Angela M. Pickart

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. 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. 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. 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.

The dystrophinopathies encompass the phenotypically variable forms of muscular dystrophy caused by pathogenic variants in the DMD gene. The dystrophinopathies include the most common inherited muscular dystrophy among 46,XY individuals, Duchenne muscular dystrophy, as well as Becker muscular dystrophy and other less common phenotypic variants. With increased access to and utilization of genetic testing in the diagnostic and carrier setting, genetic counselors and clinicians in diverse specialty areas may care for individuals with and carriers of dystrophinopathy. This practice resource was developed as a tool for genetic counselors and other health care professionals to support counseling regarding dystrophinopathies, including diagnosis, health risks and management, psychosocial needs, reproductive options, clinical trials, and treatment. Genetic testing efforts have enabled genotype/phenotype correlation in the dystrophinopathies, but have also revealed unexpected findings, further complicating genetic counseling for this group of conditions. Additionally, the therapeutic landscape for dystrophinopathies has dramatically changed with several FDA‐approved therapeutics, an expansive research pathway, and numerous clinical trials. Genotype–phenotype correlations are especially complex and genetic counselors' unique skill sets are useful in exploring and explaining this to families. Given the recent advances in diagnostic testing and therapeutics related to dystrophinopathies, this practice resource is a timely update for genetic counselors and other healthcare professionals involved in the diagnosis and care of individuals with dystrophinopathies.