By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: In most cases of chronic axonal polyneuropathy, no specific cause is found. Using a polygenic risk score for potential risk factors, based on whole genome sequencing, these investigators identified multiple significant risk factors, including diabetes, body mass index, alcohol intake, and vitamin B12 level.
SOURCE: Taams NE, Knol MJ, Hanewinckel R, et al. Genetic evidence for the most common risk factors for chronic axonal polyneuropathy in the general population. Eur J Neurol 2022; Mar 5. doi: 10.1111/ene.15311. [Online ahead of print].
Polygenic scores (PGSs), also referred to as risk scores, genetic risk scores, or genome-wide scores, summarize the effect of common genetic variants on an individual’s phenotype, yielding evidence for underlying genetic associations between risk factors and phenotype. With respect to chronic axonal polyneuropathy (CAP), known associations include diabetes, vitamin deficiency, alcohol, older age, and chemotherapy. No risk factor is found in up to 50% of CAP cases, not everyone with these risk factors develops CAP, and whether these associations are genetically linked remains unproven. PGSs can address this question, and this study developed PGSs, based on published genome-wide association studies, to determine if PGSs of diabetes, body mass index (BMI), vitamin B12 level, and alcohol intake were linked to CAP and, more particularly, to sural sensory nerve action potential amplitude.
Performed within the Rotterdam Study, an ongoing population-based Netherlands cohort study investigating several chronic diseases, this study screened 2,069 participants for CAP between 2013 and 2017, using a symptom questionnaire, neurologic examination of the legs, and sural sensory nerve conduction studies (NCS), as well as review of their medical records for a specific diagnosis of CAP and its risk factors. Questionnaire screening was comprised of 12 questions regarding abnormal sensations including, among others, numbness, tingling, burning, or stabbing, while the neurologic examination of the legs focused on sensory testing, deep tendon reflexes, and ankle dorsiflexion strength. Sural NCS were performed bilaterally using standard technique, measuring amplitude from baseline to peak, with the highest of either sural nerve used for analysis, and an amplitude < 4.0 µV considered abnormal. Statistical analysis included, but was not limited to, logistic regression analysis and permutation testing.
Among the 2,069 participants screened, 150 were insufficiently screened and two had hereditary polyneuropathy, leaving 1,917 subjects, of which 1,565 had genotyping and are included in this study. CAP was found in 215, and the remaining 1,350 served as controls. Mean age was 73.6 years, with females slightly more predominant (53.5%). CAP was more prevalent among those with higher PGSs of alcohol consumption, BMI, and diabetes, whereas it was less prevalent among those with higher PGSs of vitamin B12 level, with no association found between any of these PGSs and sural sensory nerve action potential amplitude. Polygenic association of diabetes, BMI, alcohol intake, and vitamin B12 level with CAP appears real, supporting a causal association between these well-known risk factors and CAP.
COMMENTARY
What percentage of chronic idiopathic axonal polyneuropathy (CIAP) might be the result of a single genetic mutation? In patients diagnosed with CIAP, family history is negative, age of onset is higher than for most hereditary neuropathies, and thus far no genetic cause has been identified. Recently, biallelic intronic AAGGG repeat expansions in the replication factor complex subunit 1 (RFC1) gene have been identified as the cause of CANVAS (cerebellar ataxia, neuropathy, vestibular areflexia syndrome), with sensory neuropathy seen in all patients with biallelic RFC1 expansions.
Might this expansion account for some cases of CIAP? In a retrospective analysis of 225 patients, 125 with sensory CIAP and 100 with sensorimotor CIAP, biallelic RFC1 expansions were found in 34% with sensory CIAP and none with sensorimotor CIAP.1 Sensory amplitudes were absent (26%) or reduced in a length-dependent (30%) or non-length-dependent (44%) pattern. RFC1 AAGGG biallelic expansions represent a significant genetic cause of sensory CIAP (34%).
REFERENCE
- Curro R, Salvalaggio A, Tozza S, et al. RFC1 expansions are a common cause of idiopathic sensory neuropathy. Brain 2021;144:1542-1550.
