果冻影院

This leads听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, 果冻影院 Queen Square Institute of Neurology (ION) explains 鈥淏y 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 鈥渕irroring鈥� pseudogene SORD2P, and had been missed by previous WES studies because of ambiguous mapping of the WES reads of SORD to SORD2P.鈥� and he continues 鈥淲e predict that significant fraction of the missing heritability of familial and apparently sporadic neurodegenerative conditions is hiding in 鈥渕irror DNA鈥� regions.

Senior 果冻影院 author Mary Reilly, also from the Queen Square Centre for Neuromuscular Diseases, 果冻影院 Queen Square Institute of Neurology, 听says 鈥漈he 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 果冻影院 author Henry Houlden, from the Department of Neuromuscular Diseases, 果冻影院 Queen Square Institute of Neurology, 听comments 鈥淭he 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听 reinforces the power of international collaborations which can accelerate the journey from gene identification to effective treatment鈥�

Links

• Cortese, A., Zhu, Y., Rebelo, A.P.听et al.听.听Nat Genet听52,听473鈥�481 (2020).

Image:

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