<scp><i>SORD</i></scp>‐related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages

Nicolas, Pons; Fernández‐Eulate, Gorka; Pégat, Antoine; Théaudin, Marie; Guieu, Régis; Ripellino, Paolo; Manon, Devedjian; Mace, Patrick; Masingue, Marion; Léonard-Louis, Sarah; Petiot, Philipe; Roché, Pauline; Bernard, Emilien; Françoise, Bouchour; Good, Jean-Marc; Verschueren, Annie; Grapperon, Aude-Marie; Salort, Emmanuelle; Grosset, Anais; Chanson, Jean‐Baptiste; Nadaj‐Pakleza, Aleksandra; Bédat-Millet, Anne-Laure; Choumert, Ariane; Barnier, Anne; Hamdi, Ghassen; Lesca, Gaëtan; Prieur, Fabienne; Arnaud, Bruneel; Latour, Philippe; Stojkovic, Tanya; Attarian, Shahram; Bonello‐Palot, Nathalie

doi:10.1111/ene.15793

Cited by 4 publications

(3 citation statements)

References 32 publications

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“…A confirmation of higher sorbitol levels in the CSF of SORD neuropathy patients will be of interest and will potentially inform therapeutic strategies of drug delivery to the CNS. SORD neuropathy in patients presents as moderately severe, motor dominant, axonal CMT, intermediate CMT, or dHMN 1,[27][28][29] . The average age of onset is the late teens 1 .…”

Section: Discussionmentioning

confidence: 99%

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Sord deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights

Rebelo,

Abad,

Dohrn

et al. 2023

Preprint

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BiallelicSORDmutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. PathogenicSORDloss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated aSordknockout (KO),Sord−/−, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations.Sord−/−rats had remarkably increased levels of sorbitol in serum, cerebral spinal fluid (CSF), and peripheral nerve. Moreover, serum fromSord−/−rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined inSord−/−animals starting at ∼7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de– and remyelinated axons, and a likely pathognomonic finding – enlarged “ballooned” myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary,Sord−/−rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.

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Section: Discussionmentioning

confidence: 99%

“…SORD neuropathy in patients presents as moderately severe, motor dominant, axonal CMT, intermediate CMT, or dHMN 1,27–29 . The average age of onset is the late teens 1 .…”

Section: Discussionmentioning

confidence: 99%

Sord deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights

Rebelo,

Abad,

Dohrn

et al. 2023

Preprint

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“…The dominant pathogenic variant in SORD , c.757delG; p.Ala253GlnfsTer27, is the gene most frequently associated with recessive axonal neuropathy, with a carrier frequency of ~3/1000 individuals 1 . To date, an additional 22 pathogenic variants in SORD have been reported, of which 19 are either homozygous or compound heterozygous with p.Ala253GlnfsTer27 1–7 . The SORD protein is a zinc‐dependent homotetramer composed of 38‐kDa subunits with catalytic domains that include a zinc‐binding domain and tetramer interface 8,9 It is the rate‐limiting enzyme in the polyol pathway of glucose metabolism; loss of enzyme function and consequent sorbitol accumulation may lead to synaptic degeneration and progressive dyskinesia 1 …”

Section: Introductionmentioning

confidence: 99%

Expanding the genetic and clinical spectrum of SORD‐related peripheral neuropathy by reporting a novel variant c.210T>G and evidence of subclinical muscle involvement

Xie

Zeng

et al. 2023

J Peripheral Nervous Sys

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Background and AimsBiallelic variants in the sorbitol dehydrogenase (SORD) gene have been identified as the genetic cause of autosomal recessive (AR) peripheral neuropathy (PN) manifesting as Charcot‐Marie‐Tooth disease type 2 (CMT2) or distal hereditary motor neuropathy (dHMN). We aim to observe the genetic and clinical spectrum of a cohort of patients with SORD‐related PN (SORD‐PN).MethodsA total of 107 patients with AR or sporadic CMT2/dHMN underwent molecular diagnosis by whole‐exome sequencing and subsequent Sanger sequencing validation. Available phenotypic data for SORD‐PN were collected and analyzed.ResultsEleven (10.28%) of 107 patients were identified as SORD‐PN, including 4 with CMT2 and 7 with dHMN. The SORD variant c.210T>G;p.His70Gln in F‐d3 was firstly reported and subsequent analysis showed that it resulted in loss of SORD enzyme function. Evidence of subclinical muscle involvement was frequently detected in patients with SORD‐PN, including mildly to moderately elevated serum creatine kinase (CK) levels in 10 patients, myogenic electrophysiological changes in 1 patient, and muscle edema in 5 patients undergoing lower extremity MRI. Fasting serum sorbitol level was 88‐fold higher in SORD‐PN patients (9.69±1.07mg/l) than in healthy heterozygous subjects (0.11±0.01mg/l) and 138‐fold higher than in healthy controls (0.07±0.02mg/l).InterpretationThe novel SORD variant c.210T>G;p.His70Gln and evidence of subclinical muscle involvement were identified, which expanded the genetic and clinical spectrum of SORD‐PN. Subclinical muscle involvement might be a common but easily overlooked clinical feature. The serum CK and fasting serum sorbitol levels were expected to be sensitive biomarkers confirmed by follow‐up cohort study.This article is protected by copyright. All rights reserved.

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SORDD: mutation frequency and phenotype in predominantly axonal Charcot-Marie-Tooth disease of undefined genetic cause

Arlt,

Akova-Öztürk,

Schirmacher

et al. 2024

Journal of Neurogenetics

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SORD‐related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages

Cited by 4 publications

References 32 publications

Sord deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights

Sord deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights

Expanding the genetic and clinical spectrum of SORD‐related peripheral neuropathy by reporting a novel variant c.210T>G and evidence of subclinical muscle involvement

SORDD: mutation frequency and phenotype in predominantly axonal Charcot-Marie-Tooth disease of undefined genetic cause

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