Clinical and Histopathological Features of Gelsolin Amyloidosis Associated with a Novel GSN Variant p.Glu580Lys.

Gelsolin amyloidosis typically presents with corneal lattice dystrophy and is most frequently associated with pathogenic GSN variant p.Asp214Asn. Here we report clinical and histopathological features of gelsolin amyloidosis associated with a novel GSN variant p.Glu580Lys. We studied DNA samples of seven members of a two-generation family. Exome sequencing was performed in the proband, and targeted Sanger sequencing in the others. The heterozygous GSN variant p.Glu580Lys was identified in six patients. The patients exhibited corneal dystrophy (5/6), loose skin (5/6) and/or heart arrhythmia (3/6) and one presented with bilateral optic neuropathy. The impact of the mutation on the protein structure was evaluated in silico. The substitution is located in the fifth domain of gelsolin protein, homologous to the second domain harboring the most common pathogenic variant p.Asp214Asn. Structural investigation revealed that the mutation might affect protein folding. Histopathological analysis showed amyloid deposits in the skin. The p.Glu580Lys is associated with corneal dystrophy, strengthening the association of the fifth domain of gelsolin protein with the typical amyloidosis phenotype. Furthermore, optic neuropathy may be related to the disease and is essential to identify before discussing corneal transplantation.

Distractibility predicts favourable response of functional tremor to transcranial magnetic stimulation: An electrophysiological study.

BACKGROUND: Generation of functional tremor relies on the structures involved in the control of voluntary movements. The clinical diagnosis is based on the presence of "positive signs", which are expression of cognitive and motor distractibility and reflect functional tremor dependence on explicit motor control. In patients who manifest less distractibility, habitual (implicit) control may be of greater significance. Habitual behaviours are inflexible and difficult to eradicate. OBJECTIVES: To investigate if motor and cognitive distractibility predicts response to treatment with repetitive transcranial magnetic stimulation. METHODS: 21 patients with functional tremor underwent 5-day repeated sessions of continuous theta burst stimulation over primary motor cortex. A battery of tests to provoke positive signs was performed during accelerometry recordings and the total functional tremor accelerometry score was calculated for each patient. Response to treatment was measured as change in tremor amplitude, expressed as total power of the spectra between 1 and 30 Hz. RESULTS: On the group level, cTBS significantly changed postural tremor amplitude (Z = -1.9; p = 0.05), with the median decrease of 40%, IQR (-90-(+24)). There was a positive correlation between the functional tremor accelerometry score and reduction of postural tremor amplitude with treatment (rs = -0.75, p < 10-3). Responders had higher functional tremor accelerometry scores compared to non-responders (p = 0.001). The total functional tremor accelerometry score was a significant predictor of treatment response (OR = 2.8, p = 0.03; 95% CI 1.1; 7.2). CONCLUSIONS: Patients who are more distractible are better candidates for treatment with transcranial magnetic stimulation. The likely explanation is the between-subjects differences on the reliance of functional tremor generation on explicit vs. implicit motor network.

Shaky hands are a part of motor neuron disease phenotype: clinical and electrophysiological study of 77 patients.

BACKGROUND: In the sharp contrast with the existing literature, we frequently observe minipolymyoclonus, tremor and pseudodystonic thumb posturing in patients with motor neuron disease. We conducted a clinical and electrophysiological study to describe phenomenology, prevalence and pathophysiology of involuntary movements in motor neuron disease. METHODS: We included 77 consecutive patients. Involuntary movements were assessed at rest and on action. Patients were videotaped. Arm muscle tone, power and deep tendon reflexes were evaluated. Accelerometry with electromyography was recorded in a subset of patients. RESULTS: Involuntary movements were observed in 68.9% of patients and could be separated into rest minipolymyoclonus, thumb tremor, pseudodystonic thumb posture, action minipolymyoclonus, and action tremor. One-third of patients reported negative impact of involuntary movements on hand use. Logistic regression showed that rest minipolymyoclonus and thumb tremor were more likely to occur in patients with more prominent distal muscle weakness and less spasticity. Similarly, action involuntary movements were more likely to appear in weaker patients. Patients with brisk tendon reflexes were more likely to display action tremor than action minipolymyoclonus. Action tremor was characterized by accelerometer and corresponding electromyography peak frequency, which decreased with mass loading, suggesting a mechanical-reflex tremor. CONCLUSIONS: Involuntary movements are common, but poorly recognized feature of motor neuron disease that may add to functional impairment. Results of our study suggest that involuntary movements are likely of peripheral origin, with a non-fused contraction of enlarged motor units being a common driving mechanism. Minipolymyoclonus appears if no synchronization of motor units occurs. When synchronization occurs via stretch reflex, mechanical-reflex tremor is generated.

IMG-01 The spectrum of involuntary movements in patients with motor neuron disease: a cross-sectional study.

Background: We have commonly observed involuntary jerks and tremor in patients with motor neuron disease (MND), even though these features are not considered typical for the disease.Objectives: We conducted prospective clinical and electrophysiological study to explore the prevalence, phenomenology and pathophysiology of involuntary movements in MND.Methods: Seventy-four consecutive patients were clinically examined and video-recorded. Based on regularity and distribution, movements observed at rest position were classified as minipolymyoclonus (MPMC) or rest thumb tremor (RTT) and movements present during action as action MPMC or action tremor. In 11 patients with tremor, accelerometry was recorded at (a) rest position, (b) with arms outstretched (postural condition) and (c) at postural condition with 500 g mass attached to the hand.Results: Involuntary movements were present in 54 patients (73%). Rest MPMC was present in 26 patients (35%), RTT in 22 patients (31%), action MPMC in 22 patients (30%) and action tremor in 20 patients (27%), with some overlap. Sixteen patients (22%) reported negative impact of involuntary movements on their ability to use hands. Regression model showed that lower distal muscle power and less prominent upper motor neuron involvement significantly increased the odds of MND patient having involuntary movements. Sex, age and disease duration did not significantly predict the occurrence of involuntary movements. At rest, tremor frequency ranged from 5.2 to 8.2 Hz, at postural position from 4.9 Hz to 7.6 Hz and during postural position with mass attached from 3.6 Hz to 7.6 Hz. On the group level, tremor peak frequency statistically significantly decreased from 6.1 Hz to 5 Hz without versus with loading.Discussion and conclusions: Involuntary movements are very common yet largely overlooked feature of MND that may also have negative impact on patient's functional abilities. Lower distal muscle power increases and the presence of upper motor neuron signs decreases the probability of involuntary movements. Together with finding of decrease in tremor frequency with mass loading, these results suggest that generation of involuntary movements is of peripheral origin.

Facial nerve palsy secondary to Epstein-Barr virus infection of the middle ear in pediatric population may be more common than we think.

BACKGROUND: Facial nerve palsy is a rare complication of acute otitis media (AOM). The general understanding is that this complication has a bacterial cause although bacteria can be isolated from the middle ear only in approximately two-thirds of cases of AOM. Detection of viral agents from specimens obtained during myringotomy in patients with AOM suggests a possible role of viruses in the etiology of this disease. CASE PRESENTATIONS: We studied 5 otherwise healthy 17- to 27-month-old children who were referred to the Department of Otorhinolaryngology and Cervicofacial Surgery from December 2012 to January 2016 because of AOM and ipsilateral facial nerve palsy. In all cases, serological tests were indicative of a primary Epstein-Barr virus (EBV) infection and no other causative pathogens were identified during hospitalization. In one patient, the technique of in situ hybridization (ISH) detected EBV-specific ribonucleic acid (RNA) sequences within tissue sections obtained during mastoidectomy. CONCLUSIONS: The aim of this article is to alert clinicians that AOM induced facial nerve palsy secondary to an acute EBV infection in the pediatric population is very likely more common than originally thought. To our knowledge until the present case series, only 2 cases of AOM induced facial nerve palsy secondary to an acute EBV infection have been reported and no cases of EBV infection proven by the ISH technique showing the presence of EBV-specific RNA sequences in patient's tissue biopsies have been reported until now.