Simple test brings clarity and hope for families with inherited neuropathy

A new, inexpensive urine test that measures two sugar alcohols, sorbitol and xylitol, is making it easier, faster, and far less expensive to identify a common inherited nerve disorder called SORD-related neuropathy. The test, developed through a partnership that includes the University of Rochester, Mayo Clinic, and the Clinic for Special Children in Pennsylvania, can detect people that some genetic tests miss and could speed access to emerging treatments and trials.

“Having a reliable, low-cost biochemical screen means we can diagnose patients earlier and more cheaply, get them into clinical trials sooner, and begin to learn how the disease changes over time,” said David Herrmann, MBBCh, chief of the University of Rochester Neuromuscular Division and co-senior author of new research describing the test, which appears in the journal Neurology.

SORD deficiency is believed to be among the most common causes of inherited nerve diseases, but screening for the condition is challenging, and it is not included in many current genetic tests. The ability to detect SORD deficiency through a simple urine test has brought new insight, diagnosis, and care options to families who had long lived with unexplained symptoms, including multiple generations of Old Order Amish families affected by the condition.

What is SORD deficiency?

SORD deficiency is an inherited condition that occurs when the SORD gene is not working properly, due to mutations in both copies of the gene. That gene makes an enzyme that normally helps convert the sugar alcohol sorbitol into fructose. Without the enzyme, sorbitol accumulates in cells, and over time, it damages long nerve fibers.

The same enzyme also helps metabolize xylitol, a sugar alcohol. When SORD activity is lost, xylitol accumulates alongside sorbitol. The combined rise of sorbitol and xylitol produces a distinct biochemical signature that appears in urine, which the new test detects.

Clinically, SORD deficiency most often shows up as an axonal peripheral neuropathy, and it is commonly diagnosed within the spectrum of Charcot–Marie–Tooth disease (CMT) or as distal hereditary motor neuropathy. People with this condition typically develop progressive weakness, especially in the feet and lower legs, and may experience balance or walking difficulties that begin in childhood or early adulthood.

How the urine test was developed

The University of Rochester has been deeply involved in Charcot-Marie-Tooth (CMT) research and care for decades. Rochester clinicians identified the very first patient later shown to have SORD deficiency and provided crucial research materials, including cultured cells from skin biopsies and clinical data, that helped scientists narrow down and confirm the responsible gene. Early collaborative whole-genome sequencing efforts, including work with partners at other institutions, were instrumental in pinpointing changes in SORD as the cause of this form of inherited neuropathy.

Following the 2020 report initially describing SORD-related neuropathy, the next challenge was to develop a practical method for screening patients. University of Rochester genetic counselor Jordan Bontrager, MS, CGC, collaborated with a team led by Mathew Schultz, PhD, at the Mayo Clinic to validate and expand an existing assay that measured sorbitol in urine, adding xylitol measurement and transforming the approach into a commercially available test.

“We needed something that clinics could actually use—a test that’s noninvasive, affordable, and sensitive,” Bontrager said. “By validating sorbitol and xylitol together, we now have a screen that catches patient cases, which standard short-read genetic tests sometimes miss, and it’s about one-tenth the cost of typical genetic panels.”

Why this matters for patients and families

• Faster and cheaper diagnosis: The urine screen can be used early to indicate whether SORD deficiency is likely, reducing time and cost for patients and families.
• Better detection in some cases: Because the SORD gene has a nearly identical pseudogene that can confuse or be missed by common sequencing methods, a biochemical test provides an independent readout of disease status.
• Easier sampling: Urine collection is simple and non-invasive, particularly important when testing children.
• Link to treatment: With therapies in development that aim to reduce sorbitol production, earlier diagnosis makes it possible to enroll patients in trials and, eventually, consider earlier intervention to prevent disability.

Impact on Amish families

As this test was under development, clinicians at the Clinic for Special Children in Lancaster County, Pennsylvania, identified their first Old Order Amish patient with SORD deficiency through genetic testing. Cascade screening of family members and other previously undiagnosed Amish patients with neuropathy revealed the same diagnosis stretching across multiple generations. Urine samples from these patients and unaffected relatives were submitted to the Mayo Clinic, and the new test accurately identified those with SORD deficiency.

Within the Old Order Amish, SORD deficiency is believed to be a common cause of progressive motor neuropathy. In these communities, certain recessive gene variants may be more common due to their shared genetic heritage from a small number of founders in the 18^th century, combined with their genetic isolation from the broader population.  

“For some families who had long accepted mild, unexplained symptoms as ‘normal,’ this test has brought understanding, access to genetic counseling, and a path to care,” Bontrager said. An earlier diagnosis will also enable researchers to follow patients over time and develop a better understanding of the disease's progression and natural history.

What’s next

Researchers emphasize that the urine test is a powerful complement to genetic testing, not a replacement for it. Larger studies that include people with diabetes and other causes of neuropathy will help define how the test performs in broader clinical settings. Longer studies are also needed to determine whether urine sorbitol and xylitol track disease progression or respond to treatment, providing information that could make the test useful for both monitoring and diagnosis.

“Turning a gene discovery into a clinic-ready test and then into trials is how we move from bench science to real improvements in patient care,” said Herrmann. “Making testing accurate, affordable, and easy changes who can get diagnosed, and who can get into trials. That can make a real difference for families.”