Avoid common mistakes on your manuscript.
Dear Sirs,
In 2019, non-parametric linkage analyses and genome sequencing revealed that biallelic AAGGG expansions in the replication factor C subunit 1 (RFC1) gene are a frequent cause of late-onset ataxia [1]. Subsequent studies described the phenotypic spectrum of patients with pathological RFC1 expansion: they mainly presented in their fifth decade of life with a triad of cerebellar dysfunction (i.e., gait ataxia, dysarthria, ocular motor disorders), sensory neuropathy with concomitant sensory ataxia, and vestibular areflexia bilaterally, denoted by the acronym CANVAS [1]. Quite recently, a multicentre observational study has shown that RFC1 expansion comprises a multisystemic disease with a chronic dry cough, dysautonomia, and bradykinesia as additional clinical features of variable degree [2].
It is still an outstanding issue, whether biallelic AAGGG expansion in RFC1 are not associated with an even broader phenotypic spectrum of neurodegenerative diseases.
A 64-year-old male presented with a 1-year history of progressive and painless weakness of both hands. Neurological examination revealed generalized polytopic muscle fasciculations in 4/4 levels, muscle paresis for finger adduction/abduction (r: MRC 4–5, l: MRC 4), finger extension (r: MRC 4–5, l: MRC 4), thumb opposition (r: MRC 4–5, l: MRC 4), wrist extension/flexion (r: MRC 4–5, l: MRC 4) and hip flexion (r/l: MRC 4–5). A split hand sign was conspicuous on both sides. Muscle reflexes were brisk on the left upper limb with decreased ankle jerks bilaterally. There were neither relevant sensory/proprioceptive deficits nor clinical signs of ataxia/vestibulopathy. Clinical suspicion of a degenerative motor neuron disease was confirmed by electromyography, muscle ultrasound and transcranial magnetic stimulation (for details see Table 1). Sural and superficial peroneal nerve potentials and sensory evoked potentials of the tibial nerves (P40) were absent bilaterally.
Finally, amyotrophic lateral sclerosis (ALS) was diagnosed according to the current diagnostic criteria (see Table 1). Additionally, regarding sensory nerve conduction studies and evoked potentials subclinical sensory neuropathy/neuronopathy was diagnosed.
Acquired conditions for sensory neuropathies/neuronopathies were excluded (see Table 1). The patient did not consent to a recommended additional CSF analysis.
Genetic analysis by CRISPR/Cas9 target enrichment and Oxford Nanopore long-read sequencing [3], revealed biallelic AAGGG repeat expansions (~ 400) of the RFC1 locus. Negative results of all genetic testing are listed in Table 1.
Due to the detected biallelic RFC1 repeat expansions we post-hoc performed vestibular testing by inner ear calorics and video-assisted head-impulse-test, which revealed isolated bilateral presbyvestibulopathy in the low-frequency range (see Table 1).
This case with a diagnosis of ALS, additional subclinical sensory neuro(no)pathy and bilateral presbyvestibulopathy in the low-frequency range in association with a biallelic RFC1 expansion raises the following noteworthy future question: is ALS/motor neuron disease within the phenotypic spectrum of biallelic RFC1 repeat expansions?
To our knowledge, this is the first case of an ALS patient with a concomitant subclinical sensory neuro(no)pathy and bilateral presbyvestibulopathy carrying a biallelic RFC1 repeat expansion. The number of genes associated with monogenic forms or increased risk of ALS is constantly growing including intermediate expansions of the SCA 1,2 genes and huntingtin-trinucleotide expansions [4, 5]. Acknowledging previous reports with abnormal findings in sensory nerve conduction studies in up to 20% of patients with ALS [6] and earlier morphological findings in sensory nerve biopsies suggesting loss of sensory root ganglion neurons [7], an involvement of pathological RFC1 expansions as additional monogenic form or at least genetic risk factor for ALS might be discussed. However, one must admit, that we cannot differentiate an association of pathological RFC1 expansions with a combined phenotype of ALS and sensory neuro(no)pathy in our patient from a bare coincidence of ALS with a beginning CANVAS phenotype due to RFC1 pathology. A recent study indeed found RFC1 expansions exclusively in so far “idiopathic” sensory neuropathies, but not in patients with “idiopathic” sensorimotor neuropathies [8]. Thus a clear link of RFC1 pathology with the motor system is missing so far. Since RFC1 mediated pathology affects the sensory ganglion cells and not the peripheral sensory nerves, the findings from Currò et al. are plausible [8]. A recent study revealed that pathogenic SPTLC1 mutations are not only associated with the phenotype of sensory and autonomic neuropathy (i.e. HSAN type 1), but also with juvenile onset ALS [9]. And, for the rare syndrome of “facial onset sensory motor neuronopathy” (FOSMN) typically beginning with sensory symptoms of the trigeminal nerves, underlying TDP-43 pathology in sensory ganglion cells as well as motor neurons was confirmed [10,11,12], thus classifying FOSMN currently as a rare form of motor neuron disease.
An important limitation of the presented case is, that we cannot assess the influence of rare genetic variants with small effect size or their combinatory effect in terms of polygenic risk modification.
In conclusion, the presented case with a concomitant sensory neuro(no)pathy and proven RFC1 expansion in addition to ALS should prompt a more systematical search for RFC1 expansion in larger patient cohorts with ALS and unexplained sensory involvement in order to disentangle a possible role of RFC1 pathology in ALS.
References
Cortese A, Tozza S, Yau W et al (2020) Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion. Brain J Neurol [online serial]. https://pubmed.ncbi.nlm.nih.gov/32040566/. Accessed 4 July 2021
Traschütz A, Cortese A, Reich S et al (2021) Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1 disease. Neurology [online serial]. https://pubmed.ncbi.nlm.nih.gov/33495376/. Accessed 4 July 2021
Gilpatrick T, Lee I, Graham JE et al (2020) Targeted nanopore sequencing with Cas9-guided adaptor ligation. Nat Biotechnol 38:433–438
Li P, Sun X, Xia G et al (2016) ATXN2-AS, a gene antisense to ATXN2, is associated with spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis. Ann Neurol [online serial]. https://pubmed.ncbi.nlm.nih.gov/27531668/. Accessed 4 July 2021
Dewan R, Chia R, Ding J et al (2021) Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Neuron [online serial]. https://pubmed.ncbi.nlm.nih.gov/33242422/. Accessed 4 July 2021
Pugdahl K, Fuglsang-Frederiksen A, de Carvalho M et al (2007) Generalised sensory system abnormalities in amyotrophic lateral sclerosis: a European multicentre study. J Neurol Neurosurg Psychiatry 78:746–749
Heads T, Pollock M, Robertson A, Sutherland W, Allpress S (1991) Sensory nerve pathology in amyotrophic lateral sclerosis. Acta Neuropathol (Berl) [online serial]. https://pubmed.ncbi.nlm.nih.gov/1662002/. Accessed 15 July 2021
Currò R, Salvalaggio A, Tozza S et al (2021) RFC1 expansions are a common cause of idiopathic sensory neuropathy. Brain J Neurol [online serial]. 2021. https://pubmed.ncbi.nlm.nih.gov/33969391/. Accessed 26 Sept 2021
Jo J, R C, De M et al (2021) Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis. JAMA Neurol [online serial]. https://pubmed.ncbi.nlm.nih.gov/34459874/. Accessed 26 Sept 2021
Vucic S, Tian D, Chong PST, Cudkowicz ME, Hedley-Whyte ET, Cros D (2006) Facial onset sensory and motor neuronopathy (FOSMN syndrome): a novel syndrome in neurology. Brain 129:3384–3390
Vucic S (2014) Facial onset sensory motor neuronopathy (FOSMN) syndrome: an unusual amyotrophic lateral sclerosis phenotype? J Neurol Neurosurg Psychiatry [online serial]. https://pubmed.ncbi.nlm.nih.gov/24643461/. Accessed 26 Sept 2021
Rossor A, Jaunmuktane Z, Rossor M, Hoti G, Reilly M (2019) TDP43 pathology in the brain, spinal cord, and dorsal root ganglia of a patient with FOSMN. Neurology [online serial]. https://pubmed.ncbi.nlm.nih.gov/30700593/. Accessed 26 Sept 2021
Funding
Open Access funding enabled and organized by Projekt DEAL. No funding was received for this study.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. The first draft of the manuscript was written by FS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflicts of interest
Dr. Schöberl reports no disclosures; Dr. Abicht reports no disclosures; Dr. Kuepper reports no disclosures; Dr. Voelk reports no disclosures; Dr. Sonnenfeld reports no disclosures; Dr. Tonon reports no disclosures; Ms Schaub reports no disclosures; Ms Scholz reports no disclosures; Dr. Kleinle reports no disclosures; Dr. Wolf reports no disclosures; Dr. Erdmann reports no disclosures; Dr. Reilich reports no disclosures.
Ethical approval
We have obtained the patient´s permission and informed consent for publishing of his information/case.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Schoeberl, F., Abicht, A., Kuepper, C. et al. Sensory neuropathy due to RFC1 in a patient with ALS: more than a coincidence?. J Neurol 269, 2774–2777 (2022). https://doi.org/10.1007/s00415-021-10835-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-021-10835-9