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  • Writer's pictureKenneth Raymond

Novel Gene Mutation Causing a Recessive Axon-Related CMT Subtype Identified

Updated: Dec 30, 2022

Researchers Have Identified a Variant in the SORD Gene That Is Believed to be The Most Frequent Cause of Recessive Axon-Related Charcot Marie Tooth disease, and It Might be Treatable

Researchers at the University of Miami, led by Dr. Stephen Züchner, report that they have discovered a gene mutation that is the cause of a recessive subtype of Charcot Marie Tooth disease. This mutation is believed to be the cause of the most common recessive axon-related subtype of CMT, whose underlying genetic cause had not yet been identified. This study was substantially supported by the Inherited Neuropathies Consortium. Their findings were published in Nature Genetics.

Researchers were able to query a database of 1,100 CMTers who had undergone Whole-Exome Sequencing (WES) and/or Whole-Genome Sequencing (WGS). From that group, they identified 48 CMTers from 38 families whose genetic cause had not yet been identified, who all demonstrate an axon-related subtype on Nerve Conduction Study (NCS), who all demonstrate a recessive inheritance pattern, and who were all carrying the same homozygous variant in SORD.

SORD is the name/gene symbol given to the Sorbitol Dehydrogenase 1 gene. SORD (OMIM - 182500) is an enzyme that catalyzes the interconversion of polyols and their corresponding ketoses, and, together with aldose reductase (ALDR1; OMIM - 103880), makes up the sorbitol pathway that is believed to play an important role in the development of diabetic neuropathy and diabetic complications. The first reaction of the pathway (also called the polyol pathway) is the reduction of glucose to sorbitol by ALDR1 with NADPH (OMIM - 300225) as the cofactor. SORD then oxidizes the sorbitol to fructose using NAD(+) cofactor. Whoa! That's a mouthful! What does it mean though?

SORD is responsible for converting sorbitol to fructose through a two-step process. It does this via a pathway that is implicated in diabetic neuropathy. Researchers found that, when the c.757delG (p.Ala253GlnfsTer27) variant is present in SORD, there is a complete loss of SORD protein and an increased level of sorbitol within a cell. Researchers also discovered that blood levels of fasting sorbitol were significantly increased. Each of the 48 CMTers who were found to have this variant in SORD, have a CMT disease presentation that is consistent with an axon-related subtype of CMT. Researchers were able to reproduce these findings in the lab, using a fly model.

Dr. Züchner and his team were able to demonstrate in the fly model that treatment with a class of drug called, aldose reductase inhibitor, normalized sorbitol levels within the cell.Disease phenotype was also improved after treatment with the drug. Two drugs were evaluated, Epalrestat and Renirestat, and both gave the same results. Epalrestat is a drug available in several countries and is used to treat complications from diabetes. Renistat is currently in late stages of a clinical trial assessing its possible use as a treatment for complications from diabetes. Researchers suggest that the subtype of CMT caused by the newly identified variant in SORD might be treatable with an aldose reductase inhibitor such as Epalrestat.

Approximately 90% CMTers with a demyelinating (CMT1) subtype have a genetic confirmation. Conversely, approximately 20% to 30% of CMTers with an axon-related (CMT2) subtype receive a genetic confirmation. As many as 70% of CMT2 cases are a de novo case. Because of this, identifying the underlying CMT-causing gene mutation remains difficult. This also explains the disparage between understanding the genetic causes of the CMT1 subtypes and the CMT2 subtypes. The new variant identification in SORD as being the cause of a recessive axon-related (CMT2) could serve to bridge this gap of disparity.

The researchers were able to determine that the homozygous c.757delG (p.Ala253GlnfsTer27) variant in SORD is present in ~3 per 1,000 individuals. This discovery means that this variant is potentially responsible for more than 60,000 CMT cases worldwide, with 3,000 to 5,000 cases being in the US. This would make the subtype caused by this SORD variant to be the most common recessive subtype of CMT. The researchers have not yet assigned a name to the subtype caused by this variant. This is a testament as to how new this reported discovery is.

Efforts are underway to identify undiagnosed CMTers who fit the recessive axon-related subtype profile and whose genetic cause has been elusive. The Charcot-Marie-Tooth Association, through voluntary enrollment in their Patients as Partners in Research initiative, is hoping to identify CMTer candidates for possible participation in a specialized study that is anticipated to be available within in the next several months through the University of Miami and the Inherited Neuropathies Consortium.

While there are drugs that safely and effectively treat complications of diabetes where SORD is implicated, their safety and effectiveness in treating any subtype of CMT, and especially the subtype newly discovered to be caused by this recessive variant in SORD is not understood and has not been evaluated in a patient population. Therefore, extreme caution must be exercised in moving forward from this new discovery.

What I find very interesting is that the drug, PXT-3003, that is in Phase III clinical trial, is being developed as a possible first ever treatment for CMT, and is specifically tested only for CMT1A - the most common subtype of CMT, has sorbitol as one of its constituent parts. Specifically, PXT-3003 is a fixed combination of low-dose (RS) Baclofen, Naltrexone Hydrochloride, and D-sorbitol. I find it fascinating that this Phase III Orphan-designated drug developed to potentially treat specifically CMT1A, contains D-sorbitol, and researchers have now discovered a variant in SORD that not only disrupts sorbitol's conversion to fructose, but also causes a recessive subtype of CMT. Truly fascinating.

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Kenneth Raymond
Kenneth Raymond
May 14, 2020

Hi, Cathy! The Rare Disease Network is an organization that we are not affiliated with. They are a great a organization and are a great source for information. We can't provide any assistance for their website though.

We have an article that explains in detail the language used and variables at-play with CMT genetic test results. It's called, "Here, Genie, Genie, Genie," and can be found on our main Blog page. It may give you more information than you already have regarding results that indicate VUS's.


Cathy Billoni
Cathy Billoni
May 14, 2020

Hmm, when I try to sign up it says the lage link is not working. I have 2 VUS under type 2 and have 2 family members ready to get tested at invitae and live here in Florida and want to get involved in some of these studies. Project 6601 enrollment page gives me this error if anyone can help?

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The Author

Kenneth Raymond was first diagnosed clinically with CMT1 in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. Kenneth has since devoted his life to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers. As a member of the Charcot-Marie-Tooth Association’s Advisory Board, Kenneth serves as a CMT genetics expert, a CMT-related respiratory impairment expert, and as a CMT advocate who is committed to raising CMT awareness through fact-based information rooted in the latest understandings of CMT.

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