UCL Queen Square Institute of Neurology


SORD neuropathy: an accelerated journey from gene identification to effective treatment of patients

7 May 2020

A new collaborative study, involving UCL Queen Square Institute of Neurology and University of Miami, identifies sorbitol dehydrogenase (SORD) deficiency as a slowly progressive hereditary motor axonopathy caused by a genetic defect in the second step of the polyol pathway

SORD pathway

This leads to elevated tissue and blood sorbitol. SORD deficiency is the most common recessive cause of neuropathy, for which there is a potential treatment with aldose reductase inhibitors.

The lead author Andrea Cortese, from the Queen Square Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology (ION) explains “By taking advantage of a large dataset of genetic and clinical data from patients with hereditary neuropathy, we identified 45 cases carrying a particular nonsense mutation in SORD. With an allele frequency of ~0.5% in healthy controls, the c.753delG; p.Ala253GlnfsTer27 variant in SORD represents one of the most common pathogenic alleles in humans. Intriguingly, this mutation in SORD is also constitutively present in its “mirroring” pseudogene SORD2P, and had been missed by previous WES studies because of ambiguous mapping of the WES reads of SORD to SORD2P.” and he continues “We predict that significant fraction of the missing heritability of familial and apparently sporadic neurodegenerative conditions is hiding in “mirror DNA” regions.

Senior UCL author Mary Reilly, also from the Queen Square Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology,  says ”The discovery of SORD represents a striking example of how a major genetic cause of human disease can be missed. Indeed, in our large cohort of CMT cases, SORD explain nearly 10% of undiagnosed CMT2 cases. Notably, serum fasting sorbitol levels were over 100 times higher in SORD patients, thus representing a promising biomarker for the diagnosis and monitoring of SORD neuropathy. A preclinical model show this is a potentially treatable neuropathy with a readily available group of drugs, the aldose reductase inhibitors, that can be repurposed for clinical trials.

Senior UCL author Henry Houlden, from the Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology,  comments “The identification of SORD in patients across multiple ethnicities from Europe, US, Egypt, Kuwait, Saudi Arabia and China shows the key role of large collaborative network in gene discovery studies. Also, as an example of rare diseases informing common health issues, the identification of SORD-associated neuropathy may have broader implications to the field of diabetic neuropathy and retinopathy, by shedding new light on sorbitol induced nerve toxicity.

Senior author Stephan Zuchner from University of Miami comments : Most importantly to the patients, SORD neuropathy will represent one of the first example of a treatable hereditary neuropathy. The experience with SORD neuropathy  reinforces the power of international collaborations which can accelerate the journey from gene identification to effective treatment”



SORD metabolic neuropathy (top). Schematic representation of the two-step polyol pathway converting glucose to fructose The hidden SORD mutation Bottom). Schematic representation of SORD and its paralogue SORD2P, arisen from the duplication of SORD within a 0.5 Mb region on chromosome 15