Dopa‐Responsive Parkinsonism in a Patient With Homozygous <scp><i>RFC1</i></scp> Expansions

Abstract

We read the letter titled “RFC1 Intronic Repeat Expansions Absent in Pathologically Confirmed Multiple Systems Atrophy” published online in April 20201 with great interest. In light of that letter, we would like to expand the phenotypic spectrum of RFC1 expansion-related disorders by reporting dopa-responsive parkinsonism in a 63-year-old woman. She developed parkinsonian symptoms in her early 50s, characterized by bradykinesia, resting tremor, and stiffness. The patient was started on levodopa as a symptomatic therapy with overt gait improvement (Video S1). Approximately 1 year later, she noticed oscillopsia and sensory complaints described as asymmetrical limb paresthesia that became confluent and associated with decreased vibration as well as proprioceptive sensation leading to gait unsteadiness. Head impulse test demonstrated absent vestibulo-ocular reflex bilaterally. A 20-year dry cough history was also reported. Brain magnetic resonance imaging and laboratory workup were unremarkable. Nerve conduction studies showed diffuse abnormalities restricted to sensory nerves, quantitative sudomotor axonal reflex was normal, and heart rate variability revealed incipient cardiac dysautonomia. Dopamine transporter scan highlighted a marked reduction of dopaminergic transporters in the bilateral striatum (Fig. 1A). Whole-exome sequencing failed to identify relevant variants, but triplet-repeat primed polymerase chain reaction detected biallelic (AAGGGn) intronic RFC1 expansions (Fig. 1C). Since the description of biallelic intronic RFC1 expansions as the underlying cause for cerebellar ataxia with neuropathy and vestibular areflexia syndrome in 2019, the full phenotypic spectrum related to this genetic abnormality remains to be determined.1-3 Herein we report a patient with RFC1 expansions leading to cerebellar ataxia with neuropathy and vestibular areflexia syndrome and dopa-responsive parkinsonism as part of her clinical picture. Although different cohorts involving patients with parkinsonism in the context of multiple system atrophy failed to demonstrate intronic RFC1 expansions as a causative factor,1, 3 we hypothesize that parkinsonism could be related to RFC1 in our patient. Indeed, the absence of autonomic features (with normal quantitative sudomotor axonal reflex) and hypo/anosmia combined with the lack of rapid eye movement behavior disorder all argue against the diagnosis of classical Parkinson's disease. Her benign clinical course without motor fluctuations more than a decade after levodopa start is also atypical. Lastly, the simultaneous occurrence of 2 rare conditions—homozygous RFC1 expansions and young-onset parkinsonism—just by chance would be possible but, rather, improbable. This description, although anecdotic, raises the possibility that dopa-responsive parkinsonism is part of the RFC1 clinical spectrum. Further studies in young-onset parkinsonian patients should be done to validate this assumption. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the first draft, B. Review and Critique. G.S.S.: 1B, 1C, 2A A.R.M.M.: 1A, 1B, 2B F.F.G.: 1A, 2B F.D.L.: 1A, 2B L.C.B.: 1B, 1C, 2B B.J.A.: 1C, 2B A.N.: 1A, 2B M.C.F.: 1A, 1B, 2B Video S1: A video highlighting the described patient in prelevodopa and postlevodopa treatment. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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