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Urine sorbitol and xylitol as quantitative biomarkers for SORD deficiency-related neuropathy: A review of clinical outcomes
Abstract   Peer reviewed

Urine sorbitol and xylitol as quantitative biomarkers for SORD deficiency-related neuropathy: A review of clinical outcomes

Jenny Thies, Amy White, William Laxen, Perry Loken, Karlla W. Brigatti, Tiffany Grider, Jordan Bontrager, Dawn Peck, April Studinski, Emily Lauer, …
Molecular genetics and metabolism, Vol.148(1), 110091
05/2026
DOI: 10.1016/j.ymgme.2026.110091

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Abstract

Background SORD-related Charcot-Marie-Tooth (SORD-CMT) is an autosomal recessive neuropathy caused by biallelic variants in the SORD gene, which results in impaired sorbitol metabolism and leads to elevated intracellular and circulating polyols. Detection of pathogenic variants is challenging because a highly homologous pseudogene limits the sensitivity of current clinical sequencing methods, potentially leading to undetected sequencing, copy-number, or structural variants. Given that ongoing clinical research has made significant progress toward therapeutic treatment for SORD-CMT, comprehensive diagnostic testing is increasingly important. Urine sorbitol and xylitol are clinically informative biomarkers to screen for SORD-CMT as both are markedly elevated in affected individuals. This testing is particularly useful in cases where molecular testing is unavailable or inconclusive and serves as a good first-line diagnostic tool in individuals with unexplained neuropathy. We reviewed and summarized our initial experience with clinical urine sorbitol and xylitol testing for the evaluation of suspected SORD-CMT. Where available, biochemical data were correlated with patient phenotype and genotype. Methods A retrospective review of all clinical urine sorbitol and xylitol results from the test's implementation on February 20, 2024 through November 17, 2025 was performed. For abnormal results, the molecular genotype and clinical phenotype were correlated when available. Biochemical analysis of urine sorbitol and xylitol was performed by a stable-isotope dilution gas chromatography–mass spectrometry (GC–MS) method. Results A total of 1133 urine sorbitol and xylitol tests were performed, and 32 (2.8%) specimens showed elevations in both analytes. The median age at testing among affected individuals was 39.6 years (44% female), with three individuals <18 years. Median sorbitol excretion in affected individuals was 771 mmol/mol creatinine (rr: <35), and median xylitol was 1758 mmol/mol creatinine (rr: <351). In one case the initial sorbitol value was normal, and xylitol elevated. A second sample from this individual demonstrated elevation of both analytes, consistent with SORD-CMT. This individual is affected clinically and molecularly, however, the reason for the initial normal sorbitol value is unknown. Molecular data were available for 26/32 positive cases. Thirteen were homozygous for a common pathogenic variant, c.757del. An additional 10 cases were reported to have biallelic variants in SORD that were determined to confirm affected status. Notably, 4 of these 10 cases had only one variant identified via initial clinical SORD sequencing, and a second variant detected through research testing. Lastly, 3 cases had either a single heterozygous variant identified (N = 2) or no variants identified (N = 1) on clinical SORD sequencing. Molecular data was unavailable for 6 cases, 4 of which had diagnoses of neuropathy and 2 had no clinical information. Conclusions These data provide additional evidence that urine sorbitol and xylitol excretion is a sensitive and specific test for the diagnosis of SORD-CMT. Biochemical testing detected multiple affected individuals with initially inconclusive molecular results from clinical testing with no confirmed false positives to-date. Urine sorbitol and xylitol measurement is a useful tool to aid diagnosis of individuals affected with SORD-CMT and is more clinically sensitive than molecular analysis.

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