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

Abstract Background and Aims Biallelic 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). Methods A 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. Results Eleven (10.28%) of 107 patients were identified as SORD‐PN, including four with CMT2 and seven with dHMN. The SORD variant c.210 T > 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 one patient, and muscle edema in five patients undergoing lower extremity MRI. Fasting serum sorbitol level was 88‐fold higher in SORD‐PN patients (9.69 ± 1.07 mg/L) than in healthy heterozygous subjects (0.11 ± 0.01 mg/L) and 138‐fold higher than in healthy controls (0.07 ± 0.02 mg/L). Interpretation The novel SORD variant c.210 T > 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.