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

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Spectrum of Genotypes and Phenotypes in Charcot-Marie-Tooth Disease with SORD Mutations

Overview

This multicentre study of 144 patients with biallelic SORD mutations delineates the genotype-phenotype spectrum of CMT-SORD, the most common recessive Charcot-Marie-Tooth disease. Key findings include predominant motor axonal neuropathy with foot dorsiflexion and plantar flexion weakness, elevated serum sorbitol as a reliable biomarker, and a typical disease onset in the second decade of life.

Background

Charcot-Marie-Tooth disease (CMT) encompasses a group of inherited neuropathies affecting motor and sensory axons. Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause CMT-SORD, a recessive form characterized by sorbitol accumulation due to disruption of the polyol pathway. Given the high allele frequency of pathogenic SORD variants, CMT-SORD is likely the most common recessive CMT subtype. An ongoing clinical trial of the aldose reductase inhibitor govorestat highlights the need for detailed clinical and biochemical characterization of this condition.

Data Highlights

ParameterValue/Observation
Number of patients144 from 126 families
Sex distribution69% male, 31% female
Common pathogenic allelesc.757delG (p.Ala253GlnfsTer27), c.458C>A (p.Ala153Asp)
Phenotype distribution~66% CMT2, ~33% distal hereditary motor neuropathy
Age of onsetSecond decade of life
Use of ankle foot orthoses25% of patients, typically in their 30s
Sorbitol levelsSignificantly elevated in patients vs controls and heterozygous carriers
Nerve conduction studiesMotor predominant axonal neuropathy; reduced conduction velocities in intermediate range in 25% of cases
Muscle weaknessFoot dorsiflexion and plantar flexion similarly affected; weakness worsens with age
Sex effectMale sex associated with greater distal lower limb weakness and progression

Key Findings

  • Biallelic SORD mutations cause a motor-predominant axonal neuropathy with prominent foot dorsiflexion and plantar flexion weakness.
  • The c.757delG allele is the most common pathogenic variant across multiple ancestries.
  • Serum sorbitol levels are significantly elevated in affected patients and serve as a reliable biomarker for disease diagnosis and variant pathogenicity assessment.
  • Two-thirds of patients present with CMT2 phenotype, while one-third have distal hereditary motor neuropathy.
  • Disease onset typically occurs in the second decade, with progressive weakness leading to ankle foot orthosis use in about one-quarter of patients by their 30s.
  • Male patients exhibit more severe distal lower limb weakness and faster progression compared to females.

Clinical Implications

Clinicians should consider genetic testing for SORD mutations in patients presenting with motor-predominant axonal neuropathy, especially with early onset foot dorsiflexion and plantar flexion weakness. Measurement of fasting serum sorbitol can aid in diagnosis and pathogenicity confirmation of variants. Awareness of the natural history and progression is critical as disease-modifying therapies like aldose reductase inhibitors become available.

Conclusion

CMT-SORD represents a frequent recessive axonal neuropathy with a characteristic clinical and biochemical profile. Elevated serum sorbitol is a robust biomarker, and understanding the genotype-phenotype spectrum will facilitate diagnosis and therapeutic intervention.

References

  1. Cortese et al. 2024 -- Spectrum of Genotypes and Phenotypes in Charcot-Marie-Tooth Disease Associated with SORD Mutations

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

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