Early onset facioscapulohumeral dystrophy - a systematic review using individual patient data

Infantile or early onset is estimated to occur in around 10% of all facioscapulohumeral dystrophy (FSHD) patients. Although small series of early onset FSHD patients have been reported, comprehensive data on the clinical phenotype is missing. We performed a systematic literature search on the clinical features of early onset FSHD comprising a total of 43 articles with individual data on 227 patients. Additional data from four cohorts was provided by the authors. Mean age at reporting was 18.8 years, and 40% of patients were wheelchair-dependent at that age. Half of the patients had systemic features, including hearing loss (40%), retinal abnormalities (37%) and developmental delay (8%). We found an inverse correlation between repeat size and disease severity, similar to adult-onset FSHD. De novo FSHD1 mutations were more prevalent than in adult-onset FSHD. Compared to adult FSHD, our findings indicate that early onset FSHD is overall characterized by a more severe muscle phenotype and a higher prevalence of systemic features. However, similar as in adults, a significant clinical heterogeneity was observed. Based on this, we consider early onset FSHD to be on the severe end of the FSHD disease spectrum. We found natural history studies and treatment studies to be very scarce in early onset FSHD, therefore longitudinal studies are needed to improve prognostication, clinical management and trial-readiness

Gating of Long-Term Potentiation by Nicotinic Acetylcholine Receptors at the Cerebellum Input Stage

The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation

Gating of long-term potentiation by nicotinic acetylcholine receptors at the cerebellum input stage.

The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation

Gating of long-term potentiation by nicotinic acetylcholine receptors at the cerebellum input stage

The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the a7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective a7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of a7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, a7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptatio

A 22-year follow-up reveals a variable disease severity in early-onset facioscapulohumeral dystrophy

Aim: To assess the long-term natural course of early-onset facioscapulohumeral dystrophy (FSHD), which is important for patient management and trial-readiness, and is currently lacking.Methods: We had the unique opportunity to evaluate 10 patients with early-onset FSHD after 22 years follow-up. Patients underwent a semi-structured interview, physical examination and additional genotyping.Results: Nine initial study participants (median age 37 years) were included, one patient died shortly after first publication. At first examination, one patient was wheelchair dependent, one patient walked aided, and eight patients walked unaided. After 22 years, four patients were wheelchair dependent, three walked aided, and two walked unaided. Systemic features, including hearing loss (56%), intellectual disability (44%), and a decreased respiratory function (56%), were frequent. Patients participated socially and economically with most patients living in a regular house (n = 6) and/or having a paid job (n = 4).Discussion: Patients with early-onset FSHD generally had a severe phenotype compared to classical onset FSHD. However, after 22 years of follow up they showed a wide variation in severity and, despite these physical limitations, participated socially and economically. These observations are important for patient management and should be taken into account in clinical trials. (C) 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.</p

α7-nAChR stimulation facilitates LTP <i>in vivo</i>.

<p>LFP recordings were performed from the granular layer of the Crus-IIa of the right cerebellar hemisphere in response to air-puff stimulation of the homolateral whisker pad. A TSS air-puff induction pattern was delivered at the end of a 5 min microperfusion of drugs in different combinations: TSS+Krebs’ solution (n = 7), just 50 µM nicotine (n = 6), TSS +50 µM nicotine (n = 6), TSS +100 mM choline (n = 5), TSS +50 µM nicotine +0.5 µM MLA (n = 5). <i>Left</i>, LFPs recorded before and after TSS+nicotine (average of 100 traces). <i>Right</i>, time course of the LFP amplitude changes (mean±SEM). Drug microperfusion is indicated by a bar and TSS by an arrow.</p

Nicotine microperfusion impairs VOR gain adaptation.

<p>The flocculus of the mouse was located using extracellular electrophysiological recordings during visual stimulation. (<b>A</b>) Increased complex spike activity during horizontal, contralateral movement of the visual field confirmed the location of vertical axis (VA) Purkinje cells. Based on the polarity of the waveform of Purkinje cell activity identified in each track, the location of the granule cell layer was determined, and a dye-labelled vehicle solution with or without 5–10 ng nicotine (n = 8 and n = 7, respectively) was injected. (<b>B</b>) Dye diffusion was analysed histologically and compared with the unfolded (according to points a-d) mouse floccular map <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064828#pone.0064828-Schonewille2" target="_blank">[72]</a>. Only injections covering at least 10% of the VA were included. The effect on motor learning was assessed by subjecting mice, 15 min after injection, to five 10 min sessions of in-phase vestibular and visual input, aimed at decreasing the VOR gain. (<b>C</b>) Mice injected with nicotine showed a significantly impaired ability to decrease their VOR gain. Nicotine did not affect the timing (phase) of the VOR, and the gain during the training was also not affected, indicating that the deficit is specific for adaptation rather than performance.</p

α7-nAChR activation at the mossy fibre-granule cell synapse.

<p>In A, B, and C, patch-clamp recordings performed from granule cells voltage-clamped at –70 mV in cerebellar slices. Drugs were applied for 100 seconds (black bar). (<b>A</b>) EPSC amplitude changes caused by application of nicotinic agents. (<i>Left)</i> Average traces of 10 contiguous EPSCs taken from a representative experiment (1 µM nicotine). <i>(Right)</i> Time course of EPSC amplitude changes (mean ± SEM) during application of 1 µM nicotine (n = 56), 10 mM choline (n = 5), 1 µM nicotine +10 nM MLA (n = 4), 50 nM epibatidine (n = 4), 10 nM MLA (n = 5), 1µM DHβE (n = 7). (<b>B</b>) EPSC amplitude changes in C57/BL6 (n = 4) and α7-nAChR KO mice (n = 4) during application of 1 µM nicotine. Same panel layout as in A. (<b>C</b>) The effect of postsynaptic calcium buffering (0.1 mM or 10 mM intracellular BAPTA) on the action of 1 µM nicotine (black bar). <i>(Left)</i> Average traces from 10 contiguous AMPA-EPSCs and NMDA-EPSCs (isolated with 10 µM NBQX in Mg²⁺-free medium) in representative recordings. <i>(Right)</i> Ensemble effects on AMPA-EPSC PPR and NMDA-EPSC amplitude (mean ± SEM). (<b>D</b>) Immunolabelling for α7-nAChR subunit in electron micrographs at the mossy fibre-granule cell synapse. An immunopositive pre-terminal mossy fibre (mf, bordered by arrows) opens up in a large bouton, which surrounds granule cell dendrites (<i>d</i>) (scale bar 0.5 µm). The inset shows a granule cell dendrite (<i>d</i>), contacted by a mossy fibre bouton (<i>b</i>), bearing an immunopositive post-synaptic specialisation (arrow). Scale bar 0.8 µm.</p

Postsynaptic induction of nicotine facilitated LTP through intracellular Ca²⁺ regulation.

<p>Intracellular Ca²⁺ concentration, [Ca²⁺]_i, was measured in granule cell dendrites as OG1 relative fluorescence, ΔF/F₀. Choline 10 mM was applied for 100 seconds just before a 10-pulse (100 Hz) mossy fibre burst, while holding the granule cell at –40 mV. <b>(A)</b> The sequence of pseudocolour images show higher Ca²⁺ increase in a granule cell dendritic ending when choline is perfused than in control recordings. <b>(B)</b> Time course of ΔF/F₀ in recordings obtained in control and following choline perfusion (<i>left</i>) and relative EPSC changes (taken from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064828#pone-0064828-g002" target="_blank">Fig. 2</a>) as a function of maximum ΔF/F₀ during bursts of different duration (<i>right</i>). Choline moves the point (mean±SEM, n = 5) corresponding to the 10-pulse burst from LTD to LTP (arrow).</p

Evidence for presynaptic expression of nicotine facilitated LTP.

<p>Percent changes induced by 10-pulse bursts in EPSC amplitude, release probability (<i>p</i>), coefficient of variation (<i>CV</i>), and failure rate (<i>FR</i>) between 15 and 20 min after the induction of plasticity in the experiments A-C of Fig. 2 (p<0.01 for all parameters).</p