Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD - Scorecard - MDSpire

Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD

  • By

  • Andrea Cortese

  • Maike F Dohrn

  • Riccardo Curro

  • Sara Negri

  • Petra Lassuthova

  • Chiara Pisciotta

  • Stefano Tozza

  • Abdullah Al-Ajmi

  • Changyong Feng

  • Pedro J Tomaselli

  • Gorka Fernandez-Eulate

  • Saif Haddad

  • Matilde Laurà

  • Alexander M Rossor

  • Elisa Vegezzi

  • Stefano Facchini

  • James N Sleigh

  • Adriana Rebelo

  • Danique Beijer

  • Jacquelyn Raposo

  • Mario Saporta

  • Barbora Lauerova

  • Helena F Pernice

  • Pascal Achenbach

  • Ulrike Schöne

  • Tayir Alon

  • Marcus Deschauer

  • Isabell Cordts

  • Carolin D Obermaier

  • Natalie Winter

  • Peter D Creigh

  • Janet E Sowden

  • Tyler Rehbein

  • Stefania Magri

  • Alessandro Bertini

  • Paola Saveri

  • Paolo Ripellino

  • Jingyu Huang

  • Aleksandra Nadaj-Pakleza

  • Alison Ross

  • James K L Holt

  • Kathryn M Brennan

  • Rivka Sukenik-Halevy

  • Varoona Bizaoui

  • Yesim Parman

  • Esra Battaloglu

  • Arman Cakar

  • Hadil Alrohaif

  • Simon Hammans

  • Kishore R Kumar

  • Marina L Kennerson

  • Hülya Kayserili

  • Defne A Amado

  • Katrin Hahn

  • Paola Valentino

  • Francesca Cavalcanti

  • Carlo Gaetano

  • Franco Taroni

  • Geir J Braathen

  • Henry Houlden

  • Tanya Stojkovic

  • Stojan Peric

  • Alessandra Bolino

  • Stefano C Previtali

  • Lee Yi-Chung

  • Ayşe N Başak

  • Sherifa A Hamed

  • Ricardo Rojas-Garcia

  • Kristl G Claeys

  • Wilson Marques

  • Teresa Sevilla

  • Beate Schlotter-Weigel

  • Fiore Manganelli

  • Ruxu Zhang

  • David N Herrmann

  • Steven S Scherer

  • Pavel Seeman

  • Davide Pareyson

  • Mary M Reilly

  • Michael E Shy

  • The Inherited Neuropathy Consortium

  • Stephan Züchner

  • February 13, 2025

  • 0 min

Share

Clinical Scorecard: Spectrum of Genotypes and Phenotypes in Charcot-Marie-Tooth Disease Associated with SORD Mutations

At a Glance

CategoryDetail
ConditionCharcot-Marie-Tooth disease caused by biallelic SORD mutations (CMT-SORD)
Key MechanismsLoss-of-function mutations in SORD gene leading to sorbitol dehydrogenase deficiency and sorbitol accumulation via disrupted polyol pathway
Target PopulationPatients with hereditary motor and sensory neuropathies across multiple ancestries including European, Hispanic, Chinese, Near Eastern, and Northern African
Care SettingNeuromuscular reference centers with genetic and neurologic diagnostic capabilities

Key Highlights

  • CMT-SORD is the most common recessive form of Charcot-Marie-Tooth disease with a prevalence of at least 3000 cases in the USA.
  • Disease onset typically occurs in the second decade of life, predominantly affecting foot dorsiflexion and plantar flexion muscles.
  • Fasting serum sorbitol is a reliable biomarker for diagnosis and pathogenicity assessment of SORD variants.

Guideline-Based Recommendations

Diagnosis

  • Confirm biallelic pathogenic SORD mutations via genetic testing (whole-genome, exome, targeted panels, or Sanger sequencing).
  • Measure fasting serum sorbitol levels as a biochemical biomarker to support diagnosis.
  • Perform nerve conduction studies to differentiate CMT2 (motor and sensory involvement) from distal hereditary motor neuropathy (motor only).

Management

  • Use ankle foot orthoses as needed, typically starting in the 30s, to assist ambulation.
  • Monitor for progressive distal lower limb weakness, especially foot dorsiflexion and plantar flexion.
  • Consider enrollment in clinical trials for aldose reductase inhibitors (e.g., govorestat) as disease-modifying therapies become available.

Monitoring & Follow-up

  • Regular neurologic examinations including Charcot-Marie-Tooth Examination Score (CMTESv2) to assess disease severity and progression.
  • Serial nerve conduction studies to monitor motor and sensory nerve function over time.
  • Monitor serum sorbitol levels for biochemical disease activity.

Risks

  • Progressive distal lower limb weakness leading to gait impairment.
  • Potential for increased disease severity and progression in male patients.
  • Risk of loss of independent ambulation later in life, though most maintain ambulation.

Patient & Prescribing Data

144 patients from 126 families with confirmed biallelic SORD mutations, diverse ethnic backgrounds, predominantly male (69%).

Ankle foot orthoses commonly used in third decade; ongoing clinical trials with aldose reductase inhibitor govorestat may provide disease-modifying options.

Clinical Best Practices

  • Early genetic testing for SORD mutations in patients with motor-predominant axonal neuropathy and elevated serum sorbitol.
  • Use fasting serum sorbitol measurement as a non-invasive biomarker to support diagnosis and variant pathogenicity assessment.
  • Implement multidisciplinary care including neurology, genetics, and orthotic support.
  • Monitor disease progression with standardized clinical scores and nerve conduction studies.
  • Consider clinical trial participation for emerging therapies targeting the polyol pathway.

References

Original Source(s)

Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD

  • by Andrea Cortese, Maike F Dohrn, Riccardo Curro, Sara Negri, Petra Lassuthova, Chiara Pisciotta, Stefano Tozza, Abdullah Al-Ajmi, Changyong Feng, Pedro J Tomaselli, Gorka Fernandez-Eulate, Saif Haddad, Matilde Laurà, Alexander M Rossor, Elisa Vegezzi, Stefano Facchini, James N Sleigh, Adriana Rebelo, Danique Beijer, Jacquelyn Raposo, Mario Saporta, Barbora Lauerova, Helena F Pernice, Pascal Achenbach, Ulrike Schöne, Tayir Alon, Marcus Deschauer, Isabell Cordts, Carolin D Obermaier, Natalie Winter, Peter D Creigh, Janet E Sowden, Tyler Rehbein, Stefania Magri, Alessandro Bertini, Paola Saveri, Paolo Ripellino, Jingyu Huang, Aleksandra Nadaj-Pakleza, Alison Ross, James K L Holt, Kathryn M Brennan, Rivka Sukenik-Halevy, Varoona Bizaoui, Yesim Parman, Esra Battaloglu, Arman Cakar, Hadil Alrohaif, Simon Hammans, Kishore R Kumar, Marina L Kennerson, Hülya Kayserili, Defne A Amado, Katrin Hahn, Paola Valentino, Francesca Cavalcanti, Carlo Gaetano, Franco Taroni, Geir J Braathen, Henry Houlden, Tanya Stojkovic, Stojan Peric, Alessandra Bolino, Stefano C Previtali, Lee Yi-Chung, Ayşe N Başak, Sherifa A Hamed, Ricardo Rojas-Garcia, Kristl G Claeys, Wilson Marques, Teresa Sevilla, Beate Schlotter-Weigel, Fiore Manganelli, Ruxu Zhang, David N Herrmann, Steven S Scherer, Pavel Seeman, Davide Pareyson, Mary M Reilly, Michael E Shy, The Inherited Neuropathy Consortium, Stephan Züchner

  • February 13, 2025

Related Content

Drooling Flags Severe Dermatomyositis

Three cases suggest drooling may mark advanced dermatomyositis with dysphagia, aspiration pneumonia, and poor response to treatment.

Faster Sodium Correction Gains Support

Large retrospective study links quicker correction rates with lower mortality in severe hyponatremia

A Smarter Screen for Sleep Apnea Stimulation

A four-factor staging system stratified response rates from 90.9% to 37.5% in a retrospective cohort study, although the model showed only moderate discrimination (C statistic, 0.68) and requires external validation