Motor Neuron Disorders (Motor Neuron Diseases)

name: Motor Neuron Disorders
display_name: Motor Neuron Disorders (Motor Neuron Diseases)
creation_date: "2026-06-26T00:00:00Z"
description: >-
  The motor neuron disorders are a clinically recognized group of
  neurodegenerative diseases unified by the selective degeneration of upper
  motor neurons (cortical Betz cells and the corticospinal/corticobulbar
  tracts), lower motor neurons (brainstem and spinal anterior horn cells), or
  both, with relative sparing of sensory and autonomic systems. The group spans
  the amyotrophic lateral sclerosis spectrum (combined upper and lower motor
  neuron disease), the pure upper-motor-neuron disorders (primary lateral
  sclerosis, hereditary spastic paraplegia), and the lower-motor-neuron /
  anterior-horn-cell disorders (spinal muscular atrophy, spinobulbar muscular
  atrophy, the distal hereditary motor neuronopathies). Members are kept as
  separate Disease entries because they differ in the predominant motor-neuron
  compartment (upper vs lower vs both), inheritance and causal gene, age of
  onset, and the presence of extra-motor features.
grouping_basis:
- SHARED_PHENOTYPE
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on a shared anatomical-pathological target — selective motor neuron
  degeneration — rather than on a single molecular mechanism, which is
  deliberately heterogeneous across the group (TDP-43 proteinopathy in ALS,
  SMN deficiency in SMA, polyglutamine androgen-receptor toxicity in Kennedy
  disease, axonal-transport and membrane-trafficking defects in the distal
  hereditary motor neuronopathies and hereditary spastic paraplegias). The
  members are lumped because they converge on the same vulnerable cell
  population and share a common differential-diagnostic and clinical-management
  frame (the upper- vs lower-motor-neuron examination, EMG, and respiratory and
  bulbar surveillance), but kept as separate entries because the upstream cause
  and the affected motor-neuron compartment differ. The criterion is NECESSARY
  (selective motor neuron degeneration is entailed by membership) rather than
  NECESSARY_AND_SUFFICIENT: motor neuron involvement alone does not make a
  disorder a primary motor neuron disease, since it also occurs secondarily in
  length-dependent axonal neuropathies (e.g. Charcot-Marie-Tooth disease),
  metabolic and structural myelopathies, and multisystem degenerations.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0020128
      label: motor neuron disorder
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      narrowMatch: this grouping is the curated clinical-syndrome subset of the
      broader MONDO motor neuron disorder class. MONDO:0020128 ("motor neuron
      disorder", which carries "motor neuron disease" as an exact synonym and
      subsumes the now-obsolete MONDO:0005270) is the current umbrella term;
      MONDO split the historical single class into hereditary
      (MONDO:0024257) and acquired (MONDO:0020129) branches, so no single
      narrower MONDO term captures the dismech clinical grouping that spans
      both. MONDO:0020128 includes entities beyond the dismech scope (e.g.
      facial-onset sensory and motor neuronopathy, animal motor neuron
      diseases), so its descendant set should not be treated as an exhaustive
      list of dismech curation gaps.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        MONDO lacks a precise current grouping term that is both clinical and
        scoped to human primary motor neuron disease across hereditary and
        acquired causes; MONDO:0020128 is the best broader alignment target.
membership_criteria:
- description: >-
    A motor neuron disorder is characterized by selective degeneration of
    motor neurons — upper motor neurons (Betz cells / corticospinal and
    corticobulbar tracts), lower motor neurons (brainstem and spinal anterior
    horn cells), or both — with relative sparing of sensory and autonomic
    systems. Every member exhibits at least one of these motor-neuron
    degeneration phenotypes.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    description: >-
      Degeneration of upper and/or lower motor neurons (the shared anatomical
      lesion of the group).
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: Abnormal upper motor neuron morphology/degeneration.
      phenotype_term:
        preferred_term: Abnormal upper motor neuron morphology
        term:
          id: HP:0002127
          label: Abnormal upper motor neuron morphology
    - criterion_predicate: HAS_PHENOTYPE
      description: Abnormal lower motor neuron morphology/degeneration.
      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
members:
- member: Amyotrophic Lateral Sclerosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The prototype combined upper- AND lower-motor-neuron disease: progressive
      degeneration of cortical Betz cells together with brainstem and spinal
      motor neurons, converging on TDP-43 proteinopathy in ~97% of cases.
      Predominantly sporadic; the commonest genetic cause is the C9orf72
      hexanucleotide repeat expansion. Distinguished from the pure UMN and pure
      LMN members by the obligate presence of both signs and its rapid,
      relentless course.
    gene:
      preferred_term: C9orf72
      term:
        id: hgnc:28337
        label: C9orf72
- member: Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The Western Pacific (Guam/Kii Peninsula) ALS variant in which combined
      motor neuron degeneration co-occurs with parkinsonism and dementia and a
      distinctive tau-predominant (with TDP-43) neurofibrillary pathology.
      Distinguished from classic ALS by the multisystem extra-motor involvement
      and a strong geographic/environmental (rather than monogenic) etiology.
- member: Primary Lateral Sclerosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A pure UPPER-motor-neuron disorder: progressive spasticity from
      corticospinal and corticobulbar degeneration without the clinical or
      electrophysiological lower-motor-neuron signs that define ALS.
      Distinguished by its much slower course and the diagnostic requirement
      that LMN involvement remain absent over years; a minority evolve toward
      ALS.
- member: Hereditary Spastic Paraplegia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A genetically heterogeneous group of inherited PURE (or complicated)
      upper-motor-neuron disorders in which the distal corticospinal axons
      undergo length-dependent "dying-back" degeneration, producing
      progressive lower-limb spasticity. SPAST (SPG4) is the commonest cause.
      Distinguished from PLS by its hereditary basis, earlier onset, and the
      length-dependent corticospinal (rather than global UMN) pattern.
    gene:
      preferred_term: SPAST
      term:
        id: hgnc:11233
        label: SPAST
- member: Hereditary Spastic Paraplegia 48
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      An autosomal recessive hereditary spastic paraplegia caused by AP5Z1
      (SPG48) variants disrupting the AP-5 adaptor complex and endolysosomal
      sorting, producing corticospinal-tract degeneration. Distinguished from
      SPAST-HSP by its recessive inheritance and the AP-5/autophagy-lysosomal
      mechanism.
    gene:
      preferred_term: AP5Z1
      term:
        id: hgnc:22197
        label: AP5Z1
- member: Spinal Muscular Atrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The prototype LOWER-motor-neuron / anterior-horn-cell disease: biallelic
      loss of SMN1 depletes survival motor neuron protein and causes selective
      spinal (and bulbar) motor neuron loss with no upper-motor-neuron signs.
      SMN2 copy number modifies severity. Distinguished by its recessive
      single-gene cause and its responsiveness to SMN-restoring therapy
      (nusinersen, risdiplam, onasemnogene abeparvovec).
    gene:
      preferred_term: SMN1
      term:
        id: hgnc:11117
        label: SMN1
- member: Spinal Muscular Atrophy-Progressive Myoclonic Epilepsy Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A distinct SMA caused by biallelic ASAH1 (acid ceramidase) deficiency in
      which lower-motor-neuron loss is combined with progressive myoclonic
      epilepsy — a phenotype outside the SMN spectrum. Distinguished from
      SMN-SMA by its lysosomal (sphingolipid) mechanism and the obligate
      epileptic component.
    gene:
      preferred_term: ASAH1
      term:
        id: hgnc:735
        label: ASAH1
- member: Kennedy Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      X-linked spinobulbar muscular atrophy caused by a CAG (polyglutamine)
      repeat expansion in the androgen receptor, producing a polyglutamine
      proteinopathy that selectively kills lower (bulbar and spinal) motor
      neurons, with androgen insensitivity (gynecomastia) and sensory
      involvement. Distinguished by its ligand-dependent polyQ mechanism, slow
      course, and endocrine features.
    gene:
      preferred_term: AR
      term:
        id: hgnc:644
        label: AR
- member: Distal Hereditary Motor Neuronopathy, Autosomal Dominant
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Inherited pure LOWER-motor-neuron disorders ("spinal CMT") in which
      length-dependent degeneration of distal motor axons causes distal wasting
      and weakness without sensory loss. The dominant forms include
      small-heat-shock-protein genes such as HSPB1. Distinguished from
      CMT2 by the absence of sensory involvement and from SMA by the
      length-dependent distal (rather than proximal) pattern.
    gene:
      preferred_term: HSPB1
      term:
        id: hgnc:5246
        label: HSPB1
- member: Distal Hereditary Motor Neuronopathy, Autosomal Recessive
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The recessive distal hereditary motor neuronopathies, including the
      IGHMBP2-related form (which at its severe end is SMARD1, spinal muscular
      atrophy with respiratory distress). Lower-motor-neuron degeneration with
      a distal/diaphragmatic distribution. Distinguished from the dominant
      dHMNs by inheritance and from SMN-SMA by gene and the
      respiratory/diaphragmatic predilection of the IGHMBP2 form.
    gene:
      preferred_term: IGHMBP2
      term:
        id: hgnc:5542
        label: IGHMBP2
- member: Progressive Muscular Atrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The pure LOWER-motor-neuron clinical variant of the ALS spectrum:
      progressive LMN degeneration without clinical upper-motor-neuron signs,
      sharing TDP-43 proteinopathy with ALS and frequently converting to
      clinically definite ALS over time. Distinguished from ALS by the (initial)
      absence of UMN signs and longer survival, and from the inherited LMN
      disorders by its adult sporadic onset. The TARDBP annotation below denotes
      the shared pathological protein (TDP-43 proteinopathy), not a causative
      mutation — PMA is overwhelmingly sporadic and TARDBP mutations account for
      only a small minority of cases.
    gene:
      preferred_term: TARDBP
      term:
        id: hgnc:11571
        label: TARDBP
- member: Progressive Bulbar Palsy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The BULBAR-onset variant of the ALS spectrum: degeneration of the lower
      brainstem (CN IX–XII) motor nuclei with corticobulbar (UMN) involvement,
      producing flaccid plus pseudobulbar dysarthria/dysphagia, tongue wasting
      and fasciculations, and emotional lability. Distinguished by its bulbar
      localization and high early aspiration/respiratory risk; most cases
      generalize to ALS (TDP-43 proteinopathy).
- member: Monomelic Amyotrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A benign, focal, usually self-limiting LOWER-motor-neuron disorder of
      young males driven not by a primary neurodegeneration but by a mechanical
      cause: repeated neck flexion displaces the cervical dural sac forward,
      compressing the lower cervical cord and producing ischemic anterior-horn
      injury with asymmetric distal upper-limb wasting. Distinguished from ALS
      by its focal, non-progressive course and flexion-myelopathy mechanism.
- member: Brown-Vialetto-Van Laere Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A TREATABLE inherited motor (and sensory/cranial) neuronopathy caused by
      autosomal recessive riboflavin-transporter (RFVT2/RFVT3) deficiency:
      impaired riboflavin uptake depletes FAD/FMN flavocofactors and produces
      mitochondrial flavoprotein dysfunction, degenerating cranial-nerve, motor,
      and sensory neurons with sensorineural deafness. Distinguished from the
      other members by its metabolic, vitamin-responsive mechanism — high-dose
      riboflavin halts/reverses progression.
    gene:
      preferred_term: SLC52A3
      term:
        id: hgnc:16187
        label: SLC52A3
- member: Madras Motor Neuron Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A geographically distinctive young-onset sporadic motor neuron disease of
      southern India: lower-motor-neuron and multiple lower-cranial-nerve
      (bulbar) degeneration combined with sensorineural hearing loss, with a
      comparatively benign course. Distinguished by its regional epidemiology,
      the prominent deafness, and an unknown etiology (negative
      riboflavin-transporter and C9ORF72 genetics distinguish it from
      Brown-Vialetto-Van Laere syndrome).
- member: Postpoliomyelitis Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      An ACQUIRED late motor neuron disorder: new progressive weakness, atrophy,
      and fatigue appearing decades after acute paralytic polio, attributed to
      distal degeneration of the enlarged, metabolically overloaded motor units
      created when surviving anterior-horn neurons reinnervated denervated fibers
      during recovery. Distinguished from the degenerative and inherited members
      by its post-infectious, motor-unit-overload mechanism (not poliovirus
      reactivation).
- member: Paralytic Poliomyelitis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      An ACQUIRED INFECTIOUS lower-motor-neuron disease: poliovirus enters via
      its CD155 receptor and lytically destroys anterior-horn (and brainstem)
      motor neurons, causing acute asymmetric flaccid paralysis with preserved
      sensation. Distinguished from the chronic degenerative members by its
      acute viral, vaccine-preventable etiology.
- member: Spinal Muscular Atrophy with Respiratory Distress Type 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      An autosomal recessive infantile LOWER-motor-neuron disease caused by
      IGHMBP2 (helicase) deficiency, with a characteristic DISTAL and
      DIAPHRAGMATIC predilection — early diaphragmatic palsy/respiratory failure
      is the hallmark, distinguishing it from SMN1-related SMA. Represents the
      severe infantile end of the IGHMBP2 lower-motor-neuron spectrum (the milder
      end being the autosomal recessive distal hereditary motor neuronopathy).
    gene:
      preferred_term: IGHMBP2
      term:
        id: hgnc:5542
        label: IGHMBP2
- member: Scapuloperoneal Spinal Muscular Atrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      An autosomal dominant LOWER-motor-neuron disorder caused by TRPV4
      gain-of-function: a dysregulated calcium-permeable cation channel drives
      calcium-mediated motor neuron/axon cytotoxicity in a scapuloperoneal
      (shoulder-girdle + peroneal) distribution, sometimes with vocal cord
      paralysis. Distinguished by its channelopathy mechanism and its place in
      the TRPV4 allelic spectrum (congenital distal SMA, CMT2C).
    gene:
      preferred_term: TRPV4
      term:
        id: hgnc:18083
        label: TRPV4
- member: X-Linked Infantile Spinal Muscular Atrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      An X-linked recessive infantile LOWER-motor-neuron disease caused by UBA1
      (E1 ubiquitin-activating enzyme) deficiency: impaired ubiquitin-proteasome
      proteostasis degenerates anterior-horn motor neurons, producing congenital
      hypotonia, areflexia, arthrogryposis, and fractures. Distinguished from
      SMN1-SMA by gene/inheritance and from adult X-linked Kennedy disease
      (androgen-receptor polyQ) by its distinct gene, infantile onset, and
      contracture/fracture phenotype.
    gene:
      preferred_term: UBA1
      term:
        id: hgnc:12469
        label: UBA1
- member: Konzo
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      An ACQUIRED TOXIC pure UPPER-motor-neuron disorder: high dietary
      cyanogenic-glucoside (linamarin) exposure from insufficiently processed
      bitter cassava, with low sulfur-amino-acid intake impairing cyanide
      detoxification, selectively injures the corticospinal tracts to produce
      abrupt, symmetric, permanent spastic paraparesis. The toxic
      upper-motor-neuron counterpart of lathyrism; distinguished from the
      inherited UMN members (HSP) by its epidemic dietary etiology.
notes: >-
  Worked example of a SHARED_PHENOTYPE grouping over an anatomically defined
  vulnerable cell population (the motor neuron) with deliberately heterogeneous
  upstream mechanisms. The criterion is NECESSARY (advisory audit of listed
  members) rather than NECESSARY_AND_SUFFICIENT, because secondary motor-neuron
  involvement in length-dependent neuropathies, myelopathies, and multisystem
  degenerations means motor-neuron degeneration is not sufficient to define
  membership. The membership spans the ALS spectrum (ALS, ALS-PDC, progressive
  muscular atrophy, progressive bulbar palsy), the pure upper-motor-neuron
  disorders (primary lateral sclerosis, hereditary spastic paraplegia, and the
  toxic upper-motor-neuron disorder konzo), the inherited lower-motor-neuron /
  anterior-horn disorders (spinal muscular atrophy, SMA-PME, SMARD1, X-linked
  infantile SMA, scapuloperoneal SMA, Kennedy disease, the distal hereditary
  motor neuronopathies), the riboflavin-responsive Brown-Vialetto-Van Laere
  syndrome, the regional Madras motor neuron disease, and the acquired
  poliomyelitis and postpoliomyelitis syndrome. The upper-motor-neuron arm
  overlaps the corticospinal degenerations; the TDP-43-driven members also
  appear in the TDP-43_Proteinopathies grouping, and the spinal CMT / dHMN
  members overlap the Charcot-Marie-Tooth_Diseases grouping.