Submission Details

SORD was first reported in relation to autosomal recessive Charcot-Marie-Tooth disease (CMT) in 2020 (Cortese et al., PMID: 32367058). SORD neuropathy (OMIM: 618912) is caused by loss of the enzyme sorbitol dehydrogenase, which converts sorbitol to fructose, leading to toxic accumulation of sorbitol levels. Patients with SORD variants develop CMT2 or distal hereditary motor neuropathy (dHMN). SORD deficiency is one of the most common types of recessive CMT, with an estimated prevalence of 1 to 100,000 individuals. In this curation, we have included 5 probands from three different publications, all harboring a common frameshift variant (Ala253GlnfsTer27), presented as homozygous or compound heterozygous (PMID: 32367058, 34995833, and 33875678). The most common pathogenic variant is present at a relatively high allele frequency in the population (gnomAD= 0.0004). More evidence is available in the literature, but the maximum score for the genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease association is also supported by experimental evidence (expression studies, animal model, and functional alteration in patient cells)(PMID: 32367058 and 9604875). Fibroblasts and serum from patients show abnormally increased levels of sorbitol. Loss of the SORD gene ortholog in Drosophila caused synaptic degeneration, progressive motor impairment, and increased sorbitol levels, which were rescued by treatment with aldose reductase inhibitors (PMID: 32367058). A total of 15.5 points have been obtained for this curation. In summary, SORD is definitively associated with autosomal recessive CMT. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.