Guest author: Dan Knauss

The SORD gene has attracted substantial research attention in recent years. International interest accelerated greatly after the 2020 discovery that mutations in SORD cause the most common autosomal recessive form of CMT2 and overlap with the related category of distal hereditary motor neuropathy (dHMN). Both CMT2 and dHMN are under-diagnosed rare disease categories, and up to nearly 10 percent of cases within them may be SORD-related.

Symptoms typically appear around age 17 on average, though onset can occur in early childhood or as late as a person’s forties. Common to all known cases are muscle weakness and wasting in the arms or legs; leg muscles are affected in 98 percent of identified cases.

The Researcher Behind the Discovery

Stephan Züchner, MD, PhD, chairs the genetics department at the University of Miami’s Miller School of Medicine and leads the CMT genetics effort for the Inherited Neuropathy Consortium. His team led the international collaboration that identified the SORD gene’s role in CMT. Dr. Züchner has predicted that “SORD neuropathy will represent one of the few examples of a treatable hereditary neuropathy,” because the mechanism of harm may be manageable with existing medications developed for diabetes.

SORD and the Harm Done by Sorbitol

SORD stands for sorbitol dehydrogenase (SDH), the protein the gene encodes. SDH’s normal role is to convert sorbitol into fructose. Sorbitol is a sugar alcohol derived from glucose; it is found naturally in fruit and is used as an artificial sweetener in processed foods.

Because sorbitol cannot cross cell membranes, it can accumulate rapidly when there is insufficient SDH to break it down. Normally, glucose is converted to sorbitol by an enzyme called aldose reductase and then to fructose by SDH. In uncontrolled diabetes, this second step may not keep pace with sorbitol production, and buildup in the eyes, kidneys, liver, and nerves can cause significant damage.

In SORD deficiency, organ damage of that type is not the typical outcome, but sorbitol levels rise high enough to destroy the axons (the signal-carrying fibers) in peripheral nerves. According to Dr. Züchner, a person with diabetes may have roughly twice the normal sorbitol level, while someone with SORD deficiency may have 10 to 100 times normal levels.

Excess sorbitol draws water into surrounding tissue through osmotic pressure, stressing or destroying cells. For people with SORD neuropathy, this damage occurs mainly in the motor nerve axons.

Inhibiting Sorbitol Production to Protect Nerves

The Miami team also created and studied fruit fly models with SORD deficiency. These flies showed CMT-like symptoms that were reversed by drugs known as aldose reductase inhibitors (ARIs). These drugs work by blocking aldose reductase, the enzyme that converts glucose to sorbitol in the first place, thereby reducing the amount of sorbitol the body produces. ARIs were not available in North America or Europe at the time of this writing, but clinical trials with a new type of ARI developed by Applied Therapeutics were planned.

Diagnosis and the Path to Treatment

Dr. Züchner and colleagues were enrolling CMT patients in a research study to provide fast SORD screening and map the full range of symptoms associated with SORD neuropathy. Nearly 100 patients had been identified through these efforts at the time of this article. Participants may also qualify for upcoming clinical trials.

Patients with a CMT2 diagnosis, prior negative genetic test results, and no family history of CMT in either parent are encouraged to get in touch through our contact form.

HNF is supporting Dr. Züchner’s work on a rat model to confirm the impact of SORD mutations on sorbitol levels and to test treatments that suppress sorbitol production. With multiple projects advancing in parallel, the prospect of a meaningful therapeutic option to prevent SORD neuropathy from progressing is closer than ever.

To learn more about CMT research and the GRIN registry, visit our what is CMT page.