Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes PMID: 32367058

ADC Targets in Oncology

2026-04-10

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

Nat Genet. 2020 May;52(5):473-481. doi: 10.1038/s41588-020-0615-4.

Andrea Cortese ^# ¹ ² ³ , Yi Zhu ^# ⁴ ⁵ , Adriana P Rebelo ^# ⁶ , Sara Negri ⁷ , Steve Courel ⁶ , Lisa Abreu ⁶ , Chelsea J Bacon ⁸ , Yunhong Bai ⁸ , Dana M Bis-Brewer ⁶ , Enrico Bugiardini ⁹ , Elena Buglo ⁶ , Matt C Danzi ⁶ , Shawna M E Feely ⁸ , Alkyoni Athanasiou-Fragkouli ⁹ , Nourelhoda A Haridy ⁹ ¹⁰ , Inherited Neuropathy Consortium , Rosario Isasi ⁶ , Alaa Khan ⁹ ¹¹ , Matilde Laurà ⁹ , Stefania Magri ¹² , Menelaos Pipis ⁹ , Chiara Pisciotta ¹³ , Eric Powell ⁶ , Alexander M Rossor ⁹ , Paola Saveri ¹³ , Janet E Sowden ¹⁴ , Stefano Tozza ¹⁵ , Jana Vandrovcova ⁹ , Julia Dallman ¹⁶ , Elena Grignani ⁷ , Enrico Marchioni ¹⁷ , Steven S Scherer ¹⁸ , Beisha Tang ¹⁹ , Zhiqiang Lin ²⁰ , Abdullah Al-Ajmi ²¹ , Rebecca Schüle ²² ²³ , Matthis Synofzik ²² ²³ , Thierry Maisonobe ²⁴ , Tanya Stojkovic ²⁵ , Michaela Auer-Grumbach ²⁶ , Mohamed A Abdelhamed ¹⁰ , Sherifa A Hamed ¹⁰ , Ruxu Zhang ²⁰ , Fiore Manganelli ¹⁵ , Lucio Santoro ¹⁵ , Franco Taroni ¹² , Davide Pareyson ¹³ , Henry Houlden ⁹ , David N Herrmann ¹⁴ , Mary M Reilly ⁹ , Michael E Shy ⁸ , R Grace Zhai ²⁷ ²⁸ , Stephan Zuchner ²⁹

Affiliations

1. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. [email protected].
2. Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK. [email protected].
3. Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. [email protected].
4. Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
5. Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
6. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
7. Istituiti Clinici Scientifici Maugeri IRCCS, Environmental Research Center, Pavia, Italy.
8. Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
9. Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK.
10. Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, Egypt.
11. Molecular Diagnostic Unit, Clinical Laboratory Department, King Abdullah Medical City in Makkah, Mecca, Saudi Arabia.
12. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
13. Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
14. Department of Neurology, University of Rochester, Rochester, NY, USA.
15. Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy.
16. Department of Biology, University of Miami, Coral Gables, FL, USA.
17. IRCCS Mondino Foundation, Pavia, Italy.
18. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
19. Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
20. Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
21. Division of Neurology, Department of Medicine, Al-Jahra Hospital, Al-Jahra, Kuwait.
22. Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research, and Center for Neurology, University of Tübingen, Tübingen, Germany.
23. German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
24. Department of Neurophysiology, AP-HP, Sorbonne Université, Hôpital Pitié Salpêtrière, Paris, France.
25. Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
26. Department of Orthopaedics and Traumatology, Medical University of Vienna, Vienna, Austria.
27. Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA. [email protected].
28. Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA. [email protected].
29. Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. [email protected].
# Contributed equally.

Abstract

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.