Neurology · 2025
Urine Sorbitol and Xylitol for the Diagnosis of Sorbitol Dehydrogenase Deficiency-Related Neuropathy.
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Bontrager Jordan Elliott, White Amy L, Brigatti Karlla W, Laxen William, Loken Perry R, Grider Tiffany, Oglesbee Devin, Gavrilov Dimitar K, Tortorelli Silvia, Hall Patricia L, Matern Dietrich, Lauer Emily, Pickart Angela, Salsbery Kyle, Niu Zhiyv, Smith Christy, Albright Amy, Mukherjee-Clavin Bipasha, Parmar Pooja, Mhoon Justin, Massie Rami, Pilon-Cadieux Camille, Gauthier Amelie, Alawneh Josef, Emilie Nguyen Cam-Tu, Shy Michael E, Koehler Alanna E, Carson Vincent J, Herrmann David N, Schultz Matthew J
Аннотация
BACKGROUND AND OBJECTIVES: Sorbitol dehydrogenase (SORD) deficiency, due to biallelic loss-of-function variants in the SORD gene, is a recently recognized cause of autosomal recessive hereditary neuropathy. Specific diagnosis is difficult on clinical grounds alone, and molecular genetic testing of SORD is complicated by the presence of a pseudogene. Biochemical testing of serum sorbitol is suggested as a potential biomarker. We report a novel urine biochemical profile of elevated excretion of sorbitol and a second polyol, xylitol, to aid in the identification of individuals with SORD-related neuropathy.
METHODS: Patients with confirmed or suspected SORD-related neuropathy were recruited by clinicians from 7 academic medical centers and 1 nonprofit specialty care center. Urine was analyzed by a clinically validated, gas chromatography-mass spectrometry assay to measure sorbitol and xylitol excretion. Over 700 reference samples were evaluated from residual clinical samples. Clinical and molecular findings were gathered using a standardized questionnaire.
RESULTS: Nineteen individuals with a clinical and genetic diagnosis of SORD-related neuropathy (median age 31 years, 47% female) and 715 reference samples were used to determine the initial performance of this index urine test. The median sorbitol excretion in affected individuals was 638 mmol/mol creatinine (1st percentile of disease range = 456; reference median = 7, reference 99th percentile = 198). The median xylitol excretion was 1,577 mmol/mol creatinine (1st percentile of disease range = 1,242; reference median = 7, reference 99th percentile = 102). In this patient cohort, the combination of sorbitol and xylitol yielded 100% sensitivity and specificity for SORD-related neuropathy. Four additional individuals who had clinical phenotypes compatible with SORD-related neuropathy had abnormal urine sorbitol/xylitol profile, 2 with genotypes involving a variant of unknown significance in SORD and 2 with a single heterozygous pathogenic SORD variant detected, whereas normal urine sorbitol/xylitol levels were observed in 11 asymptomatic, heterozygous carriers.
DISCUSSION: These data demonstrate the clinical utility of urine sorbitol and xylitol analysis in the screening and diagnosis of SORD deficiency-related neuropathy. In addition, this is the first description of elevated xylitol in SORD deficiency as a clinically informative biomarker, which may increase the specificity of biochemical testing.
METHODS: Patients with confirmed or suspected SORD-related neuropathy were recruited by clinicians from 7 academic medical centers and 1 nonprofit specialty care center. Urine was analyzed by a clinically validated, gas chromatography-mass spectrometry assay to measure sorbitol and xylitol excretion. Over 700 reference samples were evaluated from residual clinical samples. Clinical and molecular findings were gathered using a standardized questionnaire.
RESULTS: Nineteen individuals with a clinical and genetic diagnosis of SORD-related neuropathy (median age 31 years, 47% female) and 715 reference samples were used to determine the initial performance of this index urine test. The median sorbitol excretion in affected individuals was 638 mmol/mol creatinine (1st percentile of disease range = 456; reference median = 7, reference 99th percentile = 198). The median xylitol excretion was 1,577 mmol/mol creatinine (1st percentile of disease range = 1,242; reference median = 7, reference 99th percentile = 102). In this patient cohort, the combination of sorbitol and xylitol yielded 100% sensitivity and specificity for SORD-related neuropathy. Four additional individuals who had clinical phenotypes compatible with SORD-related neuropathy had abnormal urine sorbitol/xylitol profile, 2 with genotypes involving a variant of unknown significance in SORD and 2 with a single heterozygous pathogenic SORD variant detected, whereas normal urine sorbitol/xylitol levels were observed in 11 asymptomatic, heterozygous carriers.
DISCUSSION: These data demonstrate the clinical utility of urine sorbitol and xylitol analysis in the screening and diagnosis of SORD deficiency-related neuropathy. In addition, this is the first description of elevated xylitol in SORD deficiency as a clinically informative biomarker, which may increase the specificity of biochemical testing.