By Jennifer Langsdorf, MD
Synopsis: This is an observational, cross-sectional study of patients seen at a specialized neuromuscular center with a clinical diagnosis of hereditary polyneuropathy, without a previously identified genetic diagnosis. The goal of this study was to assess the combination of clinical reassessment with updated genetic testing, including whole genome sequencing. Reassessment improved the diagnostic clarification rate in these patients.
Source: Kodal LS, Duno M, Dysgaard T. Clinical and genetic reassessment in patients with clinically diagnosed hereditary polyneuropathy. Eur J Neurol. 2025;32(8):e70301.
Hereditary polyneuropathy can cause progressive neurologic impairment and disability, including weakness, sensory loss, foot deformities, and loss of mobility and ambulation. With standard genetic testing, an underlying genetic mutation may not be determined. Genetic identification of the cause of hereditary polyneuropathy is important to determine prognosis, to provide genetic counseling to family members, to optimize clinical care, and to provide access to potential future treatments.
This study used patient records and diagnosis codes to identify 386 patients with hereditary polyneuropathy evaluated at the Copenhagen Neuromuscular Centre between 2016 and 2023. Of these, 244 patients were excluded because of previously genetically confirmed diagnoses, and 77 others were excluded because of reasons such as death or symptom onset at older than 70 years of age. The remaining 66 genetically unconfirmed patients were invited to participate. Forty-four patients were included, for whom the mean age at symptom onset was 31.2 years. Of these patients, 47.8% had a family history of neuropathy and 95.5% had at least one previous genetic test. The most common previous genetic testing performed was next-generation sequencing of 32 genes in 81.8%.
All patients included were reassessed by neurological examination, composite scoring, blood testing for contributing causes, and whole genome sequencing. Composite scoring used either the Charcot-Marie-Tooth Examination Score (no nerve conduction study [NCS] data available) or the Charcot-Marie-Tooth Neuropathy Score, version 2 (NCS data available). Laboratory testing included antinuclear antibody (ANA), creatine kinase (CK), immunoglobulin levels, vitamin B12, and hemoglobin A1c. If indicated, imaging studies and lumbar puncture also were performed. The main outcome was the rate of diagnostic clarification achieved by reassessment including whole genome sequencing. Based on the reassessment, patients were stratified into three groups: genetic findings, nongenetic etiologies, and no identified etiology.
The most common clinical presentation of the genetically unconfirmed cases was axonal polyneuropathy in 68%. Only 11% of the unsolved cases had demyelinating polyneuropathy. Neuropathic pain was reported in 9.1% and autonomic dysfunction was reported in 7.5% of the patient cohort. Asymmetric polyneuropathy was found in 15.9% of patients.
The study identified a relevant genetic variant in 13 out of the 44 patients, yielding a genetic clarification rate of 30%. Excluding the patients with genetic variants classified as variants of underdetermined significance (VUS) and heterozygotes in disorders associated with recessive conditions, the investigators found a validated genetic variant clarification rate of 21%. The most frequent genetic finding was a homozygous c.757del in the sorbitol dehydrogenase (SORD) gene found in four out of the 44 patients. The SORD gene is associated with recessive axonal polyneuropathy with symptom onset in adolescence.
The study also was able to identify a nongenetic etiology in six out of the 44 patients (14%) for whom no previous diagnosis had been found. These causes included systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy (CIDP), tethered cord syndrome, and medullary disc protrusion. The identification of other potentially treatable causes also is of high utility. Including these patients with other nongenetic etiologies, the overall diagnostic clarification rate for this reassessment was 44% (19 out of 44 patients).
Commentary
The aim of this study was to determine if the combination of clinical reassessment with renewed genetic testing, including whole genome sequencing, improved the diagnostic clarification rate in patients with clinically diagnosed hereditary polyneuropathy. The study resulted in a diagnostic clarification rate of 44%, resulting in both confirmed genetic etiologies and the discovery of nongenetic, potentially treatable underlying causes. This highlights the utility of clinical reassessment along with whole genome sequencing for similar previously undiagnosed patients with presumed hereditary polyneuropathy, especially given the potential for therapeutic interventions.
Jennifer Langsdorf, MD, is Assistant Professor of Neurology, Peripheral Neuropathy Center, Weill Cornell Medical College.
