Distal Hereditary Motor Neuropathies (dHMN / distal SMA)

name: Distal Hereditary Motor Neuropathies
display_name: Distal Hereditary Motor Neuropathies (dHMN / distal SMA)
creation_date: "2026-08-19T00:00:00Z"
description: >-
  A curated union of the dismech Disease entries that make up the distal
  hereditary motor neuropathies (dHMN; also called distal spinal muscular
  atrophy, dSMA, or "spinal CMT") — inherited disorders in which degeneration
  of the distal axons of lower motor neurons produces slowly progressive distal
  weakness and amyotrophy with little or no sensory involvement. The
  degeneration is usually length-dependent, though not invariably so: the
  TRPV4-related forms are scapuloperoneal. The family is defined clinically and
  electrophysiologically rather than molecularly: motor nerve conduction shows a
  motor axonal pattern with chronic neurogenic change on EMG, and sensory
  responses are preserved or only mildly abnormal, which is what separates dHMN
  from the sensorimotor axonal Charcot-Marie-Tooth neuropathies (CMT2) and from
  the proximal, SMN1-related spinal muscular atrophies. Around thirty causative
  genes are known across autosomal dominant, autosomal recessive, and X-linked
  branches, and they converge on a small number of motor-axon housekeeping
  processes (chaperone-mediated protein quality control, axonal transport,
  tRNA charging and RNA metabolism, endoplasmic-reticulum function, and cation
  channels/transporters) — yet the majority of patients remain genetically
  unsolved, so the group is still held together by its phenotype. Reported
  prevalence is approximately 2.1–2.3 per 100,000. Members are kept as separate
  Disease entries because they differ in inheritance, causal gene, age of onset,
  and the presence of respiratory, pyramidal, vocal-cord, or scapuloperoneal
  features.
grouping_basis:
- SHARED_PHENOTYPE
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on a shared clinical-electrophysiological lesion — inherited,
  length-dependent, predominantly motor degeneration of distal lower-motor-neuron
  axons — rather than on a single molecular mechanism, which is deliberately
  heterogeneous across the members (small heat-shock-protein and seipin
  proteostasis failure, dynactin axonal-transport failure, glycyl-tRNA-synthetase
  and IGHMBP2 helicase RNA-handling defects, TRPV4 calcium-channel
  gain of function). The members are lumped because they share a common
  diagnostic frame (pure-motor EMG/NCS pattern, the same differential against
  CMT2 and juvenile ALS, the same genetic-testing panel) and a convergent distal
  motor axonopathy, but kept as separate entries because MONDO itself splits the
  family on inheritance (MONDO:0015362 dominant, MONDO:0015363 recessive) and
  because the individual entries differ in causal gene, onset, and extra-motor
  features.

  Four boundary decisions are recorded deliberately. First, the criteria are
  NECESSARY rather than NECESSARY_AND_SUFFICIENT: distal lower-motor-neuron
  degeneration with distal weakness is entailed by membership, but it is not
  sufficient, since the same picture arises in the sensorimotor axonal
  neuropathies (CMT2), in distal myopathies, and in acquired lower-motor-neuron
  syndromes. Second, no negated sensory leaf is curated, even though "pure
  motor" is the phrase that names the group: many forms of dHMN have minor
  sensory abnormalities, and abnormal sensory conduction with abnormal sural
  nerve biopsy is a common finding in the IGHMBP2 disorders, so a NOT leaf on
  distal sensory impairment would report correctly curated members as
  contradictions rather than police the boundary.
  Third, Charcot-Marie-Tooth Disease Type 2 is intentionally NOT a member even
  though several genes (HSPB1, HSPB8, GARS1, TRPV4) are allelic across both:
  the dismech CMT2 entry is curated as a sensorimotor neuropathy, and admitting
  it would dissolve exactly the boundary this grouping exists to record. The
  allelic overlap is captured instead in the per-member differentiating
  mechanisms and in a curated discussion. Fourth, length-dependence is treated
  as typical rather than criterial: the TRPV4-related scapuloperoneal form is
  admitted despite a shoulder-girdle-involving distribution, because the
  literature places TRPV4 in a continuous allelic series with distal HMN, and
  because the criteria test for distal lower-motor-neuron degeneration with
  distal weakness rather than for a strictly length-dependent gradient.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018894
      label: distal hereditary motor neuropathy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      exactMatch: this grouping denotes the same concept as the MONDO distal
      hereditary motor neuropathy class, whose exact synonyms ("dHMN", "dSMA",
      "distal spinal muscular atrophy") are the same names this grouping is
      curated under. The mapping relates the two concepts, not their
      enumerated extensions: the grouping is implemented as an explicit curated
      union of current dismech Disease entries rather than as an automatic
      MONDO subtree closure, so its member list is the currently curated subset
      and is expected to grow. Two of the three MONDO children —
      MONDO:0015362 (autosomal dominant) and MONDO:0015363 (autosomal
      recessive) — are curated Disease entries and are listed as members; the
      third, MONDO:0010338 (X-linked distal spinal muscular atrophy type 3,
      ATP7A), is curated as a has_subtypes subtype of Menkes_Disease rather
      than as a standalone entry, so it is not listed here.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        The member list also includes two entries that sit inside the clinical
        dHMN spectrum but are placed differently in MONDO: Spinal Muscular
        Atrophy with Respiratory Distress Type 1 (MONDO:0011436), which is a
        MONDO descendant of the recessive child MONDO:0015363, and
        Scapuloperoneal Spinal Muscular Atrophy (MONDO:0008408), which MONDO
        classifies under spinal muscular atrophy rather than under
        MONDO:0018894 despite TRPV4 being a recognized dHMN gene. The MONDO
        descendant set of MONDO:0018894 should therefore not be treated as an
        exhaustive list of dismech dHMN entries, nor this member list as an
        exhaustive reading of the MONDO subtree.
references:
- reference: PMID:22028385
  title: "The distal hereditary motor neuropathies."
- reference: PMID:33210134
  title: "The expanding genetic landscape of hereditary motor neuropathies."
- reference: PMID:38702287
  title: "Distal hereditary motor neuropathies."
- reference: PMID:36445400
  title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
membership_criteria:
- description: >-
    Every member exhibits degeneration or dysfunction of lower motor neurons and
    their distal motor axons — recorded as abnormal lower motor neuron
    morphology, motor neuron atrophy, or a motor axonal neuropathy. This is the
    shared anatomical lesion of the group and the reason the family is treated
    as a motor neuronopathy rather than as a myopathy or a sensorimotor
    neuropathy.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    description: >-
      Lower-motor-neuron / distal motor axon degeneration, in any of its curated
      phenotypic forms.
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: Abnormal lower motor neuron morphology.
      phenotype_term:
        preferred_term: Abnormal lower motor neuron morphology
        term:
          id: HP:0002366
          label: Abnormal lower motor neuron morphology
    - criterion_predicate: HAS_PHENOTYPE
      description: Motor neuron atrophy.
      phenotype_term:
        preferred_term: Motor neuron atrophy
        term:
          id: HP:0007373
          label: Motor neuron atrophy
    - criterion_predicate: HAS_PHENOTYPE
      description: Motor axonal neuropathy on nerve conduction studies.
      phenotype_term:
        preferred_term: Motor axonal neuropathy
        term:
          id: HP:0007002
          label: Motor axonal neuropathy
  evidence:
  - reference: PMID:33210134
    reference_title: "The expanding genetic landscape of hereditary motor neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary motor neuropathies are clinically and genetically diverse disorders characterized by length-dependent axonal degeneration of lower motor neurons."
    explanation: >-
      States the shared anatomical lesion — length-dependent axonal degeneration
      of lower motor neurons — that this NECESSARY criterion tests for.
  - reference: PMID:22028385
    reference_title: "The distal hereditary motor neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The distal hereditary motor neuropathies (dHMN) comprise a heterogeneous group of diseases that share the common feature of a length-dependent predominantly motor neuropathy."
    explanation: >-
      The defining review states the grouping boundary explicitly: heterogeneous
      diseases sharing one common feature, a length-dependent predominantly
      motor neuropathy.
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hereditary motor neuropathies (HMN) were first defined as a group of neuromuscular disorders characterized by lower motor neuron dysfunction, slowly progressive length-dependent distal muscle weakness and atrophy, without sensory involvement."
    explanation: >-
      Gives the historical definition of the family in the three components this
      grouping's two NECESSARY criteria test for: lower motor neuron
      dysfunction, distal weakness and atrophy, and sensory sparing.
- description: >-
    Every member exhibits distal limb weakness and/or distal amyotrophy — the
    clinical expression of the distal motor axonopathy, and the feature that
    names the group ("distal" hereditary motor neuropathy) and separates it from
    the proximal SMN1-related spinal muscular atrophies.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    description: Distal weakness or distal muscle wasting.
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: Distal muscle weakness.
      phenotype_term:
        preferred_term: Distal muscle weakness
        term:
          id: HP:0002460
          label: Distal muscle weakness
    - criterion_predicate: HAS_PHENOTYPE
      description: Distal amyotrophy.
      phenotype_term:
        preferred_term: Distal amyotrophy
        term:
          id: HP:0003693
          label: Distal amyotrophy
  evidence:
  - reference: PMID:38702287
    reference_title: "Distal hereditary motor neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous hereditary disorders characterized by a slowly progressive distal pure motor neuropathy."
    explanation: >-
      A recent review of the family defines dHMN by a slowly progressive distal
      pure motor neuropathy — the distal weakness and wasting this criterion
      tests for, and the reason "distal" is in the name of the group.
members:
- member: Distal Hereditary Motor Neuronopathy, Autosomal Dominant
  member_type: DISEASE
  disease_term:
    preferred_term: autosomal dominant distal hereditary motor neuropathy
    term:
      id: MONDO:0015362
      label: neuronopathy, distal hereditary motor, autosomal dominant
  differentiating_mechanisms:
  - description: >-
      The dominantly inherited branch: a single heterozygous variant in a
      motor-axon housekeeping gene is sufficient to cause disease, and the
      curated course is a slowly progressive, usually foot-drop-first distal
      weakness with onset later than in the recessive branch. The causal genes
      cluster on
      chaperone-mediated protein quality control (HSPB1, HSPB8), the
      endoplasmic-reticulum protein seipin (BSCL2), tRNA charging (GARS1),
      dynactin-dependent axonal transport (DCTN1), presynaptic choline transport
      (SLC5A7), and the TRPV4 cation channel. Distinguished from the recessive
      branch by inheritance and by the later, milder onset, and from CMT2 by the
      absence of clinically significant sensory loss even where the same gene
      (HSPB1, GARS1) causes both.
    gene:
      preferred_term: HSPB1
      term:
        id: hgnc:5246
        label: HSPB1
  evidence:
  - reference: PMID:38702287
    reference_title: "Distal hereditary motor neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mainly with the HSPB1, HSPB8, BICD2 and TRPV4 genes of AD-inherited transmission"
    explanation: >-
      Names the dominantly transmitted dHMN genes, which is the gene set that
      distinguishes this member from its recessive sibling.
  - reference: PMID:22028385
    reference_title: "The distal hereditary motor neuropathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The causative genes have implicated proteins with diverse functions such as protein misfolding (HSPB1, HSPB8, BSCL2), RNA metabolism (IGHMBP2, SETX, GARS), axonal transport (HSPB1, DYNC1H1, DCTN1) and cation-channel dysfunction (ATP7A and TRPV4) in motor-nerve disease."
    explanation: >-
      Gives the functional classification of the dHMN gene set as a whole
      (protein misfolding, RNA metabolism, axonal transport, cation channels),
      the scheme this member's description uses to organize its dominant genes.
      Note the quoted sentence spans all three inheritance branches and does not
      itself assign genes to the dominant one.
  - reference: PMID:33210134
    reference_title: "The expanding genetic landscape of hereditary motor neuropathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "this genetic landscape spans a discrete number of key biological processes within the peripheral nerve"
    explanation: >-
      States the convergence claim itself — that the heterogeneous gene set acts
      on a small, bounded set of peripheral-nerve processes.
- member: Distal Hereditary Motor Neuronopathy, Autosomal Recessive
  member_type: DISEASE
  disease_term:
    preferred_term: autosomal recessive distal hereditary motor neuropathy
    term:
      id: MONDO:0015363
      label: neuronopathy, distal hereditary motor, autosomal recessive
  differentiating_mechanisms:
  - description: >-
      The recessive branch: biallelic variants in IGHMBP2 (HMNR1, whose severe
      infantile end is curated separately as the SMARD1 member below), SIGMAR1
      (HMNR2, allelic to juvenile ALS16), PLEKHG5 (HMNR4), RTN2, and SORD.
      Onset is generally earlier than in the dominant branch and pyramidal
      (upper-motor-neuron) signs and respiratory involvement are commoner, which
      is what makes juvenile ALS and hereditary spastic paraplegia the principal
      differential. Distinguished from the dominant branch by inheritance and
      gene set; the SORD form matters clinically because it is potentially
      treatable.
    gene:
      preferred_term: IGHMBP2
      term:
        id: hgnc:5542
        label: IGHMBP2
  evidence:
  - reference: PMID:38702287
    reference_title: "Distal hereditary motor neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SORD gene of AR transmission which seems relatively frequent and potentially curable"
    explanation: >-
      Supports the clinical significance this member's description attaches to
      the SORD form: comparatively frequent among the recessive causes, and
      potentially treatable.
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their cumulative estimated prevalence is 2.14/100 000 and, to date, around 30 causative genes have been identified with autosomal dominant, recessive,and X-linked inheritance."
    explanation: >-
      Establishes that the family is conventionally partitioned on inheritance
      into dominant, recessive, and X-linked branches — the axis on which this
      member and its dominant sibling are split — and gives the prevalence
      figure cited in the grouping description.
- member: Spinal Muscular Atrophy with Respiratory Distress Type 1
  member_type: DISEASE
  disease_term:
    preferred_term: spinal muscular atrophy with respiratory distress type 1
    term:
      id: MONDO:0011436
      label: autosomal recessive distal spinal muscular atrophy 1
  differentiating_mechanisms:
  - description: >-
      The severe infantile extreme of the IGHMBP2 lower-motor-neuron spectrum,
      curated separately because its presentation inverts the usual dHMN
      ordering: diaphragmatic palsy with eventration and respiratory failure
      appears first, in the first months of life, and distal limb weakness
      follows. The molecular lesion is the same IGHMBP2 ATP-dependent
      helicase deficiency that at its milder end produces the recessive dHMN
      entry (and CMT2S), so the two are one allelic continuum rather than two
      mechanisms. Distinguished from the other members by its neonatal onset and
      diaphragmatic-first distribution, and from SMN1-related SMA by gene and by
      the distal (rather than proximal) limb pattern.
    gene:
      preferred_term: IGHMBP2
      term:
        id: hgnc:5542
        label: IGHMBP2
  evidence:
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive variants in the gene encoding for immunoglobulin μ-binding protein 2 (IGHMBP2) are a well established cause of SMARD1."
    explanation: >-
      Places SMARD1 inside the IGHMBP2 hereditary motor neuronopathy spectrum
      reviewed here, which is what justifies listing it alongside the recessive
      dHMN entry rather than only under the spinal muscular atrophies.
- member: Scapuloperoneal Spinal Muscular Atrophy
  member_type: DISEASE
  disease_term:
    preferred_term: scapuloperoneal spinal muscular atrophy, autosomal dominant
    term:
      id: MONDO:0008408
      label: scapuloperoneal spinal muscular atrophy, autosomal dominant
  differentiating_mechanisms:
  - description: >-
      The TRPV4 channelopathy arm: dominant gain-of-function variants in the
      calcium-permeable TRPV4 cation channel raise intracellular calcium and
      drive calcium-mediated motor-neuron and axon cytotoxicity, producing one
      phenotype in a continuous allelic series
      that also contains TRPV4-related distal HMN, congenital distal SMA with
      arthrogryposis, and CMT2C. Distinguished from the other members by mechanism (a
      channelopathy rather than a proteostasis, transport, or RNA-handling
      defect) and by distribution: weakness is scapuloperoneal, with
      shoulder-girdle involvement and frequent vocal-cord paralysis, rather than
      purely length-dependent. Listed as a member on the strength of that
      allelic and clinical continuity with dHMN, even though MONDO places
      MONDO:0008408 under spinal muscular atrophy rather than under
      MONDO:0018894.
    gene:
      preferred_term: TRPV4
      term:
        id: hgnc:18083
        label: TRPV4
  evidence:
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dominantly inherited pathogenic variants in the TRPV4 gene cause different clinical phenotypes spanning from HMN7 to scapulo-peroneal SMA"
    explanation: >-
      States the allelic continuity between the TRPV4-related distal hereditary
      motor neuronopathy phenotype and scapuloperoneal SMA at the TRPV4 locus,
      which is the basis for including this entry in the dHMN grouping. Note
      the quoted source writes "HMN7" for the TRPV4 phenotype, whereas dismech
      follows the assignment of dHMN7A to SLC5A7 and dHMN7B to DCTN1; the
      numbering is not reconciled across sources, so the allelic claim is
      carried on the gene rather than on the type number.
- member: Distal Hereditary Motor Neuronopathy Type 9
  member_type: DISEASE
  disease_term:
    preferred_term: distal hereditary motor neuronopathy type 9
    term:
      id: MONDO:0060585
      label: neuronopathy, distal hereditary motor, type 9
  differentiating_mechanisms:
  - description: >-
      The aminoacyl-tRNA synthetase arm, curated with an explicitly two-armed
      mechanism. Heterozygous WARS1 missense variants act as a dominant
      negative on the canonical aminoacylation activity of cytoplasmic
      tryptophanyl-tRNA synthetase, compromising protein synthesis and cell
      viability; the same recurrent p.His257Arg allele separately potentiates a
      non-canonical activity, enhancing the interaction of the angiostatic
      TrpRS fragment with vascular endothelial-cadherin. Which arm produces the
      observed neurite degeneration is unresolved and is carried on the disease
      entry as an open knowledge gap rather than settled in favour of the more
      familiar loss-of-charging story. That unresolved canonical/non-canonical
      split is what distinguishes this member from its siblings, whose curated
      mechanisms are single-armed: chaperone-mediated proteostasis in the
      dominant branch, IGHMBP2-dependent RNA handling in SMARD1, and TRPV4
      calcium channelopathy in scapuloperoneal SMA. WARS1 sits alongside GARS1,
      AARS1, HARS1 and YARS1 in the wider set of ARS genes whose heterozygous
      variants cause dominant peripheral neuropathy, and shares with them the
      puzzle of a housekeeping enzyme producing damage restricted to the
      longest motor axons. Kept distinct from the biallelic WARS1
      neurodevelopmental syndrome (MONDO:0957218), which shares the gene but
      not the phenotype, the inheritance pattern, or the mechanism.
    gene:
      preferred_term: WARS1
      term:
        id: hgnc:12729
        label: WARS1
  evidence:
  - reference: PMID:28369220
    reference_title: "A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability."
    explanation: >-
      The canonical arm of the two-armed mechanism that distinguishes this
      member: a dominant-negative effect on tRNA charging rather than the
      proteostasis, transport, or channelopathy defects curated for the other
      members.
  - reference: PMID:28369220
    reference_title: "A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin."
    explanation: >-
      The non-canonical arm. The same allele both loses canonical charging
      activity and gains angiostatic activity, which is why this member's
      mechanism is curated as two-armed and unresolved.
- member: Sorbitol Dehydrogenase Deficiency
  member_type: DISEASE
  disease_term:
    preferred_term: sorbitol dehydrogenase deficiency with peripheral neuropathy
    term:
      id: MONDO:0030055
      label: neuronopathy, distal hereditary motor, autosomal recessive 8
  differentiating_mechanisms:
  - description: >-
      The metabolic arm, and the only member whose lesion is an enzyme block in
      intermediary metabolism rather than a defect in a neuronal housekeeping
      process. Biallelic loss of function in SORD removes the second enzyme of
      the polyol pathway, so sorbitol produced by aldose reductase cannot be
      oxidised to fructose and accumulates in cells, serum, CSF and peripheral
      nerve. That distinguishes it from the proteostasis defects of the dominant
      branch, the IGHMBP2 RNA-handling defect of SMARD1, the TRPV4
      channelopathy of scapuloperoneal SMA, and the tRNA-charging defect of
      dHMN9: nothing about the injured protein is neuron-specific, and the
      selectivity for long motor axons is unexplained rather than attributable
      to the substrate. Two consequences follow that no other member shares.
      First, the disease has a direct biochemical readout - fasting serum
      sorbitol runs about two orders of magnitude above control - so it can be
      diagnosed, and variants of uncertain significance adjudicated, without
      resolving the genotype, which matters because the SORD2P pseudogene makes
      short-read sequencing unreliable. Second, the block is approachable from
      upstream: inhibiting aldose reductase reduces flux into sorbitol instead of
      replacing the missing enzyme, which is the rationale for the govorestat
      programme and has no counterpart among the other members. The entry also
      straddles the group boundary - roughly two-thirds of patients are labelled
      CMT2 and one-third dHMN on the same allele spectrum - and is kept here
      because MONDO indexes it under the recessive dHMN branch.
    gene:
      preferred_term: SORD
      term:
        id: hgnc:11184
        label: SORD
  evidence:
  - reference: PMID:32367058
    reference_title: "Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy."
    explanation: >-
      Names the metabolic step whose loss defines this member, and which none of
      the other members share.
  - reference: PMID:32367058
    reference_title: "Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes."
    explanation: >-
      The upstream substrate-reduction strategy that is unique to this member
      among the dHMN entries.
discussions:
- discussion_id: dhmn_terminology_reflects_phenotype_not_substrate
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is "distal hereditary motor neuropathy" a mechanistically meaningful
    grouping, or a phenotypic convenience label that will dissolve as the
    genetics are resolved?
  rationale: >-
    This grouping is drawn on a clinical-electrophysiological phenotype, not on
    a shared molecular mechanism, and at least one recent review argues that the
    conventional dHMN / distal SMA vocabulary oversimplifies pathophysiology
    because it does not track a biological substrate. The counter-argument is
    that the label still does real clinical work — it selects a genetic-testing
    panel and a differential diagnosis — and that the alternative proposals
    reorganize rather than abolish the group. The grouping is retained with
    SHARED_PHENOTYPE listed first in grouping_basis to make the dependency on
    phenotype explicit rather than implied.
  evidence:
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "we acknowledge that the terminology commonly used (e.g. HMN, dHMN, distal SMA) may oversimplify pathophysiology as it does not necessarily reflect a biological substrate or clinical phenotype"
    explanation: >-
      Directly states the objection to the conventional terminology on which
      this grouping's boundary is drawn.
- discussion_id: dhmn_pure_motor_boundary_is_not_absolute
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    How should the "pure motor" boundary against CMT2 be curated, given that
    sensory abnormalities are common in genetically confirmed dHMN?
  rationale: >-
    The clinical definition of dHMN is a pure motor neuropathy, and that is what
    separates it from the axonal sensorimotor CMT2 neuropathies. But minor
    sensory abnormalities occur in many forms, and abnormal sensory conduction
    velocities with pathological sural nerve biopsies are a common finding in
    the IGHMBP2 disorders — so the boundary is a matter of degree.
    This is why no negated sensory criterion is curated here: a NOT leaf on
    distal sensory impairment would report correctly curated members (notably
    Spinal Muscular Atrophy with Respiratory Distress Type 1, which curates
    HP:0000763 Sensory neuropathy) as contradictions of the grouping they
    genuinely belong to. The boundary is therefore recorded in prose and audited
    by a curator, not enforced by the criteria evaluator.
  evidence:
  - reference: PMID:22028385
    reference_title: "The distal hereditary motor neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many forms of dHMN have minor sensory abnormalities"
    explanation: >-
      Establishes that sensory abnormality does not exclude a disorder from the
      dHMN family, which is the reason a negated sensory criterion is not used.
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The common finding of abnormal sensory conduction velocities and pathological sural nerve biopsies (reduction of the larger myelinated fibres along different stages of axonal degeneration and atrophy) is in contrast with the definition of a pure motor neuronopathy."
    explanation: >-
      Says in terms that in the IGHMBP2 disorders the common finding of abnormal
      sensory conduction and abnormal sural nerve biopsy contradicts the
      definition of a pure motor neuronopathy — which is why a negated sensory
      criterion would misfire on this grouping's SMARD1 member.
- discussion_id: dhmn_missing_heritability
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What accounts for the missing heritability of dHMN — roughly two-thirds of
    clinically definite cases have no molecular diagnosis despite around thirty
    known genes?
  rationale: >-
    The diagnostic yield in a pure hereditary motor neuropathy phenotype is only
    about a third, far below that achieved in Charcot-Marie-Tooth disease. Until
    that gap closes, the grouping cannot be re-drawn on molecular lines: the
    phenotype is doing the classification work because for most patients there
    is no genotype to classify on. Candidate explanations include genes not yet
    associated with the phenotype, non-coding and structural variation, and
    repeat expansions that standard exome pipelines miss.
  proposed_experiments:
  - experiment_id: dhmn_genome_long_read_exome_negative
    name: Genome and long-read sequencing of exome-negative dHMN cohorts
    description: >-
      Apply short-read genome and long-read sequencing to clinically definite,
      exome-negative dHMN cohorts to capture non-coding regulatory variants,
      structural variants, and repeat expansions inaccessible to exome capture,
      and quantify the incremental diagnostic yield over the current ~32.5%.
  evidence:
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the diagnostic yield in patients with a pure HMN phenotype is still ∼32.5%, at latest estimate"
    explanation: >-
      Quantifies the gap: despite around thirty known genes, only about a third
      of patients with a pure hereditary motor neuropathy phenotype receive a
      molecular diagnosis.
  - reference: PMID:36445400
    reference_title: "Early onset hereditary neuronopathies: an update on non-5q motor neuron diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "more than 60% of patients with HMN remain genetically uncharacterized"
    explanation: >-
      States the size of the gap from the other direction: despite
      next-generation sequencing, the majority of patients have no molecular
      diagnosis.
  - reference: PMID:33210134
    reference_title: "The expanding genetic landscape of hereditary motor neuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there is considerable missing heritability compared to other inherited neuropathies such as Charcot-Marie-Tooth disease"
    explanation: >-
      States the missing-heritability gap and benchmarks it against CMT, where
      molecular diagnosis is far more often achieved.
- discussion_id: dhmn_module_conformance_backfill
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Should Spinal Muscular Atrophy with Respiratory Distress Type 1 and
    Scapuloperoneal Spinal Muscular Atrophy declare conforms_to against
    peripheral_axonal_degeneration, as the two parent dHMN entries already do?
  rationale: >-
    The two dHMN parent entries each declare
    "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
    on their length-dependent axonopathy node, which makes the shared mechanism
    machine-checkable. The two spectrum members added here do not, so a
    CONFORMS_TO_MODULE criterion cannot yet be curated on this grouping without
    reporting them as contradictions. The fix belongs in those two disorder
    entries, not here; once both declare conformance, a third NECESSARY criteria
    block asserting module conformance could be added to make the mechanistic
    (as opposed to phenotypic) half of grouping_basis auditable.
notes: >-
  Worked example of a SHARED_PHENOTYPE grouping whose members are the curated
  subset of a MONDO family class, in the case where both of the class's curated
  children already exist as Disease entries. The grouping deliberately adds
  nosology rather than mechanism: the conserved distal motor axonopathy the
  members share is already modeled once, in the kb/modules/
  peripheral_axonal_degeneration module, which both parent entries conform to at
  its "Distal Axonal Degeneration and Demyelination" node. What that module
  cannot say — because it is a disease-agnostic final common pathway shared with
  diabetic, toxic, chemotherapy-induced, and inflammatory neuropathy — is which
  diseases constitute the dHMN family, why they are grouped, where the boundary
  against CMT2 and against proximal SMA falls, and what distinguishes each
  member from its siblings. That is what this entry records.

  Overlaps with two existing groupings by design: Motor_Neuron_Disorders (which
  lists the two parent dHMN entries, SMARD1, and Scapuloperoneal SMA among its
  much broader membership spanning the ALS spectrum and the upper-motor-neuron
  disorders) and Charcot-Marie-Tooth_Diseases (which shares causal genes but
  not membership, since CMT2 is curated as a sensorimotor neuropathy).

  The X-linked branch: MONDO:0010338 (X-linked distal spinal muscular atrophy
  type 3) is the third MONDO child of MONDO:0018894 and IS already curated — as
  a has_subtypes entry ("ATP7A-related distal motor neuropathy") on
  Menkes_Disease, the mildest point of the ATP7A allelic spectrum — but not as a
  standalone Disease, so it has no Disease.name for members[].member to resolve
  to and is deliberately not listed above. Promoting it to a standalone entry,
  and then adding it here, is the natural way to complete the family; that is a
  scoping decision about the ATP7A spectrum and belongs in its own issue rather
  than in this grouping.

  Other recognized dHMN genes with no standalone dismech entry include DNAJB2,
  BICD2, DYNC1H1, REEP1, and VRK1; ClinGen has gene-disease validity
  assertions keyed directly on MONDO:0018894 for BSCL2 (Definitive), SETX
  (Definitive), FBXO38 (Moderate), and WARS1 (Limited). WARS1 is no longer in
  that first list: it is curated as the standalone Distal Hereditary Motor
  Neuronopathy Type 9 entry (MONDO:0060585) and is listed in members[] above.