Dystrophinopathies (DMD-Related Disorders)

name: Dystrophinopathies
display_name: Dystrophinopathies (DMD-Related Disorders)
creation_date: "2026-10-01T00:00:00Z"
description: >-
  The dystrophinopathies are the disorders caused by pathogenic variants in the
  X-linked DMD gene, which encodes dystrophin, the cytoskeletal protein that links
  F-actin to the dystrophin-glycoprotein complex at the sarcolemma of skeletal and
  cardiac muscle. They form one allelic spectrum whose clinical form is set by how
  much functional dystrophin survives and in which tissue. Duchenne muscular
  dystrophy is the severe end, with essentially absent dystrophin. Becker
  muscular dystrophy is the milder skeletal form, with reduced or internally
  deleted but partly functional dystrophin. X-linked dilated cardiomyopathy is
  the cardiac-selective form, in which dystrophin is lost from the ventricular
  myocardium while skeletal muscle is largely spared. Dilated cardiomyopathy is
  common to all three, and heterozygous carrier females are at risk of
  cardiomyopathy across the spectrum.
grouping_basis:
- SHARED_MECHANISM
- SHARED_GENE_FAMILY
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped as the allelic series of a single gene. Every member is caused by
  pathogenic variants in DMD and every member's primary pathology is loss of
  dystrophin function in striated muscle; the members are kept as separate
  Disease entries because they differ in onset, rate of progression, the tissue
  that bears the deficit, prognosis, and therapy (exon-skipping antisense
  oligonucleotides and micro-dystrophin gene therapy are developed and approved
  for Duchenne, while cardiac-selective disease is managed as dilated
  cardiomyopathy, up to heart transplantation). The grouping deliberately
  follows the GeneReviews "dystrophinopathies" scope, which includes
  DMD-associated dilated cardiomyopathy, rather than the narrower MONDO class
  DMD-related muscular dystrophy (MONDO:0700285), which covers only the
  skeletal-muscle forms; X-linked dilated cardiomyopathy shares the gene, the
  protein and the dystrophin-glycoprotein-complex mechanism and differs only in
  which tissue loses dystrophin. The DMD-gene criterion is NECESSARY rather than
  NECESSARY_AND_SUFFICIENT because a contiguous Xp21 deletion that includes DMD
  together with neighbouring genes would carry DMD without being a
  dystrophinopathy as its primary identity.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0700285
      label: DMD-related muscular dystrophy
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      broadMatch: this grouping contains the MONDO class. MONDO:0700285 is the
      DMD-gene muscular dystrophy class, whose asserted subclasses are Duchenne
      muscular dystrophy (MONDO:0010679), Becker muscular dystrophy
      (MONDO:0010311) and, below Becker, muscular dystrophy, pseudohypertrophic,
      with Internalized capillaries (MONDO:0008034). This grouping adds X-linked
      dilated cardiomyopathy (dilated cardiomyopathy 3B, MONDO:0010542), which
      MONDO places under familial dilated cardiomyopathy rather than under
      MONDO:0700285, so the grouping is broader than the class and exactMatch or
      narrowMatch would be false.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Duchenne and Becker muscular dystrophy members sit inside MONDO:0700285;
        X-linked dilated cardiomyopathy does not, which is expected under
        broadMatch.
  - term:
      id: MONDO:0016147
      label: neuromuscular disease caused by qualitative or quantitative defects of dystrophin
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      closeMatch: MONDO:0016147 is the MONDO import of the Orphanet group
      Orphanet:207085 and is the closest MONDO concept to "dystrophinopathy" by
      label and intent. It is not used as an exact match because MONDO's
      asserted subclasses of it are only dilated cardiomyopathy 3B
      (MONDO:0010542) and isolated asymptomatic elevation of creatine
      phosphokinase (MONDO:0016103); Duchenne and Becker muscular dystrophy are
      not placed under it, so an exactMatch would report two of the three
      members as outside the class.
    consistency:
    - reference: MONDO
      consistent: INCONSISTENT
      notes: >-
        Duchenne muscular dystrophy (MONDO:0010679) and Becker muscular
        dystrophy (MONDO:0010311) are not descendants of MONDO:0016147 even
        though the class is labelled as dystrophin-defect disease. This looks
        like a MONDO classification gap rather than a scope difference and is a
        candidate for a MONDO request.
membership_criteria:
- description: >-
    A member is a disorder caused by pathogenic variants in DMD, the dystrophin
    gene, with loss or reduction of dystrophin function in skeletal and/or
    cardiac muscle as its primary pathology.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_GENE
    description: Causal gene DMD.
    gene:
      preferred_term: DMD
      term:
        id: hgnc:2928
        label: DMD
  evidence:
  - reference: PMID:20301298
    reference_title: Dystrophinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The dystrophinopathies cover a spectrum of X-linked muscle disease ranging
      from mild to severe that includes Duchenne muscular dystrophy, Becker
      muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM).
    explanation: >-
      GeneReviews defines the dystrophinopathy spectrum as exactly the three
      members listed here, which is the scope this grouping adopts.
  - reference: PMID:20301298
    reference_title: Dystrophinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      by identification of a hemizygous pathogenic variant in DMD on molecular
      genetic testing in a male and of a heterozygous pathogenic variant in DMD
      on molecular genetic testing in a female
    explanation: >-
      The diagnosis of any dystrophinopathy rests on a pathogenic DMD variant,
      supporting the DMD causal-gene criterion.
members:
- member: Duchenne Muscular Dystrophy
  member_type: DISEASE
  disease_term:
    preferred_term: Duchenne muscular dystrophy
    term:
      id: MONDO:0010679
      label: Duchenne muscular dystrophy
  differentiating_mechanisms:
  - description: >-
      The severe, dystrophin-absent form. Variants that disrupt the DMD reading
      frame (out-of-frame deletions and duplications, nonsense variants) produce
      prematurely truncated, unstable dystrophin, so skeletal and cardiac muscle
      contain essentially no functional protein. The resulting sarcolemmal
      fragility gives early-childhood onset, loss of ambulation by about age 12
      and near-universal cardiomyopathy in adulthood. Because the defect is a
      reading-frame break, Duchenne is the member targeted by exon-skipping
      antisense oligonucleotides, which restore the frame to yield an internally
      deleted, Becker-like dystrophin.
    gene:
      preferred_term: DMD
      term:
        id: hgnc:2928
        label: DMD
    evidence:
    - reference: PMID:16770791
      reference_title: >-
        Entries in the Leiden Duchenne muscular dystrophy mutation database: an
        overview of mutation types and paradoxical cases that confirm the
        reading-frame rule.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In Duchenne patients, mutations induce a shift in the reading frame
        leading to prematurely truncated, dysfunctional dystrophins.
      explanation: >-
        States the reading-frame-disrupting, truncated-dystrophin mechanism that
        separates Duchenne from Becker muscular dystrophy.
    - reference: PMID:2674948
      reference_title: >-
        Dystrophin diagnosis: comparison of dystrophin abnormalities by
        immunofluorescence and immunoblot analyses.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        all Duchenne muscular dystrophy patient muscle contained no detectable
        dystrophin, Becker muscular dystrophy patient muscle had clearly abnormal
        dystrophin
      explanation: >-
        Muscle biopsy data distinguishing absent dystrophin in Duchenne from
        present but abnormal dystrophin in Becker.
- member: Becker Muscular Dystrophy
  member_type: DISEASE
  disease_term:
    preferred_term: Becker muscular dystrophy
    term:
      id: MONDO:0010311
      label: Becker muscular dystrophy
  differentiating_mechanisms:
  - description: >-
      The milder skeletal form, with reduced or internally deleted but partly
      functional dystrophin. Most variants are in-frame deletions or
      duplications that preserve the reading frame, so an internally shortened
      protein retaining its actin-binding and dystrophin-glycoprotein-complex
      binding ends is made. Onset is later and progression slower than in
      Duchenne, but dilated cardiomyopathy is the main cause of death and can be
      severe despite mild skeletal weakness. The reading-frame rule predicts the
      phenotype rather than defining it: a minority of Becker patients carry
      out-of-frame or nonsense variants.
    gene:
      preferred_term: DMD
      term:
        id: hgnc:2928
        label: DMD
    evidence:
    - reference: PMID:16770791
      reference_title: >-
        Entries in the Leiden Duchenne muscular dystrophy mutation database: an
        overview of mutation types and paradoxical cases that confirm the
        reading-frame rule.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In Becker patients, in-frame mutations allow the synthesis of internally
        deleted, but largely functional dystrophins.
      explanation: >-
        States the in-frame, partially functional dystrophin mechanism that
        distinguishes Becker from Duchenne muscular dystrophy.
    - reference: PMID:2491009
      reference_title: >-
        The molecular basis for Duchenne versus Becker muscular dystrophy:
        correlation of severity with type of deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The correlation between phenotype and type of deletion mutation is in
        agreement with the "reading frame" theory in 92% of cases
      explanation: >-
        Quantifies how well the reading-frame rule separates the Duchenne and
        Becker phenotypes in deletion patients, and that it is not absolute.
    - reference: PMID:39499670
      reference_title: >-
        Natural history of Becker muscular dystrophy: DMD gene mutations predict
        clinical severity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ten per cent of patients carried out-of-frame mutations, 4% nonsense
        mutations and 86% in-frame deletions/duplications.
      explanation: >-
        Shows that in-frame variants predominate in Becker muscular dystrophy
        but that out-of-frame and nonsense variants also occur, so the frame
        rule is predictive rather than diagnostic.
  notes: >-
    MONDO places muscular dystrophy, pseudohypertrophic, with Internalized
    capillaries (MONDO:0008034, OMIM:159050) as a subclass of Becker muscular
    dystrophy. It is not listed as a separate member; see the grouping notes.
- member: X-linked Dilated Cardiomyopathy
  member_type: DISEASE
  disease_term:
    preferred_term: X-linked dilated cardiomyopathy
    term:
      id: MONDO:0010542
      label: dilated cardiomyopathy 3B
  differentiating_mechanisms:
  - description: >-
      The cardiac-selective form. The paradigmatic lesion removes the DMD
      muscle (M) promoter and first exon, abolishing the muscle dystrophin
      isoform. Skeletal muscle compensates by up-regulating the brain (B)
      isoform from an intact downstream promoter, but the B isoform is not
      expressed in human ventricular myocardium, so dystrophin is lost where it
      matters for the heart. The result is rapidly progressive dilated
      cardiomyopathy in young men with little or no skeletal myopathy, and a
      later, milder cardiomyopathy in carrier females.
    gene:
      preferred_term: DMD
      term:
        id: hgnc:2928
        label: DMD
    evidence:
    - reference: PMID:22455600
      reference_title: >-
        The absence of dystrophin brain isoform expression in healthy human heart
        ventricles explains the pathogenesis of 5' X-linked dilated
        cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        the B isoform is well expressed in heart but confined to the atria. Since
        the B isoform can functionally replace the M isoform in the skeletal
        muscle, its expression in the heart could potentially exert the same
        rescue function.
      explanation: >-
        The paper's own conclusion on the isoform-compensation mechanism that
        confines dystrophin loss to the heart and separates this member from the
        skeletal dystrophinopathies: the B isoform rescues skeletal muscle but is
        absent from the ventricles.
    - reference: PMID:26066469
      reference_title: >-
        X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of
        Dystrophinopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        X-linked dilated cardiomyopathy (XLDCM) is a distinct phenotype of
        dystrophinopathy characterized by preferential cardiac involvement
        without any overt skeletal myopathy.
      explanation: >-
        Establishes X-linked dilated cardiomyopathy as a dystrophinopathy and
        names the cardiac-selective phenotype that differentiates it.
discussions:
- discussion_id: dystrophinopathy_curation_gaps
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Which further DMD-related conditions should be curated before they can be
    listed as members?
  rationale: >-
    Two MONDO classes in this space have no DisMech entry. Muscular dystrophy,
    pseudohypertrophic, with Internalized capillaries (MONDO:0008034,
    OMIM:159050) is asserted in MONDO as a subclass of Becker muscular dystrophy
    and carries no MONDO definition; whether it is a distinct entity or a
    historical description within the Becker spectrum needs the primary report
    before it is curated, and until then it is treated as covered by the Becker
    member rather than as a separate member. Isolated asymptomatic elevation of
    creatine phosphokinase (MONDO:0016103), the mild end of the GeneReviews
    spectrum, sits under MONDO:0016147 and could become a member if curated as
    a DMD-related entry. Manifesting female carriers are described in the
    member entries rather than as a separate disease.
notes: >-
  Created to resolve the curation stub for DMD-related muscular dystrophy
  (MONDO:0700285). That MONDO class is a grouping of the skeletal-muscle
  dystrophinopathies rather than a single disease, and both of its curated
  descendants already have Disease entries, so it is modelled here as a
  Grouping rather than as a new Disease entry. No member entry for
  MONDO:0008034 was created.