Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG) exp ] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) 11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

The normal galvanic vestibulocollic responses indicate that sound sensitivity in patients with the Tullio phenomenon is likely to occur distal to the vestibular nerve, probably at the level of the receptors. Both click hypersensitivity and dehiscence of the anterior (superior) semicircular canal are associated with the Tullio phenomenon but as the CT scan abnormality can occur in clinically unaffected ears, click testing is important for specific diagnosis. Abnormal sound sensitivity, as demonstrated by click responses, confirms that the radiologic abnormality is function significant.

IntroductionMal de Debarquement Syndrome (MdDS) is a neurological condition typically characterized by a sensation of motion, that persists longer than a month following exposure to passive motion (e.g., cruise, flight, etc.). The most common form of MdDS is motion triggered (MT). However, recently it has been acknowledged that some patients develop typical MdDS symptoms without an apparent motion trigger. These cases are identified here as spontaneous or other onset (SO) MdDS. This study aimed to address similarities and differences between the MdDS subtypes. Diagnostic procedures were compared and extensive diagnostic guidelines were proposed. Second, potential triggers and associated psychological components of MdDS were revealed.MethodsThis was a retrospective online survey study for MT and SO MdDS patients. Participants were required to respond to a set of comprehensive questions regarding epidemiological details, as well as the diagnostic procedures and onset triggers.ResultsThere were 370 patients who participated in the surveys. It is indicated that MdDS is often misdiagnosed; more so for the SO group. In addition to the apparent self-motion, both groups reported associated levels of stress, anxiety and depression.DiscussionIt appears at present that both MdDS subtypes are still poorly recognised. This was the first attempt to evaluate the diagnostic differences between MdDS subtypes and to propose a set of comprehensive diagnostic guidelines for both MdDS subtypes. In addition, the current research addressed that associated symptoms such as stress, anxiety and depression should also be considered when treating patients. We hope this study will help the medical community to broaden their awareness and diagnostic knowledge of this condition.Electronic supplementary materialThe online version of this article (10.1007/s00415-017-8725-3) contains supplementary material, which is available to authorized users.

The 0.5/1 kHz frequency ratio, 0.5 kHz asymmetry ratio and caloric test combined, separated MD from VM with a sensitivity of 90.0% and specificity of 70.0%.

Vestibular‐dependent responses in leg muscles following transmastoid galvanic stimulation have been well characterized. Here we describe the properties of vestibulocollic responses evoked by transmastoid galvanic stimulation. In twelve healthy human subjects we examined the averaged responses in unrectified sternocleidomastoid (SCM) EMG evoked by transmastoid stimulation using current pulses of 4 mA intensity and 2 ms duration. In ten subjects we also examined the effects of unilateral vestibular stimulation with the indifferent electrode at the vertex. In further experiments we studied the effects of different levels of background muscle activation, head position, current intensity and current duration. We compared these responses with click‐evoked vestibulocollic responses in SCM. A clearly defined biphasic response, beginning with a surface positivity, was recorded in the SCM ipsilateral to the side of cathode placement in all subjects. We refer to this as the p13/n23 [g] (galvanic) response, given the close similarity, in terms of waveform and latencies, to the previously described click‐evoked p13/n23 vestibulocollic response. The amplitude of this response was linearly related to background muscle activation, current intensity and current duration, but independent of head position. Unilateral galvanic stimulation revealed the p13/n23 [g] response to be solely generated by the cathode. A biphasic response beginning with a surface negativity (n12/p20 [g]) contralateral to the cathode was seen in all subjects and was generated by both the cathode contralaterally and the anode ipsilaterally. Both the p13/n23 [g] and n12/p20 [g] potentials were abolished by selective vestibular nerve section and unaffected by severe sensorineural deafness. We conclude that galvanic stimulation evokes short‐latency vestibulocollic reflexes. These vestibulocollic reflexes have properties that are distinct from those described for galvanic‐evoked vestibular reflexes in leg muscles, and which may be related to their differing physiological roles.