Severe distinct dysautonomia in RFC1-related disease associated with Parkinsonism

Abstract

Biallelic repeat expansions in replication factor C subunit 1 (RFC1) have recently been found to cause cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). Additional features that have been described include Parkinsonism and a multiple system atrophy (MSA)-like syndrome. CANVAS can include features of dysautonomia, but they are much milder than typically seen in MSA. We report a detailed autonomic phenotype of multisystem RFC1-related disease presenting initially as CANVAS. Our patient presented aged 61 with a sensory ataxic neuropathy who rapidly developed widespread autonomic failure and Parkinsonism. The autonomic profile was of a mixed pre- and post-ganglionic syndrome with progressive involvement of sympathetic and parasympathetic cardiovascular and sudomotor function. The Parkinsonism did not respond to levodopa. We present a patient with CANVAS and biallelic RFC1 expansions who developed Parkinsonism with severe autonomic involvement similar to that seen in classical MSA. The link between MSA and CANVAS remains uncertain.

Keywords: CANVAS; MSA; Parkinsons; RFC1; autonomic.

FIGURE 1

(A) DaT scan showing bilaterally markedly diminished basal ganglia uptake. (B) Southern blot of genomic DNA; two bands adjacent to the ladder corresponding to expansion sizes of n = 553 (white arrow) and n = 703 (black arrow), respectively. (C) (i) BP profile showing an example of normal response to Valsalva manoeuvre (ii) abnormal response to Valsalva manoeuvre in our patient; absent phase 2 late recovery (white arrow), and absent phase 4 overshoot (black arrow). (D) BP profile showing severe BP drop over 5 minutes of 60° head up tilt. (E) (i) Ambulatory 24 hours BP monitoring showing evidence of orthostatic hypotension and absent nocturnal circadian fall in BP. Blue line—systolic BP (SBP), orange line—diastolic BP (DBP). (ii) Corresponding heart rate. (F) Thermoregulatory sweat test shows (i) global anhidrosis with (ii) heart rate (lower dark blue trace), skin temperature (upper light blue trace) and (iii) inner ear temperature rise during the test. (G) Dynamic sweat test with (i) almost preserved sweating in upper limbs and (ii) severely reduced sweating in lower limbs