TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations - Scorecard - MDSpire

TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations

  • By

  • Gage P Kosmanopoulos

  • Jack K Donohue

  • Maya Hoke

  • Simone Thomas

  • Margo A Peyton

  • Linh Vo

  • Thomas O Crawford

  • Reza Sadjadi

  • David N Herrmann

  • Sabrina W Yum

  • Mary M Reilly

  • Steven S Scherer

  • Richard S Finkel

  • Richard A Lewis

  • Davide Pareyson

  • Chiara Pisciotta

  • David Walk

  • Michael E Shy

  • Charlotte J Sumner

  • Inherited Neuropathies Consortium - Rare Disease Clinical Research Network

  • Eleonora Cavalca

  • Luca Crivellari

  • John Day

  • Matilde Laura

  • Stefania Magri

  • Isabella Moroni

  • Bipasha Mukherjee-Clavin

  • Emanuela Pagliano

  • Alex Rossor

  • Paola Saveri

  • Giulia Schirinzi

  • Mariola Skorupinska

  • Janet Sowden

  • Franco Taroni

  • Elizabeth Wood

  • Brett A McCray

  • June 25, 2024

  • 0 min

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Clinical Scorecard: Registry of TRPV4-Related Neuromuscular Disorders Reveals Bulbar, Skeletal, and Proximal Limb Symptoms

At a Glance

CategoryDetail
ConditionTRPV4-related neuromuscular disease including Charcot-Marie-Tooth disease type 2C and forms of spinal muscular atrophy
Key MechanismsDominant missense mutations cause gain of TRPV4 ion channel function leading to increased calcium influx and cytotoxicity
Target PopulationPatients with pathogenic TRPV4 variants presenting with motor-predominant neuromuscular symptoms
Care SettingNeuromuscular specialty clinics and clinical trial settings

Key Highlights

  • TRPV4 mutations cause motor-predominant neuromuscular disease with proximal limb weakness, vocal fold weakness, respiratory dysfunction, and skeletal abnormalities.
  • Disease shows bimodal age of onset with a major peak in the first 2 years of life; infantile onset cases have less sensory involvement and slower progression.
  • TRPV4 antagonists rescue gain-of-function channel activity in models, representing a promising therapeutic strategy.

Guideline-Based Recommendations

Diagnosis

  • Genetic testing to identify pathogenic TRPV4 missense mutations in patients with motor-predominant neuropathy or motor neuronopathy features.
  • Clinical assessment including CMT Examination Scores (CMTES) focusing on motor function, proximal limb weakness, vocal fold function, and respiratory status.

Management

  • Supportive care addressing ambulatory difficulties, respiratory support as needed, and management of skeletal deformities such as scoliosis and arthrogryposis.
  • Consideration of TRPV4 antagonist therapies in clinical trial settings given preclinical efficacy and safety data.

Monitoring & Follow-up

  • Regular evaluation of motor function progression using validated scales like CMTES.
  • Monitoring for vocal fold weakness and respiratory dysfunction including pulmonary function tests.
  • Assessment of skeletal abnormalities and orthopedic complications.

Risks

  • Progressive motor disability with severe ambulatory difficulties.
  • Respiratory compromise requiring ventilatory support in a subset of patients.
  • Skeletal deformities including scoliosis and foot deformities impacting quality of life.

Patient & Prescribing Data

68 patients with known pathogenic TRPV4 variants, including infantile and later onset cases

Small molecule TRPV4 antagonists have demonstrated safety in other indications and rescue pathogenic gain-of-function in preclinical models, supporting their potential use in TRPV4-related neuromuscular disease clinical trials.

Clinical Best Practices

  • Incorporate outcome measures sensitive to non-length dependent motor dysfunction, vocal fold weakness, and respiratory impairment in clinical assessments and trials.
  • Recognize phenotypic heterogeneity including overlap between CMT2C and spinal muscular atrophy presentations in TRPV4 mutation carriers.
  • Provide multidisciplinary care addressing neuromuscular, respiratory, and orthopedic complications.

References

Original Source(s)

TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations

  • by Gage P Kosmanopoulos, Jack K Donohue, Maya Hoke, Simone Thomas, Margo A Peyton, Linh Vo, Thomas O Crawford, Reza Sadjadi, David N Herrmann, Sabrina W Yum, Mary M Reilly, Steven S Scherer, Richard S Finkel, Richard A Lewis, Davide Pareyson, Chiara Pisciotta, David Walk, Michael E Shy, Charlotte J Sumner, Inherited Neuropathies Consortium - Rare Disease Clinical Research Network, Eleonora Cavalca, Luca Crivellari, John Day, Matilde Laura, Stefania Magri, Isabella Moroni, Bipasha Mukherjee-Clavin, Emanuela Pagliano, Alex Rossor, Paola Saveri, Giulia Schirinzi, Mariola Skorupinska, Janet Sowden, Franco Taroni, Elizabeth Wood, Brett A McCray

  • June 25, 2024

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