Multisystemic RFC1-Related Disorder: Expanding the Phenotype Beyond Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome

Maria João Malaquias; Luis Braz; Cláudia Santos Silva; Joana Damásio; André Jorge; João M Lemos; Catarina F Campos; Daniela Garcez; Miguel Oliveira Santos; Ana G Velon; André Caetano; Margarida Calejo; Preza Fernandes; Ângela Rego; Sandra Castro; Ana P Sousa; Marcio Neves Cardoso; Marco Fernandes; Miguel M Pinto; Ricardo Taipa; Ana M Lopes; Jorge Oliveira; Marina Magalhães; for RFC1 Repeat Expansion National Study Group

doi:10.1212/CPJ.0000000000200190

Multisystemic RFC1-Related Disorder: Expanding the Phenotype Beyond Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome

Neurol Clin Pract. 2023 Oct;13(5):e200190. doi: 10.1212/CPJ.0000000000200190. Epub 2023 Sep 5.

Authors

Maria João Malaquias¹, Luis Braz¹, Cláudia Santos Silva¹, Joana Damásio¹, André Jorge¹, João M Lemos¹, Catarina F Campos¹, Daniela Garcez¹, Miguel Oliveira Santos¹, Ana G Velon¹, André Caetano¹, Margarida Calejo¹, Preza Fernandes¹, Ângela Rego¹, Sandra Castro¹, Ana P Sousa¹, Marcio Neves Cardoso¹, Marco Fernandes¹, Miguel M Pinto¹, Ricardo Taipa¹, Ana M Lopes¹, Jorge Oliveira¹, Marina Magalhães¹; for RFC1 Repeat Expansion National Study Group

Affiliation

¹ Department of Neurology (MJM, LB), Centro Hospitalar Universitário de São João, Porto; Department of Neurology (CSS, CFC, MOS), Centro Hospitalar Universitário Lisboa Norte; Centro de Estudos Egas Moniz (CSS), Faculdade de Medicina da Universidade de Lisboa; Department of Neurology (JD, MCM), Centro Hospitalar Universitário do Porto; Department of Neurology (AJ, JML), Centro Hospitalar Universitário de Coimbra; Department of Neurology (DG), Instituto Português de Oncologia de Lisboa Francisco Gentil; Department of Neurology (AGV), Centro Hospitalar De Trás-Os-Montes e Alto Douro, Vila Real; Department of Neurology (AC, MF), Centro Hospitalar de Lisboa Ocidental; Department of Neurology (MC), Unidade Local de Saúde de Matosinhos, Porto; Department of Cardiology (PF), Centro Hospitalar Universitário Lisboa Central; Department of Otolaryngology, Head and Neck Surgery (ÂR, SC); Department of Neurophysiology (APS, MNC); Neuropathology Unit (MMP, RT), Centro Hospitalar Universitário do Porto; Center for Predictive and Preventive Genetics (CGPP) (AML, JO), Institute for Molecular and Cell Biology (IBMC), Instituto de Investigacão e Inovação em Saúde (i3S), Universidade do Porto; and Department of Neurology (MCM), Centro Hospitalar do Tâmega e Sousa, Penafiel, Portugal.

Abstract

Background and objectives: The RFC1 spectrum has become considerably expanded as multisystemic features beyond the triad of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) have started to be unveiled, although many still require clinical replication. Here, we aimed to clinically characterize a cohort of RFC1-positive patients by addressing both classic and multisystemic features. In a second part of this study, we prospectively assessed small nerve fibers (SNF) and autonomic function in a subset of these RFC1-related patients.

Methods: We retrospectively enrolled 67 RFC1-positive patients from multiple neurologic centers in Portugal. All patients underwent full neurologic and vestibular evaluation, as well as neuroimaging and neurophysiologic studies. For SNF and autonomic testing (n = 15), we performed skin biopsies, quantitative sensory testing, sudoscan, sympathetic skin response, heart rate deep breathing, and tilt test.

Results: Multisystemic features beyond CANVAS were present in 82% of the patients, mainly chronic cough (66%) and dysautonomia (43%). Other features included motor neuron (MN) affection and motor neuropathy (18%), hyperkinetic movement disorders (16%), sleep apnea (6%), REM and non-REM sleep disorders (5%), and cranial neuropathy (5%). Ten patients reported an inverse association between cough and ataxia severity. A very severe epidermal denervation was found in skin biopsies of all patients. Autonomic dysfunction comprised cardiovascular (67%), cardiovagal (54%), and/or sudomotor (50%) systems.

Discussion: The presence of MN involvement, motor neuropathy, small fiber neuropathy, or extrapyramidal signs should not preclude RFC1 testing in cases of sensory neuronopathy. Indeed, the RFC1 spectrum can overlap not only with multiple system atrophy but also with hereditary motor and sensory neuropathy, hereditary sensory and autonomic neuropathy, and feeding dystonia phenotypes. Some clinical-paraclinical dissociations can pose diagnostic challenges, namely large and small fiber neuropathy and sudomotor dysfunction which are usually subclinical.