Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Andrea Cortese, Yi Zhu, Adriana P Rebelo, Sara Negri, Steve Courel, Lisa Abreu, Chelsea J Bacon, Yunhong Bai, Dana M Bis-Brewer, Enrico Bugiardini, Elena Buglo, Matt C Danzi, Shawna M E Feely, Alkyoni Athanasiou-Fragkouli, Nourelhoda A Haridy, Rosario Isasi, Alaa Khan, Matilde Laurà, Stefania Magri, Menelaos PipisChiara Pisciotta, Eric Powell, Alexander M Rossor, Paola Saveri, Janet E Sowden, Stefano Tozza, Jana Vandrovcova, Julia Dallman, Elena Grignani, Enrico Marchioni, Steven S Scherer, Beisha Tang, Zhiqiang Lin, Abdullah Al-Ajmi, Rebecca Schüle, Matthis Synofzik, Thierry Maisonobe, Tanya Stojkovic, Michaela Auer-Grumbach, Mohamed A Abdelhamed, Sherifa A Hamed, Ruxu Zhang, Fiore Manganelli, Lucio Santoro, Franco Taroni, Davide Pareyson, Henry Houlden, David N Herrmann, Mary M Reilly, Michael E Shy

Research output: Contribution to journalArticlepeer-review


Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes.

Original languageEnglish
Pages (from-to)473-481
Number of pages9
JournalNature Genetics
Issue number5
Publication statusPublished - May 2020


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