Vestibular function testing in patients with RFC1 mutations

Abstract

We read with interest the recent article by Tagliapietra et al. about RFC1 mutations in chronic idiopathic axonal polyneuropathy [undefined]. We are concerned about a limitation in this article, as well as in another recent article about the same subject [undefined]. It seems that there was no quantitative vestibular function testing in any of the 459 patients reported in these two articles. In our view, claiming absence of vestibular impairment in these patients is equivalent to claiming absence of sensory impairment in patients who have not had nerve conduction studies. We first reported what became the CANVAS phenotype as Cerebellar Ataxia with Bilateral Vestibulopathy [3]. Later, when we realized that somatosensory impairment was an integral part of the syndrome, we renamed it Cerebellar Ataxia Neuropathy Vestibular Areflexia Syndrome (CANVAS) [undefined]. In these patients, the severe bilateral vestibular loss with normal hearing was the chief clue to the fact that CANVAS was a specific syndrome, perhaps even a disease, rather than just the chance association of unrelated abnormalities. Here, to illustrate the importance of quantitative vestibular function testing in RFC1 patients, we show video head impulse testing (vHIT) in a patient with CANVAS. A male born in 1946 was referred in 2014 to a neurologist with increasing ataxia for about 2 years. His Romberg test was positive, and although clinically, there was no consistent sensory impairment and his tendon reflexes were preserved, his sensory action potentials were absent, so the diagnosis of sensory neuropathy was made. It was noted that he had a chronic cough and had seen a chest specialist about this; the cough was attributed to chronic obstructive pulmonary disease from smoking. A caloric vestibular test was ordered, the responses were symmetrical, at the low end of the normal range with peak nystagmus velocities: cold 9 and 10 deg/s, warm 14 and 12 deg/s. We reviewed the actual recordings and confirmed the findings. A video head impulse test was not done. A cause for the neuropathy was not found. His balance continued to deteriorate. In 2017, he was referred to another neurologist who confirmed the previous findings, found that the clinical head impulse test was positive and ordered repeat vestibular function tests at the same laboratory that had done the caloric tests 3 years before. The caloric tests were almost the same as in 2015. A vHIT was now done and showed marked impairment of all six semicircular canals (Fig. 1). He was then referred to one of us (GMH). The principal abnormal findings then were as follows: ataxia of gait and of all four limbs but no dysarthria; positive Romberg test even on a firm surface; impaired visually-enhanced vestibulo-ocular reflexes (VVOR) due to combined impairment of vestibulo-ocular reflexes and of visual smooth pursuit eye movements [3–6], but no gazeevoked nystagmus; impaired vibration sense in fingers and toes but preserved joint position sense; and preserved tendon reflexes. When questioned he confirmed that he experienced motion-induced oscillopsia. Nerve conduction studies again showed absent median, ulnar and sural sensory action potentials but normal motor conduction [7, 8]. MRI showed mild cerebellar atrophy in the pattern described in CANVAS [undefined]. Audiogram showed a severe age-related high-frequency hearing loss. A biallelic pathogenic AAGGG repeat expansion was detected in the RFC1 gene (Genetics Laboratory, University of Chicago). One of his sisters, living in the UK, had been diagnosed as having a severe axonal neuropathy. * Gábor M. Halmágyi [email protected]