Reply to: “Dopa‐Responsive Parkinsonism in a Patient With Homozygous RFC1 Expansions”

We would like to thank da Silva Schmitt and colleagues for their response to our publication concerning the RFC1 repeat expansion in pathologically confirmed multiple systems atrophy.1 da Silva Schmitt and colleagues describe an interesting patient who presents with dopa-responsive parkinsonism and is positive for the RFC1 AAGGG repeat expansion on triplet-repeat primed polymerase chain reaction (TP-PCR). The parkinsonian symptoms manifested as bradykinesia, resting tremor, and stiffness and were supported by a reduction of dopaminergic transporters uptake in bilateral striatum in the dopamine transporter scan. Interestingly, the patient demonstrated impaired vestibulo-ocular reflexes bilaterally and a 20-year history of a chronic dry cough and sensory neuropathy, which are all main features of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In addition, the patient did not present with autonomic features, rapid eye movement behavior disorder, and hypo/anosmia, conflicting a diagnosis of classical Parkinson's disease. Although da Silva Schmitt and colleagues ruled out other relevant variants using whole-exome sequencing, and TP-PCR yielded a positive result, it is important to confirm all TP-PCR positive cases with Southern blotting. Southern blotting TP-PCR positive cases rules out carriers and false positives. It also allows for the accurate sizing of the expansion, which would be interesting in this case because of the phenotypic differences seen in this patient.2 Since the identification of RFC1 expansions in CANVAS we have seen this disorder as a clinical spectrum.3 This ranges from mild ataxia with sensory neuropathy, to the CANVAS clinical syndrome, through to a more rapidly progressive ataxia with parkinsonism, autonomic dysfunction, and an abnormal dopamine transporter scan; a clinical overlap between CANVAS and multiple systems atrophy, with RFC1 expansions on repeat-primed PCR and Southern blotting (unpublished data). We predict that the phenotypic spectrum associated with the RFC1 repeat expansion is likely to be broader than previously described as in the report of da Silva Schmitt and colleagues. It would therefore be of great importance to screen larger cohorts of patients, particularly in cohorts of different ethnic origins with atypical and even typical parkinsonism, as well as ataxic disorders for the RFC1 expansion, to confirm its prevalence and further define the RFC1 clinical spectrum. We thank all patients and families for their support as well as clinical and laboratory collaborators who are essential to our work. We are grateful for support from The Wellcome Trust, Medical Research Council, the Rosetree Trust, Ataxia UK, the Multiple Systems Atrophy Trust, The Multiple Systems Atrophy Coalition, and The National Institute for Health Research University College London Hospitals Biomedical Research Centre. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. First Draft, B. Review and Critique. R.S.: 1A, 1B, 1C, 1D, 2A, 2B, 2C, 3A, 3B. W.Y.: 1B, 1C, 2B, 2C, 3A, 3B V.C.: 1C, 3A, 3B S.R.: 1C, 3A, 3B E.O.C.: 3A, 3B N.W.: 3A, 3B A.C.: 1A, 2C, 3A, 3B H.H.: 1A, 1B, 1C, 1D, 2A, 2B, 2C, 3A, 3B

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