Natural history study of SORD neuropathy

Introduction: We have recently established biallelic mutations in the sorbitol dehydrogenase (SORD) gene as a common and potentially treatable cause of axonal neuropathy. This global observational study aims at reporting the full genotype-phenotype spectrum of SORD neuropathy and at defining valid outcome parameters for future clinical trials. Methods: Through an international network of collaborators, we have identified 149 individuals with biallelic mutations in SORD. Clinical data were collected according to a standardised protocol. Genetic and clinical data from 101 patients are available and are presented. Results: Seventy-three cases carried the common c.753delG;(p.Ala253GlnfsTer27) variant in a homozygous state. In 27 cases, the c.753delGvariant was found in compound-heterozygosity with a second missense or nonsense variant, including c.458C>A;(p.Ala153Asp) which appeared to be the second most common mutation (n = 18). Fasting serum sorbitol level was elevated (14.2 ± 2.7 gr/L, n.v.<0.25), without significant differences across different genotypes. Patients were diagnosed with CMT2 (64%), dHMN (31%), and CMT intermediate (5%). The mean age of symptom onset, including difficulty walking and running, was 17 ± 10 years (range 3-51 years). Foot dorsal and plantar flexion were weak (MRC<5) in 96% and 79% of patients, respectively, while sensation was preserved in over 60% of the cases. The neuropathy was mild in two thirds of cases, who did not require walking aids,. MRC scores of foot dorsiflexion correlated inversely with the age of the subjects and declined significantly over 1 year, while CMTES did not (n = 23), Conclusions: SORD neuropathy appears to be a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsal and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition and can provide functional validation of variants within the expanding genotype spectrum of the disease. Foot dorsiflexion strength represents a promising outcome measure which should be considered in future therapeutic trials on this condition.