Clinical phenotyping is key to differentiating RFC1-associated neuropathy from immune-mediated neuropathy

TL;DR

The paper discusses how clinical phenotyping helps distinguish RFC1-related neuropathy from immune-related neuropathy.

Contribution

It emphasizes the importance of clinical features in differentiating RFC1-associated neuropathy from immune-mediated forms.

Findings

RFC1 repeat expansions are not linked to inflammatory neuropathies.

Clinical phenotyping is essential for accurate diagnosis and differentiation of neuropathy types.

Abstract

This scientific commentary refers to ‘Pathologic RFC1 repeat expansions do not contribute to the development of inflammatory neuropathies’, by Nagy et al. (https://doi.org/10.1093/braincomms/fcae163).

Full text

This scientific commentary refers to ‘Pathologic RFC1 repeat expansions do not contribute to the development of inflammatory neuropathies’, by Nagy et al. (https://doi.org/10.1093/braincomms/fcae163).

Biallelic pathogenic intronic AAGGG repeat expansions in the RFC1 gene were found to be associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) in 2019.^1^ Since then, several groups have identified biallelic RFC1 repeat expansions in a small number of patients previously diagnosed with immune-mediated neuropathies.^2‐4^ These findings raise the question of whether patients with inflammatory neuropathies should be screened for RFC1 repeat expansions. The study by Nagy et al.^5^ in this issue of Brain Communications sought to answer this question by screening a large number of patients (n = 259) with various forms of immune-mediated neuropathies for pathogenic RFC1 repeat expansions.

Unlike the preceding groups, Nagy et al.^5^ did not identify any patients with biallelic pathogenic RFC1 repeat expansions within their cohort. In addition, they found that the carrier frequency of pathogenic RFC1 repeat expansions in their cohort was comparable to the general population. Their findings may be attributed to differences in clinical presentation of RFC1-associated neuropathy compared to immune-mediated neuropathy (Table 1). Typically, RFC1-associated neuropathy is a slowly progressive, sensory predominant axonal neuropathy with little to no motor involvement.^1,2^ In contrast, immune-mediated neuropathies usually present with mixed sensorimotor involvement, with chronic inflammatory demyelinating polyneuropathy (CIDP), the most common chronic immune-mediated neuropathy, presenting with a demyelinating picture.^6^ Nagy et al.^5^’s cohort consisted of patients with CIDP, multifocal motor neuropathy (MMN) and acute inflammatory demyelinating neuropathy (AIDP), all conditions with a different clinical phenotype to that of RFC1-associated sensory neuropathy. In Hirano et al.^4^’s cohort, patients who were found to have biallelic pathogenic RFC1 expansions (4 out of 240) were diagnosed with Guillain–Barre syndrome (GBS), idiopathic sensory ataxic neuropathy, myelin-associated glycoprotein neuropathy and sensory autonomic neuropathy, all conditions with a predominantly sensory presentation though motor involvement was also present in 3 out of 4 patients. Similarly, 7 out of 42 patients with chronic idiopathic axonal neuropathy from Currò et al.^2^’s cohort with biallelic RFC1 pathogenic variants were previously diagnosed with an inflammatory cause including CIDP, Sjogren’s syndrome, vasculitis, post-infectious and paraneoplastic. Therefore, clinical presentation, nerve conduction study findings and nerve biopsy results are likely able to differentiate patients who have an immune-mediated neuropathy from those who have a sensory axonal neuropathy that could be associated with RFC1 (Table 1, note that no new data was generated in support of this commentary).

The phenotypic spectrum of RFC1-associated disorders continues to expand. Widespread neurodegeneration has been demonstrated with the presence of cerebral and cerebellar atrophy on MRI, increased CSF neurofilament light chain levels and total tau.^8^ Common symptoms include chronic cough, dysarthria, dysphagia, falls, cerebellar and vestibular dysfunction.^2^ Presence of these symptoms may be useful to identify patients who are more likely to have RFC1-mediated neuropathy.

Interestingly, some patients with biallelic RFC1 repeat expansions were reported to respond to immune-therapy.^4^ It is possible that RFC1-associated neuropathy can co-exist with immune-mediated processes. The carrier frequency and therefore population prevalence of pathogenic RFC1 expansions are not insignificant,^9^ and therefore, co-existence with immune-mediated neuropathies should be considered. This has implications for treatment and may be relevant in individuals with known RFC1 neuropathy who may be progressing faster than expected, or in individuals with diagnosed immune-mediated neuropathy who stop responding to treatment.

The underlying pathophysiology of RFC1-associated neuropathy remains unknown. Therefore, it is unclear if carriers of pathogenic RFC1 expansions could be at risk of neuropathy. Nagy et al.^5^ reported that the carrier frequency for pathogenic RFC1 alleles in their cohort was comparable to controls. This finding contributes to evidence that there is no increased risk of neuropathy in carriers of pathogenic RFC1 expansions. Further studies into the pathogenesis of RFC1-mediated neuropathy will provide insights into the mechanisms of disease and the implications for heterozygous carriers.

In an era of increasing use of genetic testing, identification of patients who are most likely to have a genetic neuropathy is important for efficient utilization of health resources and to minimize side effects of unnecessary investigations and treatments (e.g. sural nerve biopsies, immunotherapy). However, the study by Nagy et al. does not support routine testing of the RFC1 gene in patients with immune-mediated neuropathy. Instead, the best approach may be accurate phenotyping to prioritize those individuals who would benefit from RFC1 testing.

Overall, Nagy et al.’s paper contributes to the growing literature exploring the presence of biallelic pathogenic RFC1 expansions in various forms of neuropathy. Their findings highlight the importance of clinical assessment and consideration of investigation findings to differentiate RFC1-associated neuropathy from immune-mediated neuropathy, a distinction of high clinical relevance given the therapeutic implications.