-rays as part of the diagnostic workup for hypomyelination with skeletal abnormalities.
- name: AIFM1 molecular genetic testing
  description: >-
    Sequencing of AIFM1, including evaluation of exon 7-region variants and
    splice effects, can confirm the molecular diagnosis in the appropriate
    clinical context.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:27102849
    reference_title: "Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing performed in two subjects showed a single plausible candidate - the p.Asp237Gly variant in AIFM1 (chr. Xq26.1).
    explanation: >-
      Exome sequencing identified AIFM1 as the molecular diagnosis in affected subjects.
differential_diagnoses:
- name: Spondyloepiphyseal dysplasia, Kondo-Fu type
  description: >-
    MBTPS1-related spondyloepiphyseal dysplasia, Kondo-Fu type can be discussed
    with overlapping SEMD terminology, but Falcon deep research found it is a
    distinct autosomal recessive entity characterized by elevated plasma
    lysosomal enzymes and cataracts rather than the X-linked AIFM1
    hypomyelination syndrome modeled here.
  evidence:
  - reference: PMID:32420688
    reference_title: "Spondyloepimetaphyseal dysplasia with elevated plasma lysosomal enzymes caused by homozygous variant in MBTPS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report the second individual with this newly described autosomal recessive spondyloepiphyseal dysplasia (OMIM #618392), presenting severe growth retardation, cataract and dysmorphic features, mainly retromicrognathia.
    explanation: >-
      This supports Kondo-Fu/MBTPS1 disease as an autosomal recessive spondyloepiphyseal dysplasia with cataract and dysmorphic features, distinct from the AIFM1 X-linked hypomyelination syndrome.
datasets: []
📚

References & Deep Research

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 23 citations 2026-05-08T12:32:46.336847

1. Disease Information

1.1 Overview

SEMD-BT is an ultra-rare Mendelian skeletal dysplasia historically defined by radiographic involvement of the spine (spondylo-), epiphyses (epimetaphyseal/epiphyseal), and metaphyses, with short stature and variable extraskeletal features. In modern molecular literature, “Bieganski type” is most consistently tied to a severe X-linked disorder with hypomyelinating leukodystrophy/neurodegeneration and a skeletal dysplasia phenotype (AIFM1), while a separate autosomal recessive SEMD/SED phenotype with elevated plasma lysosomal enzymes is caused by MBTPS1. (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11, carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, kondo2018site1proteasedeficiency pages 1-2)

1.2 Key identifiers

  • MONDO: Open Targets lists “spondyloepimetaphyseal dysplasia, Bieganski type” as MONDO_0010275. URL: https://platform.opentargets.org/ (OpenTargets Search: spondyloepimetaphyseal dysplasia Bieganski type,spondyloepimetaphyseal dysplasia-MBTPS1)
  • OMIM:
  • For the AIFM1-linked X-linked entity, later sources cite SEMD-MR as MIM 300232. (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, temtamy2007geneticheterogeneityin pages 18-20)
  • For the MBTPS1-linked Kondo–Fu skeletal dysplasia entity, multiple sources cite MIM 618392. (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, liaqat2024acaseof pages 1-2)

ICD-10/ICD-11, MeSH, and Orphanet identifiers were not retrievable from the currently available evidence corpus in this run; therefore, they are not asserted here.

1.3 Common synonyms / alternative names (as used in sources)

  • AIFM1-associated: “X-linked spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H)”; “X-linked hypomyelination with spondylometaphyseal dysplasia”; “SEMD with neurodegeneration”; “SEMD-MR”. (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11)
  • MBTPS1-associated: “Spondyloepiphyseal dysplasia, Kondo–Fu type (SEDKF)”; “spondyloepimetaphyseal dysplasia with elevated plasma lysosomal enzymes”; “MBTPS1-related spondyloepiphyseal dysplasia”. (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, kondo2018site1proteasedeficiency pages 1-2, raggio2024exomesequencingreveals pages 1-2)

1.4 Evidence sources

Most information is from aggregated disease-level literature (case reports/series and reviews), not EHR-derived cohort studies. (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4, carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, kondo2018site1proteasedeficiency pages 1-2)

2. Etiology

2.1 Disease causal factors (genetic)

Two primary genetic etiologies appear in the literature under overlapping SEMD terminology:

(A) AIFM1-related X-linked SEMD with cerebral hypomyelination/neurodegeneration

  • Gene: AIFM1 (apoptosis-inducing factor mitochondria-associated 1). (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4)
  • Inheritance: X-linked recessive (male predominance, no male-to-male transmission). (temtamy2007geneticheterogeneityin pages 18-20)
  • Abstract quote (supporting definition and gene-region mechanism): “Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD‐H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy. Recently, SMD‐H has been associated with variants confined to a specific intra‐genic locus involving Exon 7…”. (American Journal of Medical Genetics Part A; Jan 2021; https://doi.org/10.1002/ajmg.a.62072) (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4)

(B) MBTPS1-related autosomal recessive SEMD/SED with elevated plasma lysosomal enzymes (SED Kondo–Fu type)

  • Gene: MBTPS1 (membrane bound transcription factor peptidase, site 1), encoding Site-1 protease (S1P). (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, kondo2018site1proteasedeficiency pages 1-2)
  • Inheritance: Autosomal recessive (biallelic loss-of-function / compound heterozygosity / homozygosity). (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, liaqat2024acaseof pages 1-2, raggio2024exomesequencingreveals pages 4-6)
  • Abstract quote (causal claim and key biochemical phenotype): “Here, we report a pediatric patient with an amorphic and a severely hypomorphic mutation in MBTPS1… a frequency of functional MBTPS1 transcripts of approximately 1%, a finding that is associated with skeletal dysplasia and elevated blood lysosomal enzymes.” (JCI Insight; Jul 2018; https://doi.org/10.1172/jci.insight.121596) (kondo2018site1proteasedeficiency pages 1-2)

2.2 Risk factors / protective factors / gene–environment interactions

For both entities, the available evidence supports monogenic causation and does not identify validated environmental risk factors, protective factors, or gene–environment interactions beyond standard Mendelian recurrence risks. (temtamy2007geneticheterogeneityin pages 18-20, kondo2018site1proteasedeficiency pages 1-2)

3. Phenotypes (clinical and radiographic)

3.1 AIFM1-associated X-linked SEMD with hypomyelination (SMD-H)

Phenotype types: developmental/neurologic signs, skeletal dysplasia, characteristic neuroimaging.

Key reported phenotypes (with suggested HPO terms): - Hypomyelinating leukodystrophy / delayed myelination (HP:0003432 Abnormal myelination; HP:0002188 Hypomyelination). (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4, temtamy2007geneticheterogeneityin pages 18-20) - Progressive neurodegeneration involving CNS/PNS (HP:0002344 Progressive neurologic deterioration; HP:0003324 Generalized hypotonia; HP:0001263 Global developmental delay). (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4) - Microcephaly (HP:0000252 Microcephaly) and intellectual disability (HP:0001249 Intellectual disability) noted in historical descriptions. (temtamy2007geneticheterogeneityin pages 18-20) - Skeletal dysplasia involving spine/metaphyses/epiphyses (HP:0002650 Spondyloepimetaphyseal dysplasia; HP:0000925 Abnormality of the vertebral column; HP:0002758 Abnormal metaphysis morphology; HP:0002657 Abnormal epiphysis morphology). (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11, temtamy2007geneticheterogeneityin pages 18-20) - Kyphoscoliosis / thoracolumbar deformity (HP:0002751 Kyphoscoliosis; HP:0005619 Thoracolumbar kyphosis) and joint contractures (HP:0001371 Flexion contracture). (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11, temtamy2007geneticheterogeneityin pages 18-20)

Temporal pattern: onset around infancy with progressive neurologic decline; skeletal findings may be more apparent later in childhood. (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4)

Radiographic and imaging descriptors (examples): “irregular, flared and cupped metaphyses with metaphyseal striations,” small irregular epiphyses, platyspondyly/hyperkyphosis, and brain MRI “diffuse supratentorial hypomyelination”. (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11)

3.2 MBTPS1-associated SEDKF / SEMD with elevated plasma lysosomal enzymes

Phenotype types: disproportionate growth failure, ophthalmologic findings, skeletal radiographic findings, and characteristic laboratory abnormalities.

Key phenotypes (with suggested HPO terms): - Severe short stature / growth retardation (HP:0004322 Short stature). (raggio2024exomesequencingreveals pages 1-2, carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, raggio2024exomesequencingreveals pages 2-4) - Early-onset cataracts (HP:0000518 Cataract). (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, liaqat2024acaseof pages 1-2, raggio2024exomesequencingreveals pages 2-4) - Spondyloepiphyseal/epimetaphyseal dysplasia on X-ray (HP:0002650 Spondyloepimetaphyseal dysplasia; HP:0000925 Abnormality of the vertebral column; HP:0002808 Kyphosis). (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, kondo2018site1proteasedeficiency pages 1-2, raggio2024exomesequencingreveals pages 4-6) - Low bone mineral density / osteopenia (HP:0004349 Low bone mineral density; HP:0000938 Osteopenia). (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, chen2023casereportrecombinant pages 4-6, raggio2024exomesequencingreveals pages 1-2) - Hernias (HP:0000023 Inguinal hernia; HP:0001537 Umbilical hernia). (chen2023casereportrecombinant pages 4-6, liaqat2024acaseof pages 1-2, raggio2024exomesequencingreveals pages 2-4) - Craniosynostosis (HP:0001363 Craniosynostosis) and epilepsy/seizures (HP:0001250 Seizures) in some cases. (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3) - Elevated plasma lysosomal enzymes with normal leukocyte enzyme activity (laboratory phenotype; map to LOINC/SNOMED locally). (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, carvalho2020spondyloepimetaphysealdysplasiawith pages 3-4, kondo2018site1proteasedeficiency pages 1-2)

Recent quantitative statistics (2024): A 2024 case report summarizing previous cases reported that “80% had low stature, 70% low weight, 80% had bilateral cataracts and 70% showed Spondyloepiphyseal dysplasia on X-rays.” (Diagnostics; Jan 2024; https://doi.org/10.3390/diagnostics14030313) (raggio2024exomesequencingreveals pages 1-2)

Example laboratory values (2020 case report): multiple plasma lysosomal enzymes were markedly elevated; e.g., total plasma beta-hexosaminidases 3,975 nmol/h/ml (reference 400–1,400); iduronate-2-sulfatase 1,080 nmol/4 h/ml (reference 167–475); alpha-N-acetylgalactosaminidase 648 nmol/17 h/ml (reference 60–240). (carvalho2020spondyloepimetaphysealdysplasiawith pages 3-4)

4. Genetic / Molecular Information

4.1 Causal genes

  • AIFM1 (X-linked disorder with hypomyelination + skeletal dysplasia). (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4)
  • MBTPS1 (autosomal recessive SEDKF/SEMD with elevated plasma lysosomal enzymes). (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, kondo2018site1proteasedeficiency pages 1-2)

4.2 Pathogenic variants and variant classes

AIFM1 entity (X-linked)

  • p.Asp237Gly in AIFM1 identified by WES as the single plausible candidate segregating with disease in two families; reported as novel and predicted pathogenic in silico. (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2)
  • Multiple families show variants clustered at/near AIFM1 intron 6/exon 7 boundary, with evidence supporting exon 7 skipping as a shared pathogenic mechanism. (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11)

MBTPS1 entity (autosomal recessive)

Primary literature variants include: - Homozygous nonsense: p.Trp983Ter (NM_003791.2 c.2948G>A; exon 22) (2020 case report). (carvalho2020spondyloepimetaphysealdysplasiawith pages 3-4) - Compound heterozygous (2024): c.2355delG p.Met785fs (frameshift, predicted NMD) and c.1094A>G p.Asp365Gly (missense). (raggio2024exomesequencingreveals pages 4-6) - Splice-altering synonymous: c.774C>T (p.A258=) causing exon 6 skipping (validated by transcript analysis/minigene assay; 2023). Abstract quote: “The transcript analysis in vivo exhibited that the synonymous variant c.774C > T caused exon 6 skipping. The minigene splice assay in vitro confirmed the alteration of MBTPS1 mRNA splicing…”. (Frontiers in Pediatrics; Jan 2023; https://doi.org/10.3389/fped.2022.1056141) (raggio2024exomesequencingreveals pages 1-2) - Compound heterozygous (2024): c.2255G>T p.(Gly752Val) and c.2831+5G>T with RNA-seq showing exon 21 skipping and predicted frameshift p.(Ser901fs28*) with nonsense-mediated decay. (liaqat2024acaseof pages 1-2) - First described S1P deficiency (2018): biallelic variants resulting in ~1% functional MBTPS1 transcripts. (kondo2018site1proteasedeficiency pages 1-2)

Population allele frequencies / ClinVar classifications were not directly retrievable from the current evidence set; therefore, ACMG category assertions are not made here.

4.3 Modifier genes / epigenetics / chromosomal abnormalities

No validated modifier genes, epigenetic signatures, or recurrent chromosomal abnormalities specific to SEMD-BT were identified in the retrieved primary literature in this run. (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, kondo2018site1proteasedeficiency pages 1-2)

5. Environmental Information

No non-genetic environmental contributors are established for these monogenic skeletal dysplasias in the retrieved evidence. (kondo2018site1proteasedeficiency pages 1-2)

6. Mechanism / Pathophysiology

6.1 MBTPS1 (Site-1 protease) deficiency: ER stress, collagen trafficking, and lysosomal enzyme mistargeting

Upstream trigger: biallelic MBTPS1 variants reduce functional S1P activity. (kondo2018site1proteasedeficiency pages 1-2)

Causal chain (proposed in primary literature): 1. Residual S1P activity may be sufficient for some systemic lipid homeostasis, but insufficient for ER and lysosomal functions in chondrocytes. (kondo2018site1proteasedeficiency pages 1-2) 2. Defective S1P impairs activation of the ER stress transducer BBF2H7, causing ER retention of collagen in chondrocytes. (kondo2018site1proteasedeficiency pages 1-2) 3. S1P deficiency partially impairs mannose-6-phosphate (M6P)-dependent delivery to lysosomes, resulting in abnormal secretion/elevation of lysosomal enzymes in blood. (kondo2018site1proteasedeficiency pages 1-2) 4. These combined defects contribute to chondrocyte apoptosis and lysosomal enzyme-mediated degradation of bone matrix, producing the skeletal dysplasia phenotype. (kondo2018site1proteasedeficiency pages 1-2)

Abstract quote (mechanistic): “The defective S1P function specifically impairs activation of the ER stress transducer BBF2H7, leading to ER retention of collagen in chondrocytes. S1P deficiency also causes abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate-dependent delivery to lysosomes.” (JCI Insight; Jul 2018; https://doi.org/10.1172/jci.insight.121596) (kondo2018site1proteasedeficiency pages 1-2)

Ontology suggestions: - GO Biological Process (examples): ER stress response; protein folding; collagen fibril organization; lysosomal transport; glycoprotein trafficking; chondrocyte apoptosis. - CL cell types (examples): chondrocyte (CL:0000138); osteoblast (CL:0000062). - UBERON (examples): cartilage (UBERON:0002416); growth plate cartilage (UBERON:0002597); vertebral column (UBERON:0001137).

6.2 AIFM1 exon 7-region variants: hypomyelination + skeletal dysplasia via tissue-specific AIFM1 effects

Primary literature supports a genotype–phenotype pattern in which variants near exon 7 (often splice-affecting) associate with the combined skeletal + hypomyelination syndrome, with evidence that exon 7 skipping is a common mechanism. (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11)

Mechanistic interpretation (from authors): exon 7 of AIFM1 is proposed to be “integral to its functional role in cells involved in cartilage and bone development and turnover,” and RNA evidence supports aberrant splicing with exon 7 loss. (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11)

Ontology suggestions: - GO BP: myelination; mitochondrial respiratory chain complex assembly; apoptosis regulation. - CL: oligodendrocyte (CL:0000128); chondrocyte (CL:0000138). - UBERON: cerebral white matter (UBERON:0004706); cartilage; vertebral column.

7. Anatomical Structures Affected

7.1 Organ/system level

  • Skeletal system (spine, epiphyses/metaphyses; kyphosis/kyphoscoliosis; osteopenia). (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11, carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, raggio2024exomesequencingreveals pages 4-6)
  • Central nervous system white matter (hypomyelination in AIFM1-associated entity). (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11)
  • Eye lens (cataracts in MBTPS1-associated entity). (raggio2024exomesequencingreveals pages 1-2, carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, liaqat2024acaseof pages 1-2)

7.2 Tissue/cell level

  • Growth plate cartilage and chondrocytes are highlighted as especially vulnerable in MBTPS1 deficiency. (kondo2018site1proteasedeficiency pages 1-2)

7.3 Subcellular level (MBTPS1 mechanism)

  • Endoplasmic reticulum (collagen retention) and Golgi/lysosome trafficking axis (M6P pathway) are implicated. (kondo2018site1proteasedeficiency pages 1-2)

8. Temporal Development

  • AIFM1 entity: infancy onset (~1 year) with progressive neurodegeneration; skeletal findings may be recognized as the child develops. (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4)
  • MBTPS1 entity: congenital/early-childhood onset with severe growth failure, early cataracts, and evolving spinal/epiphyseal findings; some later complications (sleep apnea, back pain, etc.) noted in case summaries. (raggio2024exomesequencingreveals pages 1-2, chen2023casereportrecombinant pages 4-6, raggio2024exomesequencingreveals pages 4-6)

9. Inheritance and Population

9.1 Inheritance

  • AIFM1-associated: X-linked recessive. (temtamy2007geneticheterogeneityin pages 18-20)
  • MBTPS1-associated: autosomal recessive. (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, liaqat2024acaseof pages 1-2, raggio2024exomesequencingreveals pages 4-6)

9.2 Epidemiology

Formal prevalence/incidence estimates were not identified in the retrieved evidence; available data are case-based. - A 2021 review-style case expansion states “To date 19 patients from 8 families have been reported” for SMD-H (AIFM1 exon 7–region). (American Journal of Medical Genetics Part A; Jan 2021; https://doi.org/10.1002/ajmg.a.62072) (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4) - A 2024 MBTPS1 case report states it is (to their knowledge) the 7th molecularly confirmed SEDKF case worldwide (2018–2023) and the 10th case with MBTPS1-related phenotypes. (Diagnostics; Jan 2024; https://doi.org/10.3390/diagnostics14030313) (raggio2024exomesequencingreveals pages 4-6)

10. Diagnostics

10.1 Clinical and imaging diagnosis

  • Skeletal survey / X-ray: used to identify spondyloepiphyseal/epimetaphyseal dysplasia, metaphyseal irregularity, vertebral body changes, osteopenia, and craniosynostosis-related skull changes (e.g., “copper-beaten skull”). (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11, carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, carvalho2020spondyloepimetaphysealdysplasiawith pages 3-4, raggio2024exomesequencingreveals pages 4-6)
  • Brain MRI: essential in suspected AIFM1-associated SMD-H, showing diffuse hypomyelination and reduced white matter volume. (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11)
  • Ophthalmologic exam: cataracts are common in MBTPS1-associated disease. (raggio2024exomesequencingreveals pages 1-2, carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, liaqat2024acaseof pages 1-2)

10.2 Laboratory biomarkers

  • Plasma lysosomal enzymes: a key clue for MBTPS1 deficiency; elevation in plasma with normal leukocyte enzyme activity is repeatedly described. (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, carvalho2020spondyloepimetaphysealdysplasiawith pages 3-4, kondo2018site1proteasedeficiency pages 1-2)

10.3 Genetic testing approach

  • Exome/genome sequencing is repeatedly used to diagnose both AIFM1- and MBTPS1-related disorders. (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2, kondo2018site1proteasedeficiency pages 1-2, raggio2024exomesequencingreveals pages 4-6)
  • RNA studies / splice assays can be required, since synonymous or intronic variants may act through exon skipping (AIFM1 exon 7; MBTPS1 exon 6 or exon 21). (edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 8-11, raggio2024exomesequencingreveals pages 1-2, liaqat2024acaseof pages 1-2)

10.4 Differential diagnosis

Differential considerations include other SEMD/SMD subtypes and lysosomal-storage-disorder-like phenocopies; an older SEMD radiologic review emphasizes distinguishing SEMD forms from Dyggve–Melchior–Clausen (DMC) by features such as the iliac crest “lacy” appearance, which was absent in the Bieganski-described neurocognitive SEMD form. (temtamy2007geneticheterogeneityin pages 18-20)

11. Outcomes / Prognosis

  • AIFM1 entity: primary literature describes progressive neurodegeneration with severe disability and death in adolescence in historical families (as summarized in later genetic work). (mierzewska2017spondyloepimetaphysealdysplasiawith pages 1-2)
  • MBTPS1 entity: outcomes appear variable; complications include severe growth failure, orthopedic morbidity (kyphosis, spinal changes), sleep apnea, seizures in some, and ectodermal findings in newer reports; robust survival statistics are not available due to limited case numbers. (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, liaqat2024acaseof pages 1-2, raggio2024exomesequencingreveals pages 4-6)

12. Treatment / Management

12.1 Disease-modifying / targeted therapy

No approved disease-modifying therapy was identified for either entity in the retrieved evidence.

12.2 Supportive and symptomatic management (real-world implementations)

  • Orthopedic monitoring and management for kyphosis/kyphoscoliosis, hip dysplasia, and osteopenia/low bone mineral density are implicit in reported care; specific surgical outcome series were not retrieved. (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3, raggio2024exomesequencingreveals pages 4-6)
  • Cataract surgery has been performed (e.g., congenital lamellar cataract surgically removed). (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3)
  • Sleep apnea management is reported as a clinical feature requiring recognition (MBTPS1 case). (raggio2024exomesequencingreveals pages 1-2)
  • Seizure management is required in cases with epilepsy. (carvalho2020spondyloepimetaphysealdysplasiawith pages 1-3)

12.3 Growth hormone (GH) therapy (reported application)

A 2023 case report describes recombinant human growth hormone (rhGH) treatment in MBTPS1-associated SEDKF, with the authors concluding: “Growth hormone therapy can repair growth retardation in patients with spondyloepiphyseal dysplasia, Kondo-Fu type; however, more evidence of such patient cases is required to support this hypothesis.” (Frontiers in Pediatrics; Feb 2023; https://doi.org/10.3389/fped.2023.1068718) (chen2023casereportrecombinant pages 4-6)

12.4 MAXO term suggestions (examples)

  • Cataract extraction (MAXO term for cataract surgery)
  • Treatment with recombinant human growth hormone (MAXO term for GH therapy)
  • Physical therapy / orthopedic surveillance
  • Antiseizure medication therapy

12.5 Clinical trials

A clinical trials registry search in this run did not yield clearly relevant interventional trials specifically for SEMD-BT/MBTPS1/AIFM1 skeletal dysplasia. (OpenTargets Search: spondyloepimetaphyseal dysplasia Bieganski type,spondyloepimetaphyseal dysplasia-MBTPS1)

13. Prevention

Primary prevention is not applicable for established Mendelian disorders, but genetic counseling and reproductive options (carrier testing in X-linked families; carrier testing and prenatal/preimplantation diagnosis in autosomal recessive MBTPS1 families) are the standard prevention framework; specific guidelines were not retrieved in the current evidence set. (temtamy2007geneticheterogeneityin pages 18-20, raggio2024exomesequencingreveals pages 4-6)

14. Other Species / Natural Disease

No naturally occurring veterinary analogs were identified in the retrieved evidence corpus.

15. Model Organisms

The retrieved primary mechanism paper emphasizes chondrocyte-specific vulnerability and includes experimental correction of variants and ER stress reduction to mitigate collagen-trafficking defects, implying utility of cellular models (patient-derived cells/chondrocytes) for mechanism and therapeutic screening. (kondo2018site1proteasedeficiency pages 1-2)

16. Recent developments and latest research (prioritize 2023–2024)

2023: Synonymous MBTPS1 variant proven pathogenic via splicing assays

A 2023 report provides direct functional evidence that a synonymous MBTPS1 variant (c.774C>T) is pathogenic by causing exon 6 skipping, validated in vivo and with a minigene assay, and notes partial restoration of exon inclusion with an antisense oligonucleotide in vitro. (Frontiers in Pediatrics; Jan 2023; https://doi.org/10.3389/fped.2022.1056141) (raggio2024exomesequencingreveals pages 1-2)

2024: Expanded MBTPS1 phenotype and variant spectrum

  • A 2024 diagnostics case report adds new compound heterozygous variants (c.2355delG p.Met785fs and c.1094A>G p.Asp365Gly) and provides cross-case feature frequencies (e.g., cataracts and SED on imaging). (Diagnostics; Jan 2024; https://doi.org/10.3390/diagnostics14030313) (raggio2024exomesequencingreveals pages 1-2, raggio2024exomesequencingreveals pages 4-6)
  • A 2024 AJMG-A report describes additional systemic/ectodermal features and uses RNA-seq to confirm exon skipping and predicted NMD for a splice variant (Dec 2024; https://doi.org/10.1002/ajmg.a.63499). (liaqat2024acaseof pages 1-2)

Expert perspective / authoritative synthesis

A key expert mechanistic statement from the 2018 JCI Insight paper is that these findings “define a new congenital human skeletal disorder” and “reveal that S1P is particularly required for skeletal development in humans.” (JCI Insight; Jul 2018; https://doi.org/10.1172/jci.insight.121596) (kondo2018site1proteasedeficiency pages 1-2)

Limitations of this report

  • Several requested identifiers (Orphanet, ICD-10/ICD-11, MeSH) and population allele frequency statistics (gnomAD) could not be confirmed from the retrievable evidence in this tool run; they are therefore not asserted.
  • Because the name “Bieganski type” is ambiguous across sources, a definitive single-entity KB entry should be anchored to one gene/OMIM/MONDO axis after curation; this report provides the evidence needed to make that disambiguation. (OpenTargets Search: spondyloepimetaphyseal dysplasia Bieganski type,spondyloepimetaphyseal dysplasia-MBTPS1, edgerley2021aifm1‐associatedx‐linkedspondylometaphyseal pages 1-4, raggio2024exomesequencingreveals pages 1-2, kondo2018site1proteasedeficiency pages 1-2)

References

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  10. (chen2023casereportrecombinant pages 4-6): Congli Chen, Jin Wu, and Ying Liu. Case report: recombinant human growth hormone therapy in a patient with spondyloepiphyseal dysplasia, kondo-fu type. Frontiers in Pediatrics, Feb 2023. URL: https://doi.org/10.3389/fped.2023.1068718, doi:10.3389/fped.2023.1068718. This article has 8 citations.

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