Abstract Details

Title SORD Neuropathy: Gene Identification and Proposal for a Follow Up Multi-Centre Natural History Study

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S12 - Interventional/Observational Studies of Neuromuscular Diseases (4:32 PM-4:40 PM)

Poster/Presentation
Number 004

Background

80% of axonal CMT remain genetically unconfirmed

Objective

To report on the identification of biallelic mutation in SORD as a common and treatable cause of axonal CMT and to outline the design of and foster participation to a multicentre natural history study of SORD neuropathy

Design/Methods

We took advantage of the largest collection of over 1,100 WES from CMT in the GENESIS analysis platform, looking for genes for which significant DNA variants are present in multiple families as well as for individual alleles overrepresented in CMT cases

Results

We identified 45 cases from 38 families across multiple ethnicities, carrying a particular nonsense mutation in SORD, c.753delG;p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state. With an allele frequency of 0.004, the p.Ala253GlnfsTer27 variant represents one of the most common pathogenic alleles in humans. SORD is an enzyme that converts sorbitol into fructose, in the two-step polyol pathway that has been implicated in diabetic neuropathy. In patient-derived fibroblasts, we find a complete loss of SORD protein and increased intracellular sorbitol. Also, serum fasting sorbitol level was over 100 times higher in patients compared to healthy individuals. In Drosophila, we show that loss of SORD orthologues causes synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes.

Conclusions

We demonstrate biallelic mutations in sorbitol dehydrogenase (SORD) as the most frequent recessive form of hereditary neuropathies. Since the time of publication of the gene identification study we have identified additional 40 cases carrying biallelic mutations in SORD. The current multi-centre natural history study aims to 1) foster case identification 2) elucidate the full genotype and phenotype spectrum 3) identify sensitive outcome measures 4) validate the role of sorbitol as a biomarker of SORD neuropathy.

Authors/Disclosures
PRESENTER	No disclosure on file
Maike Dohrn, MD (Department of Neurology, RWTH Aachen University Hospital)	Dr. Dohrn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea, Alnylam, Pfizer, Amicus. Dr. Dohrn has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicus, Akcea. Dr. Dohrn has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Akcea, Alnylam, Pfizer. The institution of Dr. Dohrn has received research support from Pfizer. Dr. Dohrn has received research support from German Research Foundation.
	No disclosure on file
Adriana Rebelo	No disclosure on file
	No disclosure on file
	No disclosure on file
Shawna Feely (University of Iowa Hospitals & Clinics)	Shawna Feely has nothing to disclose.
	No disclosure on file
	No disclosure on file
Sherifa A. Hamed, MD, MBBS (Assiut University, Faculty of Medicine)	No disclosure on file
	No disclosure on file
	No disclosure on file
Franco Taroni, MD	The institution of Dr. Taroni has received research support from Italian Ministry of Health. The institution of Dr. Taroni has received research support from Fondazione Regionale per la Ricerca Biomedica.
Davide Pareyson, MD (Fondazione IRCCS Istituto Neurologico Carlo Besta)	No disclosure on file
Henry Houlden	No disclosure on file
David N. Herrmann, MD, FAAN (University of Rochester Medical Center)	Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acceleron. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint global. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurogene. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Herrmann has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Regenacy. Dr. Herrmann has received intellectual property interests from a discovery or technology relating to health care.
Mary Reilly, MD, FRCP, FRCPI (National Hospital for Neurology and Neurosurgery)	The institution of Mary Reilly, MD, FRCP, FRCPI has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alynlam. Mary Reilly, MD, FRCP, FRCPI has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AKCEA. Mary Reilly, MD, FRCP, FRCPI has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Inflectis. The institution of Mary Reilly, MD, FRCP, FRCPI has received research support from MRC. The institution of Mary Reilly, MD, FRCP, FRCPI has received research support from NIH. The institution of Mary Reilly, MD, FRCP, FRCPI has received research support from MDA.
Michael E. Shy, MD, FAAN (University of Iowa)	Dr. Shy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Shy has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for DTx Pharma. The institution of Dr. Shy has received research support from NIH. The institution of Dr. Shy has received research support from Muscular Dystrophy Association. The institution of Dr. Shy has received research support from Charcot Marie Tooth Association. The institution of Dr. Shy has received research support from Applied Therapeutics.
	No disclosure on file
	No disclosure on file
Stephan Zuchner, MD, FAAN (University of Miami School of Medicine)	Dr. Zuchner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Zuchner has received research support from Muscular Dystrophy Association. The institution of Dr. Zuchner has received research support from CMT Association. Dr. Zuchner has received intellectual property interests from a discovery or technology relating to health care.