Scapuloperoneal Spinal Muscular Atrophy

Mendelian MONDO:0008408 Pathograph 7 Show in embeddings browser Motor Neuron Disease Neuromuscular Disease

Scapuloperoneal spinal muscular atrophy (SPSMA; Stark-Kaeser type) is a rare autosomal dominant lower-motor-neuron disorder caused by heterozygous (typically gain-of-function) missense variants in TRPV4, a calcium-permeable cation channel of the transient receptor potential vanilloid subfamily. Anterior-horn cell and motor-axon degeneration produces a characteristic scapuloperoneal distribution of weakness and wasting — shoulder-girdle and scapular (scapular winging) involvement together with peroneal/distal lower-limb weakness and foot drop — with areflexia and relative sensory sparing in the SMA form. Onset ranges from congenital (sometimes with arthrogryposis and skeletal dysplasia) to adult; additional features include vocal cord paralysis, laryngeal and respiratory involvement, and scoliosis. SPSMA lies within an allelic TRPV4 neuromuscular spectrum that also includes congenital distal spinal muscular atrophy and hereditary motor and sensory neuropathy type IIC / Charcot-Marie-Tooth disease type 2C (CMT2C), with which it overlaps clinically. The proposed mechanism is altered/increased channel activity of mutant TRPV4 with dysregulated calcium influx that is cytotoxic to motor neurons; in mouse knock-in models the toxicity is non-cell-autonomous, acting through endothelial cells to disrupt the blood-spinal cord barrier. The phenotype is predominantly motor (anterior horn) with relative sensory sparing in the SMA presentation.

Ask OpenScientist

Ask a research question about Scapuloperoneal Spinal Muscular Atrophy. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

4
Pathophys.
10
Phenotypes
7
Pathograph
1
Genes
3
Medical Actions
3
Differentials
7
References
🏷

Classifications

Harrison's Chapter
NEUROLOGIC
⚙

Pathophysiology

4
TRPV4 Channel Gain-of-Function
Heterozygous missense substitutions in TRPV4 — most clustering in the intracellular N-terminal ankyrin-repeat domain (e.g., R269H, R315W, R316C, R232C, R316H) — produce a gain of channel function. Patch-clamp studies show mutant channels carry much larger whole-cell currents and a higher open probability than wild-type, establishing increased constitutive calcium channel activity rather than loss of function as the core molecular defect.
TRPV4 hgnc:18083
Calcium ion transmembrane transport GO:0070588 ↑ INCREASED
Calcium channel activity (constitutive) GO:0005262 ↑ INCREASED
Downstream
Dysregulated Calcium Influx and Cytotoxicity Increased constitutive channel activity raises intracellular calcium influx to cytotoxic levels.
Show evidence (3 references)
PMID:21454511 SUPPORT In Vitro
"the three previously reported TRPV4 mutant channels have a physiological localization and display an increased calcium channel activity, leading to increased cytotoxicity in three different cell types."
Establishes increased (constitutive) calcium channel activity of mutant TRPV4 as the molecular defect.
PMID:21454511 SUPPORT In Vitro
"Single channel recordings showed that the mutant channels have higher open probability, due to a modification of gating, and no change in single-channel conductance."
Higher open probability of the mutant channel demonstrates the gain-of-function gating change.
PMID:20037587 SUPPORT In Vitro
"Functional analysis revealed that increased calcium channel activity is a distinct property of both SPSMA- and CMT2C-causing mutant proteins."
Shows the SPSMA-causing mutant protein shares the increased calcium channel activity property.
Dysregulated Calcium Influx and Cytotoxicity
The gain-of-function channel drives excessive calcium ion influx and raises intracellular calcium, linking the TRPV4 mutation to altered calcium homeostasis. The resulting hypercalcemic state is cytotoxic; in heterologous cells expressing mutant TRPV4, cell death is reversible by the TRPV channel antagonist ruthenium red, implicating calcium overload as the toxic effector.
motor neuron CL:0000100
Calcium ion transmembrane transport (influx) GO:0070588 ↑ INCREASED Intracellular calcium ion homeostasis GO:0006874 ⚠ ABNORMAL
Downstream
Lower Motor Neuron and Motor Axon Degeneration Sustained calcium overload is cytotoxic to lower motor neurons and their axons, producing motor-neuron loss and motor axonopathy.
Show evidence (3 references)
PMID:21288981 SUPPORT In Vitro
"Cells transfected with R232C and R316H displayed increased intracellular Ca(2+) levels and reversible cell death by the TRPV channel antagonist, ruthenium red."
Mutant TRPV4 raises intracellular calcium and causes cell death reversible by channel blockade.
PMID:21288981 SUPPORT In Vitro
"Reversible hypercalcemic gain-of-function of mutant TRPV4 instead of loss-of-function appears to be pathologically important."
Identifies hypercalcemic gain-of-function as the pathologically important cytotoxic mechanism.
PMID:20037587 SUPPORT In Vitro
"Our findings link mutations in TRPV4 to altered calcium homeostasis and peripheral neuropathies, implying a pathogenic mechanism"
Connects TRPV4 mutation to altered calcium homeostasis as the pathogenic mechanism.
Lower Motor Neuron and Motor Axon Degeneration
Calcium-mediated cytotoxicity drives degeneration of anterior-horn lower motor neurons and their motor axons, the substrate of the spinal muscular atrophy phenotype. In knock-in mouse models carrying disease mutations (R269C, R232C), the degeneration is regional and the motor-neuron loss is non-cell-autonomous — driven by mutant channel activity in neural vascular endothelial cells with focal blood-spinal cord barrier breakdown — and is rescued by a TRPV4 antagonist.
motor neuron CL:0000100
Calcium ion import (cytotoxic) GO:0070509 ↑ INCREASED
Downstream
Scapuloperoneal Denervation Pattern Chronic neurogenic denervation of shoulder-girdle and peroneal muscles produces the characteristic scapuloperoneal distribution of weakness and wasting.
Show evidence (3 references)
PMID:38776392 SUPPORT Model Organism
"TRPV4 mutant mice exhibited weakness, early lethality, and regional motor neuron loss."
Knock-in mouse models recapitulate weakness and regional motor neuron loss.
PMID:38776392 SUPPORT Model Organism
"mutant TRPV4 channels can drive motor neuron degeneration in a non-cell autonomous manner by precipitating focal breakdown of the BSCB."
Demonstrates non-cell-autonomous motor neuron degeneration via blood-spinal cord barrier breakdown.
PMID:20037588 SUPPORT Human Clinical
"Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system."
Frames SPSMA within the lower-motor-neuron spinal muscular atrophy / hereditary motor neuropathy group.
Scapuloperoneal Denervation Pattern
Topographically selective denervation produces the scapuloperoneal phenotype — progressive atrophy and weakness of the shoulder-girdle/scapular muscles (scapular winging) and the peroneal/distal lower-limb muscles (foot drop) — with areflexia and relative sensory sparing. Additional features include vocal cord paralysis, scoliosis, and, in congenital-onset cases, arthrogryposis and skeletal dysplasia.
motor neuron CL:0000100
Show evidence (2 references)
PMID:26948711 SUPPORT Human Clinical
"Scapuloperoneal spinal muscular atrophy (SPSMA) is a rare autosomal dominant disorder caused by heterozygous mutations in the transient receptor potential cation channel (TRPV4) gene, characterized by progressive scapuloperoneal atrophy and weakness."
Defines the scapuloperoneal atrophy/weakness distribution of SPSMA.
PMID:26948711 SUPPORT Human Clinical
"Additional features, such as vocal cord paralysis, scoliosis and/or arthrogryposis, are likely to occur."
Documents the additional vocal cord, scoliosis, and arthrogryposis features of SPSMA.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Scapuloperoneal Spinal Muscular Atrophy 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

10
Musculoskeletal 3
Skeletal muscle atrophy Skeletal muscle atrophy HP:0003202
Show evidence (1 reference)
PMID:26948711 SUPPORT Human Clinical
"characterized by progressive scapuloperoneal atrophy and weakness"
Documents the progressive muscle atrophy of SPSMA.
Scoliosis Scoliosis HP:0002650
Show evidence (1 reference)
PMID:26948711 SUPPORT Human Clinical
"Additional features, such as vocal cord paralysis, scoliosis and/or arthrogryposis, are likely to occur."
Scoliosis is a recognized additional feature of SPSMA.
Abnormality of the skeletal system Abnormality of the skeletal system HP:0000924
Show evidence (1 reference)
PMID:22526352 SUPPORT Human Clinical
"In another child with congenital dSMA, in this case associated with bone abnormalities, we detected a previously reported mutation (p.R232C)."
Congenital TRPV4 distal SMA can be associated with bone abnormalities.
Other 7
Scapular winging Scapular winging HP:0003691
Show evidence (1 reference)
PMID:26948711 SUPPORT Human Clinical
"characterized by progressive scapuloperoneal atrophy and weakness"
Scapuloperoneal atrophy and weakness produces the scapular winging of SPSMA.
Upper limb muscle weakness Upper limb muscle weakness HP:0003484
Show evidence (1 reference)
PMID:26948711 SUPPORT Human Clinical
"characterized by progressive scapuloperoneal atrophy and weakness"
The scapulo- component of the scapuloperoneal pattern is upper-limb/shoulder-girdle weakness.
Foot drop Foot dorsiflexor weakness HP:0009027
Show evidence (1 reference)
PMID:26948711 SUPPORT Human Clinical
"characterized by progressive scapuloperoneal atrophy and weakness"
The peroneal component of the scapuloperoneal pattern manifests as ankle dorsiflexor weakness / foot drop.
Distal lower limb muscle weakness Distal lower limb muscle weakness HP:0009053
Show evidence (1 reference)
PMID:22526352 SUPPORT Human Clinical
"The recent identification of mutations in the gene encoding transient receptor potential vanilloid 4 (TRPV4) in distal spinal muscular atrophy (dSMA)"
TRPV4 causes a distal SMA phenotype with distal lower-limb weakness.
Vocal cord paralysis Vocal cord paralysis HP:0001605
Show evidence (2 references)
PMID:26948711 SUPPORT Human Clinical
"Additional features, such as vocal cord paralysis, scoliosis and/or arthrogryposis, are likely to occur."
Vocal cord paralysis is a recognized additional feature of SPSMA.
PMID:22526352 SUPPORT Human Clinical
"In a girl with dSMA and vocal cord paralysis, we detected a new variant (p.P97R)"
TRPV4-related distal SMA presents with vocal cord paralysis.
Arthrogryposis multiplex congenita Arthrogryposis multiplex congenita HP:0002804
Show evidence (1 reference)
PMID:26948711 SUPPORT Human Clinical
"Additional features, such as vocal cord paralysis, scoliosis and/or arthrogryposis, are likely to occur."
Arthrogryposis is a recognized additional feature, prominent in congenital-onset cases.
EMG neuropathic changes EMG: neuropathic changes HP:0003445
Show evidence (1 reference)
PMID:26948711 SUPPORT Human Clinical
"The disorder should be considered in scapuloperoneal syndromes with autosomal dominant inheritance and a neurogenic pattern."
SPSMA shows a neurogenic (neuropathic) electrophysiological pattern.
🧬

Genetic Associations

1
TRPV4
Gene: TRPV4 hgnc:18083
Autosomal Dominant
Show evidence (3 references)
PMID:20037588 SUPPORT Human Clinical
"we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families."
Establishes heterozygous ankyrin-domain TRPV4 mutations as the cause of SPSMA and the allelic spectrum.
PMID:20037587 SUPPORT Human Clinical
"SPSMA and CMT2C are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 4 (TRPV4)."
Establishes SPSMA and CMT2C as allelic TRPV4 disorders.
PMID:26948711 SUPPORT Human Clinical
"We report the first Italian family with SPSMA, harboring the c.806G>A mutation in TRPV4 gene (p. R269H)."
Provides a representative pathogenic TRPV4 variant (R269H) segregating in an SPSMA family.
💊

Medical Actions

3
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Counseling for autosomal dominant recurrence risk (50% to offspring), variable/age-dependent expressivity, and predictive/cascade testing once a pathogenic TRPV4 variant is identified.
Physical Therapy and Orthotic Support
Action: physical therapy MAXO:0000011
Supportive rehabilitation including physical therapy and ankle-foot orthoses to manage peroneal weakness, foot drop, and gait, plus scapular stabilization for shoulder-girdle weakness.
Target Phenotypes: Foot drop HP:0009027
Supportive and Multidisciplinary Care
Action: supportive care MAXO:0000950
No disease-modifying therapy is established; management is supportive and multidisciplinary, including orthopedic management of scoliosis and foot deformity, laryngeal/ENT assessment for vocal cord paralysis, and respiratory monitoring. TRPV4 channel antagonists rescue motor phenotypes in cellular and mouse models and are an investigational therapeutic direction.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Scapuloperoneal Spinal Muscular Atrophy:

Facioscapulohumeral muscular dystrophy (FSHD)
Overlapping Features FSHD produces overlapping scapular winging and scapuloperoneal weakness but is a myopathy with facial involvement and a myopathic EMG/biopsy, contrasting with the neurogenic pattern of SPSMA.
Charcot-Marie-Tooth disease type 2C (HMSN2C)
Overlapping Features The allelic TRPV4 disorder CMT2C is an axonal sensorimotor neuropathy with vocal cord and diaphragmatic involvement; SPSMA is the more purely motor, scapuloperoneal-predominant phenotype with relative sensory sparing.
Scapuloperoneal myopathy
Overlapping Features Myopathic scapuloperoneal syndromes (e.g., desminopathy, FHL1-related) share the scapuloperoneal distribution but show myopathic rather than neurogenic electrophysiology and muscle histology.
{ }

Source YAML

click to show 
name: Scapuloperoneal Spinal Muscular Atrophy
creation_date: "2026-06-26T00:00:00Z"
category: Mendelian
description: >
  Scapuloperoneal spinal muscular atrophy (SPSMA; Stark-Kaeser type) is a rare
  autosomal dominant lower-motor-neuron disorder caused by heterozygous
  (typically gain-of-function) missense variants in TRPV4, a calcium-permeable
  cation channel of the transient receptor potential vanilloid subfamily.
  Anterior-horn cell and motor-axon degeneration produces a characteristic
  scapuloperoneal distribution of weakness and wasting — shoulder-girdle and
  scapular (scapular winging) involvement together with peroneal/distal lower-limb
  weakness and foot drop — with areflexia and relative sensory sparing in the SMA
  form. Onset ranges from congenital (sometimes with arthrogryposis and skeletal
  dysplasia) to adult; additional features include vocal cord paralysis, laryngeal
  and respiratory involvement, and scoliosis. SPSMA lies within an allelic TRPV4
  neuromuscular spectrum that also includes congenital distal spinal muscular
  atrophy and hereditary motor and sensory neuropathy type IIC / Charcot-Marie-Tooth
  disease type 2C (CMT2C), with which it overlaps clinically. The proposed mechanism
  is altered/increased channel activity of mutant TRPV4 with dysregulated calcium
  influx that is cytotoxic to motor neurons; in mouse knock-in models the toxicity
  is non-cell-autonomous, acting through endothelial cells to disrupt the
  blood-spinal cord barrier. The phenotype is predominantly motor (anterior horn)
  with relative sensory sparing in the SMA presentation.
disease_term:
  preferred_term: scapuloperoneal spinal muscular atrophy, autosomal dominant
  term:
    id: MONDO:0008408
    label: scapuloperoneal spinal muscular atrophy, autosomal dominant
parents:
- Motor Neuron Disease
- Neuromuscular Disease
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
references:
- reference: PMID:20037588
  title: "Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C."
- reference: PMID:20037587
  title: "Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4."
- reference: PMID:21454511
  title: "Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies."
- reference: PMID:21288981
  title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
- reference: PMID:38776392
  title: "Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice."
- reference: PMID:26948711
  title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
- reference: PMID:22526352
  title: "TRPV4 mutations in children with congenital distal spinal muscular atrophy."
external_assertions:
- name: OMIM SPSMA (TRPV4)
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:181405
  description: OMIM phenotype entry for scapuloperoneal spinal muscular atrophy, autosomal dominant (TRPV4-related).
pathophysiology:
- name: TRPV4 Channel Gain-of-Function
  description: >
    Heterozygous missense substitutions in TRPV4 — most clustering in the
    intracellular N-terminal ankyrin-repeat domain (e.g., R269H, R315W, R316C,
    R232C, R316H) — produce a gain of channel function. Patch-clamp studies show
    mutant channels carry much larger whole-cell currents and a higher open
    probability than wild-type, establishing increased constitutive calcium
    channel activity rather than loss of function as the core molecular defect.
  genes:
  - preferred_term: TRPV4
    term:
      id: hgnc:18083
      label: TRPV4
  molecular_functions:
  - preferred_term: Calcium channel activity (constitutive)
    term:
      id: GO:0005262
      label: calcium channel activity
    modifier: INCREASED
  biological_processes:
  - preferred_term: Calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: INCREASED
  evidence:
  - reference: PMID:21454511
    reference_title: "Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the three previously reported TRPV4 mutant channels have a physiological localization and display an increased calcium channel activity, leading to increased cytotoxicity in three different cell types."
    explanation: Establishes increased (constitutive) calcium channel activity of mutant TRPV4 as the molecular defect.
  - reference: PMID:21454511
    reference_title: "Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Single channel recordings showed that the mutant channels have higher open probability, due to a modification of gating, and no change in single-channel conductance."
    explanation: Higher open probability of the mutant channel demonstrates the gain-of-function gating change.
  - reference: PMID:20037587
    reference_title: "Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional analysis revealed that increased calcium channel activity is a distinct property of both SPSMA- and CMT2C-causing mutant proteins."
    explanation: Shows the SPSMA-causing mutant protein shares the increased calcium channel activity property.
  downstream:
  - target: Dysregulated Calcium Influx and Cytotoxicity
    description: >
      Increased constitutive channel activity raises intracellular calcium influx
      to cytotoxic levels.
    causal_link_type: DIRECT
- name: Dysregulated Calcium Influx and Cytotoxicity
  description: >
    The gain-of-function channel drives excessive calcium ion influx and raises
    intracellular calcium, linking the TRPV4 mutation to altered calcium
    homeostasis. The resulting hypercalcemic state is cytotoxic; in heterologous
    cells expressing mutant TRPV4, cell death is reversible by the TRPV channel
    antagonist ruthenium red, implicating calcium overload as the toxic effector.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Calcium ion transmembrane transport (influx)
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: INCREASED
  - preferred_term: Intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:21288981
    reference_title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cells transfected with R232C and R316H displayed increased intracellular Ca(2+) levels and reversible cell death by the TRPV channel antagonist, ruthenium red."
    explanation: Mutant TRPV4 raises intracellular calcium and causes cell death reversible by channel blockade.
  - reference: PMID:21288981
    reference_title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Reversible hypercalcemic gain-of-function of mutant TRPV4 instead of loss-of-function appears to be pathologically important."
    explanation: Identifies hypercalcemic gain-of-function as the pathologically important cytotoxic mechanism.
  - reference: PMID:20037587
    reference_title: "Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings link mutations in TRPV4 to altered calcium homeostasis and peripheral neuropathies, implying a pathogenic mechanism"
    explanation: Connects TRPV4 mutation to altered calcium homeostasis as the pathogenic mechanism.
  downstream:
  - target: Lower Motor Neuron and Motor Axon Degeneration
    description: >
      Sustained calcium overload is cytotoxic to lower motor neurons and their
      axons, producing motor-neuron loss and motor axonopathy.
    causal_link_type: DIRECT
- name: Lower Motor Neuron and Motor Axon Degeneration
  description: >
    Calcium-mediated cytotoxicity drives degeneration of anterior-horn lower motor
    neurons and their motor axons, the substrate of the spinal muscular atrophy
    phenotype. In knock-in mouse models carrying disease mutations (R269C, R232C),
    the degeneration is regional and the motor-neuron loss is non-cell-autonomous —
    driven by mutant channel activity in neural vascular endothelial cells with
    focal blood-spinal cord barrier breakdown — and is rescued by a TRPV4 antagonist.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Calcium ion import (cytotoxic)
    term:
      id: GO:0070509
      label: calcium ion import
    modifier: INCREASED
  evidence:
  - reference: PMID:38776392
    reference_title: "Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TRPV4 mutant mice exhibited weakness, early lethality, and regional motor neuron loss."
    explanation: Knock-in mouse models recapitulate weakness and regional motor neuron loss.
  - reference: PMID:38776392
    reference_title: "Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mutant TRPV4 channels can drive motor neuron degeneration in a non-cell autonomous manner by precipitating focal breakdown of the BSCB."
    explanation: Demonstrates non-cell-autonomous motor neuron degeneration via blood-spinal cord barrier breakdown.
  - reference: PMID:20037588
    reference_title: "Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spinal muscular atrophies (SMA, also known as hereditary motor neuropathies) and hereditary motor and sensory neuropathies (HMSN) are clinically and genetically heterogeneous disorders of the peripheral nervous system."
    explanation: Frames SPSMA within the lower-motor-neuron spinal muscular atrophy / hereditary motor neuropathy group.
  downstream:
  - target: Scapuloperoneal Denervation Pattern
    description: >
      Chronic neurogenic denervation of shoulder-girdle and peroneal muscles
      produces the characteristic scapuloperoneal distribution of weakness and
      wasting.
    causal_link_type: DIRECT
- name: Scapuloperoneal Denervation Pattern
  description: >
    Topographically selective denervation produces the scapuloperoneal phenotype —
    progressive atrophy and weakness of the shoulder-girdle/scapular muscles
    (scapular winging) and the peroneal/distal lower-limb muscles (foot drop) —
    with areflexia and relative sensory sparing. Additional features include vocal
    cord paralysis, scoliosis, and, in congenital-onset cases, arthrogryposis and
    skeletal dysplasia.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  evidence:
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scapuloperoneal spinal muscular atrophy (SPSMA) is a rare autosomal dominant disorder caused by heterozygous mutations in the transient receptor potential cation channel (TRPV4) gene, characterized by progressive scapuloperoneal atrophy and weakness."
    explanation: Defines the scapuloperoneal atrophy/weakness distribution of SPSMA.
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features, such as vocal cord paralysis, scoliosis and/or arthrogryposis, are likely to occur."
    explanation: Documents the additional vocal cord, scoliosis, and arthrogryposis features of SPSMA.
phenotypes:
- category: Neuromuscular
  name: Scapular winging
  description: >
    Winging of the scapula reflecting shoulder-girdle (periscapular) muscle
    weakness, a hallmark of the scapuloperoneal distribution.
  phenotype_term:
    preferred_term: Scapular winging
    term:
      id: HP:0003691
      label: Scapular winging
  evidence:
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by progressive scapuloperoneal atrophy and weakness"
    explanation: Scapuloperoneal atrophy and weakness produces the scapular winging of SPSMA.
- category: Neuromuscular
  name: Upper limb muscle weakness
  description: >
    Proximal upper-limb / shoulder-girdle weakness as part of the scapuloperoneal
    distribution.
  phenotype_term:
    preferred_term: Upper limb muscle weakness
    term:
      id: HP:0003484
      label: Upper limb muscle weakness
  evidence:
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by progressive scapuloperoneal atrophy and weakness"
    explanation: The scapulo- component of the scapuloperoneal pattern is upper-limb/shoulder-girdle weakness.
- category: Neuromuscular
  name: Foot drop
  description: >
    Foot drop (ankle dorsiflexor weakness) from peroneal/distal lower-limb
    involvement, the peroneal component of the scapuloperoneal distribution.
  phenotype_term:
    preferred_term: Foot drop
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  evidence:
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by progressive scapuloperoneal atrophy and weakness"
    explanation: The peroneal component of the scapuloperoneal pattern manifests as ankle dorsiflexor weakness / foot drop.
- category: Neuromuscular
  name: Distal lower limb muscle weakness
  description: Peroneal-pattern distal lower-limb weakness.
  phenotype_term:
    preferred_term: Distal lower limb muscle weakness
    term:
      id: HP:0009053
      label: Distal lower limb muscle weakness
  evidence:
  - reference: PMID:22526352
    reference_title: "TRPV4 mutations in children with congenital distal spinal muscular atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The recent identification of mutations in the gene encoding transient receptor potential vanilloid 4 (TRPV4) in distal spinal muscular atrophy (dSMA)"
    explanation: TRPV4 causes a distal SMA phenotype with distal lower-limb weakness.
- category: Neuromuscular
  name: Skeletal muscle atrophy
  description: Muscle wasting in the scapuloperoneal distribution.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by progressive scapuloperoneal atrophy and weakness"
    explanation: Documents the progressive muscle atrophy of SPSMA.
- category: Neurologic
  name: Vocal cord paralysis
  description: >
    Laryngeal involvement with vocal cord paralysis, a recurrent feature of the
    TRPV4 neuromuscular spectrum including SPSMA and CMT2C.
  phenotype_term:
    preferred_term: Vocal cord paralysis
    term:
      id: HP:0001605
      label: Vocal cord paralysis
  evidence:
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features, such as vocal cord paralysis, scoliosis and/or arthrogryposis, are likely to occur."
    explanation: Vocal cord paralysis is a recognized additional feature of SPSMA.
  - reference: PMID:22526352
    reference_title: "TRPV4 mutations in children with congenital distal spinal muscular atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a girl with dSMA and vocal cord paralysis, we detected a new variant (p.P97R)"
    explanation: TRPV4-related distal SMA presents with vocal cord paralysis.
- category: Musculoskeletal
  name: Scoliosis
  description: Spinal deformity occurring as part of the skeletal involvement.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features, such as vocal cord paralysis, scoliosis and/or arthrogryposis, are likely to occur."
    explanation: Scoliosis is a recognized additional feature of SPSMA.
- category: Musculoskeletal
  name: Arthrogryposis multiplex congenita
  description: >
    Congenital contractures in early-onset / congenital cases, reflecting in-utero
    motor-neuron involvement.
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features, such as vocal cord paralysis, scoliosis and/or arthrogryposis, are likely to occur."
    explanation: Arthrogryposis is a recognized additional feature, prominent in congenital-onset cases.
- category: Musculoskeletal
  name: Abnormality of the skeletal system
  description: >
    Bone abnormalities / skeletal dysplasia accompanying congenital-onset TRPV4
    distal SMA, reflecting the channel's pleiotropic role in skeleton.
  phenotype_term:
    preferred_term: Abnormality of the skeletal system
    term:
      id: HP:0000924
      label: Abnormality of the skeletal system
  evidence:
  - reference: PMID:22526352
    reference_title: "TRPV4 mutations in children with congenital distal spinal muscular atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In another child with congenital dSMA, in this case associated with bone abnormalities, we detected a previously reported mutation (p.R232C)."
    explanation: Congenital TRPV4 distal SMA can be associated with bone abnormalities.
- category: Neuromuscular
  name: EMG neuropathic changes
  description: >
    A neurogenic (neuropathic) pattern on electromyography reflecting chronic motor
    denervation, distinguishing SPSMA from scapuloperoneal myopathy.
  phenotype_term:
    preferred_term: EMG neuropathic changes
    term:
      id: HP:0003445
      label: "EMG: neuropathic changes"
  evidence:
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder should be considered in scapuloperoneal syndromes with autosomal dominant inheritance and a neurogenic pattern."
    explanation: SPSMA shows a neurogenic (neuropathic) electrophysiological pattern.
genetic:
- name: TRPV4
  gene_term:
    preferred_term: TRPV4
    term:
      id: hgnc:18083
      label: TRPV4
  inheritance:
  - name: Autosomal Dominant
  notes: >
    Heterozygous TRPV4 missense variants, most affecting the intracellular
    N-terminal ankyrin-repeat domain (e.g., R269H, R315W, R316C, R232C, R316H),
    cause SPSMA. They are typically gain-of-function with increased calcium channel
    activity. TRPV4 variants produce an allelic neuromuscular spectrum that also
    includes congenital distal SMA and HMSN type IIC / CMT2C, which overlap
    clinically with SPSMA; expressivity is variable and can worsen across
    generations.
  evidence:
  - reference: PMID:20037588
    reference_title: "Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report that mutations in the TRPV4 gene cause congenital distal SMA, scapuloperoneal SMA, HMSN 2C. We identified three missense substitutions (R269H, R315W and R316C) affecting the intracellular N-terminal ankyrin domain of the TRPV4 ion channel in five families."
    explanation: Establishes heterozygous ankyrin-domain TRPV4 mutations as the cause of SPSMA and the allelic spectrum.
  - reference: PMID:20037587
    reference_title: "Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SPSMA and CMT2C are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 4 (TRPV4)."
    explanation: Establishes SPSMA and CMT2C as allelic TRPV4 disorders.
  - reference: PMID:26948711
    reference_title: "TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the first Italian family with SPSMA, harboring the c.806G>A mutation in TRPV4 gene (p. R269H)."
    explanation: Provides a representative pathogenic TRPV4 variant (R269H) segregating in an SPSMA family.
differential_diagnoses:
- name: Facioscapulohumeral muscular dystrophy (FSHD)
  description: >
    FSHD produces overlapping scapular winging and scapuloperoneal weakness but is
    a myopathy with facial involvement and a myopathic EMG/biopsy, contrasting with
    the neurogenic pattern of SPSMA.
- name: Charcot-Marie-Tooth disease type 2C (HMSN2C)
  description: >
    The allelic TRPV4 disorder CMT2C is an axonal sensorimotor neuropathy with vocal
    cord and diaphragmatic involvement; SPSMA is the more purely motor,
    scapuloperoneal-predominant phenotype with relative sensory sparing.
- name: Scapuloperoneal myopathy
  description: >
    Myopathic scapuloperoneal syndromes (e.g., desminopathy, FHL1-related) share the
    scapuloperoneal distribution but show myopathic rather than neurogenic
    electrophysiology and muscle histology.
treatments:
- name: Genetic counseling
  description: >
    Counseling for autosomal dominant recurrence risk (50% to offspring),
    variable/age-dependent expressivity, and predictive/cascade testing once a
    pathogenic TRPV4 variant is identified.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Physical Therapy and Orthotic Support
  description: >
    Supportive rehabilitation including physical therapy and ankle-foot orthoses to
    manage peroneal weakness, foot drop, and gait, plus scapular stabilization for
    shoulder-girdle weakness.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Foot drop
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
- name: Supportive and Multidisciplinary Care
  description: >
    No disease-modifying therapy is established; management is supportive and
    multidisciplinary, including orthopedic management of scoliosis and foot
    deformity, laryngeal/ENT assessment for vocal cord paralysis, and respiratory
    monitoring. TRPV4 channel antagonists rescue motor phenotypes in cellular and
    mouse models and are an investigational therapeutic direction.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
datasets: []
📚

References & Deep Research

References

7
PMID:20037588
Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C.
No top-level findings curated for this source.
PMID:20037587
Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4.
No top-level findings curated for this source.
PMID:21454511
Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies.
No top-level findings curated for this source.
PMID:21288981
TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.
No top-level findings curated for this source.
PMID:38776392
Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice.
No top-level findings curated for this source.
PMID:26948711
TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature.
No top-level findings curated for this source.
PMID:22526352
TRPV4 mutations in children with congenital distal spinal muscular atrophy.
No top-level findings curated for this source.