Dopa‐Responsive Parkinsonism in a Patient With Homozygous RFC1 Expansions

Abstract

We read the letter titled "RFC1 Intronic Repeat Expansions Absent in Pathologically Confirmed Multiple Systems Atrophy" published online in April 2020 1 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

Biallelic expansion in RFC1 as a rare cause of Parkinson’s disease

“…We found that the clinical phenotype of the three patients was consistent with PD and that their extrapyramidal symptoms unambiguously responded to levodopa. Patient 3 resembled a previous case of parkinsonism with biallelic RFC1 (AAGGG) exp in levodopa response, age of onset, dopamine transporter imaging and the presence of chronic cough 8 . However, the disease course appears to have been considerably milder in the previous patient, as her neuropathy was restricted to sensory fibers and, most importantly, she had ataxia 8 , which was not present in our patients.…”

“…Patient 3 resembled a previous case of parkinsonism with biallelic RFC1 (AAGGG) exp in levodopa response, age of onset, dopamine transporter imaging and the presence of chronic cough 8 . However, the disease course appears to have been considerably milder in the previous patient, as her neuropathy was restricted to sensory fibers and, most importantly, she had ataxia 8 , which was not present in our patients. Another patient has been reported with levodopa-responsive lower body parkinsonism and with incomplete CANVAS 7 .…”

“…We found that none of our patients had ataxia and that one patient (P1) was lacking all the three core features of CANVAS. The expansion in RFC1 has also been found in occasional patients with MSA, in a patient with CANVAS and levodopa responsive parkinsonism and in a patient with features of Lewy body dementia 4 – 8 . Bradykinesia has been reported in 26 % of ataxic RFC1 patients and it co-occurs with autonomic dysfunction yielding MSA-C phenotype in 19 % of the patients 7 .…”

“…Involvement of dopaminergic neurons in the striatum has been described in a patient with CANVAS and features of Lewy body dementia 4 . Furthermore, one patient with cerebellar ataxia, vestibulopathy and levodopa responsive lower body parkinsonism and another patient with the clinical triad of CANVAS and levodopa responsive parkinsonism have been reported 7 , 8 . Here we report on screening of a population-based cohort of Finnish patients with medicated parkinsonism for RFC1 (AAGGG) exp .…”

“…The phenotype associated with the expansion in RFC1 is multisystemic including cerebellar, neuropathic, autonomic, extrapyramidal, cognitive and even pyramidal signs 3 – 8 . Biallelic (AAGGG) exp in RFC1 commonly manifests as CANVAS or late-onset ataxia with chronic cough 3 .…”