Risdiplam in Type 1 Spinal Muscular Atrophy.

BACKGROUND: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. METHODS: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. RESULTS: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. CONCLUSIONS: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

Nocturnal vestibular stimulation using a rocking bed improves a severe sleep disorder in a patient with mitochondrial disease.

Mitochondrial diseases are rare genetic disorders often accompanied by severe sleep disorders. We present the case of a 12-year-old boy diagnosed with a severe primary mitochondrial disease, exhibiting ataxia, spasticity, progressive external ophthalmoplegia, cardiomyopathy and severely disrupted sleep, but no cognitive impairment. Interestingly, his parents reported improved sleep during night train rides. Based on this observation, we installed a rocking bed in the patient's bedroom and performed different interventions, including immersive multimodal vestibular, kinesthetic and auditory stimuli, reminiscent of the sensory experiences encountered during train rides. Over a 5-month period, we conducted four 2-week nocturnal interventions, separated by 1-week washout phases, to determine the subjectively best-perceived stimulation parameters, followed by a final 4-week intervention using the optimal parameters. We assessed sleep duration and quality using the Mini Sleep Questionnaire, monitored pulse rate changes and used videography to document nocturnal interactions between the patient and caregivers. Patient-reported outcome measures, clinical examinations and personal outcomes of specific interests were used to document daytime sleepiness, restlessness, anxiety, fatigue, cognitive performance and physical posture. In the final 4-week intervention, sleep duration increased by 25%, required caregiver interactions reduced by 75%, and caregiving time decreased by 40%. Subjective fatigue, assessed by the Checklist Individual Strength, decreased by 40%, falling below the threshold of severe fatigue. Our study suggests that rocking beds could provide a promising treatment regime for selected patients with persistent severe sleep disorders. Further research is required to validate these findings in larger patient populations with sleep disorders and other conditions.

0.05% Chlorhexidine Gluconate Irrigation in Trauma/Emergency General Surgical Laparotomy Wounds Closure: A Pilot Study.

INTRODUCTION: Patients who undergo exploratory laparotomy (EL) in an emergent setting are at higher risk for surgical site infections (SSIs) compared to the elective setting. Packaged Food and Drug Administration-approved 0.05% chlorhexidine gluconate (CHG) irrigation solution reduces SSI rates in nonemergency settings. We hypothesize that the use of 0.05% CHG irrigation solution prior to closure of emergent EL incisions will be associated with lower rates of superficial SSI and allows for increased rates of primary skin closure. METHODS: A retrospective observational study of all emergent EL whose subcutaneous tissue were irrigated with 0.05% CHG solution to achieve primary wound closure from March 2021 to June 2022 were performed. Patients with active soft-tissue infection of the abdominal wall were excluded. Our primary outcome is rate of primary skin closure following laparotomy. Descriptive statistics, including t-test and chi-square test, were used to compare groups as appropriate. A P value <0.05 was statistically significant. RESULTS: Sixty-six patients with a median age of 51 y (18-92 y) underwent emergent EL. Primary wound closure is achieved in 98.5% of patients (65/66). Bedside removal of some staples and conversion to wet-to-dry packing changes was required in 27.3% of patients (18/66). We found that most of these were due to fat necrosis. We report no cases of fascial dehiscence. CONCLUSIONS: In patients undergoing EL, intraoperative irrigation of the subcutaneous tissue with 0.05% CHG solution is a viable option for primary skin closure. Further studies are needed to prospectively evaluate our findings.

Treatment of spinal muscular atrophy with Onasemnogene Abeparvovec in Switzerland: a prospective observational case series study.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder leading to early death in the majority of affected individuals without treatment. Recently, targeted treatment approaches including Onasemnogene Abeparvovec (OA) were introduced. This study describes the first real-world experience with OA in Switzerland. METHODS: Prospective observational case series study using data collected within the Swiss Registry for Neuromuscular Disorders from SMA patients treated with OA. Development of motor, bulbar and respiratory function, appearance of scoliosis, and safety data (platelet count, liver function, and cardiotoxicity) were analyzed. RESULTS: Nine individuals were treated with OA and followed for 383 ± 126 days: six SMA type 1 (of which two with nusinersen pretreatment), one SMA type 2, and two pre-symptomatic individuals. In SMA type 1, CHOP Intend score increased by 28.1 from a mean score of 20.5 ± 7.6 at baseline. At end of follow-up, 50% of SMA type 1 patients required nutritional support and 17% night-time ventilation; 67% developed scoliosis. The SMA type 2 patient and two pre-symptomatically treated individuals reached maximum CHOP Intend scores. No patient required adaptation of the concomitant prednisolone treatment, although transient decrease of platelet count and increase of transaminases were observed in all patients. Troponin-T was elevated prior to OA treatment in 100% and showed fluctuations in 57% thereafter. CONCLUSIONS: OA is a potent treatment for SMA leading to significant motor function improvements. However, the need for respiratory and especially nutritional support as well as the development of scoliosis must be thoroughly evaluated in SMA type 1 patients even in the short term after OA treatment.

Effects of the COVID-19 Pandemic on Access to Education and Social Participation in Children and Adolescents with Duchenne Muscular Dystrophy in Switzerland.

Two-thirds of patients with Duchenne muscular dystrophy (DMD) have cognitive and neuropsychiatric problems. Concerning their quality of life, negative factors are the lack of qualifying education and social participation in sporting and leisure activities. Adapted assistance in education and participation in social life are thus important. During the coronavirus disease 2019 (COVID-19) pandemic, the pediatric population was less severely impacted by the disease, but by the restrictions associated. The aim of this study was to evaluate the impact of the COVID-19 pandemic regarding access to education and social participation for young patients with DMD in Switzerland. We conducted a survey study from May to August 2021 assessing the impact of the COVID-19 pandemic on access to education and social participation in 8 to 18 years old patients with DMD in Switzerland. Of 60 sent surveys, 40 were returned and included. Mean age of participants was 13.5 years (±3.1 standard deviation); 23/40 of the participants were wheelchair bound, 21/40 attended a special school, and 19/40 a regular school. Of the 22/40 participants receiving assistance at school, 7/40 reported a change caused by the pandemic: for 5/7, the assistance was paused. Of the 12 boys and adolescents attending sporting activities, 10 had to suspend these. Nine attended other leisure activities; for 3/9, these activities were paused. The COVID-19 pandemic had direct effects on school assistance, sporting, and leisure activities in young patients with DMD in Switzerland. It is important to ensure that school assistance and leisure activities are rapidly resumed.

Disposable, lightweight shield decreases operator eye and brain radiation dose when attached to safety eyewear during fluoroscopically guided interventions.

OBJECTIVE: Long-term radiation exposure from fluoroscopically guided interventions (FGIs) can cause cataracts and brain tumors in the operator. We have previously demonstrated that leaded eyewear does not decrease the operator eye radiation dose unless lead shielding has been added to the lateral and inferior portions. Therefore, we have developed a disposable, lightweight, lead-equivalent shield that can be attached to the operator's eyewear that conforms to the face and adheres to the surgical mask. In the present study, we evaluated the efficacy of our new prototype in lowering the operator brain and eye radiation dose when added to both leaded and nonleaded eyewear. METHODS: The attenuating efficacy of leaded eyewear alone, leaded eyewear plus the prototype, and nonleaded eyewear plus the prototype were compared with no eyewear protection in both a simulated setting and clinical practice. In the simulation, optically stimulated, luminescent nanoDot detectors (Landauer, Inc, Glenwood, Ill) were placed inside the ocular, temporal lobe, and midbrain spaces of a head phantom (ATOM model-701; CIRS, Norfolk, Va). The phantom was positioned to represent a primary operator performing right femoral access. Fluorography was performed on a plastic scatter phantom at 80 kVp for an exposure of 3 Gy reference air kerma. In the clinical setting, nanoDots were placed below the operator's eye both inside and outside the prototype during the FGIs. The median and interquartile ranges were calculated for the dose at each nanoDot location for the phantom and clinical studies. The average dose reduction was also recorded. RESULTS: Wearing standard leaded eyewear alone did not decrease the operator ocular or brain radiation dose. In the phantom experiment, the leaded glasses plus the prototype reduced the radiation dose to the lens, temporal lobe, and midbrain by 83% (P < .001), 78% (P < .001), and 75% (P < .001), respectively. The nonleaded glasses plus the prototype also reduced the dose to the lens, temporal lobe, and midbrain by 85% (P < .001), 81% (P < .001), and 71% (P < .001), respectively. A total of 15 FGIs were included in the clinical setting, with a median reference air kerma of 98.4 mGy. The use of our prototype led to an average operator eye dose reduction of 89% (P < .001). CONCLUSIONS: Attaching our prototype to both leaded and nonleaded glasses significantly decreased the eye and brain radiation dose to the operator. This face shield attachment provided meaningful radiation protection and should be considered as either a replacement or an adjunct to routine eyewear.

European Neuromuscular Centre consensus statement on anaesthesia in patients with neuromuscular disorders.

BACKGROUND AND PURPOSE: Patients with neuromuscular conditions are at increased risk of suffering perioperative complications related to anaesthesia. There is currently little specific anaesthetic guidance concerning these patients. Here, we present the European Neuromuscular Centre (ENMC) consensus statement on anaesthesia in patients with neuromuscular disorders as formulated during the 259th ENMC Workshop on Anaesthesia in Neuromuscular Disorders. METHODS: International experts in the field of (paediatric) anaesthesia, neurology, and genetics were invited to participate in the ENMC workshop. A literature search was conducted in PubMed and Embase, the main findings of which were disseminated to the participants and presented during the workshop. Depending on specific expertise, participants presented the existing evidence and their expert opinion concerning anaesthetic management in six specific groups of myopathies and neuromuscular junction disorders. The consensus statement was prepared according to the AGREE II (Appraisal of Guidelines for Research & Evaluation) reporting checklist. The level of evidence has been adapted according to the SIGN (Scottish Intercollegiate Guidelines Network) grading system. The final consensus statement was subjected to a modified Delphi process. RESULTS: A set of general recommendations valid for the anaesthetic management of patients with neuromuscular disorders in general have been formulated. Specific recommendations were formulated for (i) neuromuscular junction disorders, (ii) muscle channelopathies (nondystrophic myotonia and periodic paralysis), (iii) myotonic dystrophy (types 1 and 2), (iv) muscular dystrophies, (v) congenital myopathies and congenital dystrophies, and (vi) mitochondrial and metabolic myopathies. CONCLUSIONS: This ENMC consensus statement summarizes the most important considerations for planning and performing anaesthesia in patients with neuromuscular disorders.

Use of a 2 Dimensional Vessel Navigator Roadmap Decreases Patient Radiation Dose Compared to Standard 3D Mapping for Fenestrated Endovascular Aneurysm Repair.

OBJECTIVE: For fenestrated endovascular aneurysm repair (FEVAR), the implementation of the VesselNavigator (Philips Healthcare, Best, The Netherlands) to provide a 3-dimensional vessel roadmap has been shown to reduce patient radiation exposure. Unfortunately, FEVAR radiation doses remain substantial despite utilization of this technology. Traditionally, registration of the live fluoroscopy with the pre-operative CTA is performed via the acquisition of a low-dose cone-beam CT scan. However, this registration can also be accomplished with the acquisition of 2D X-rays using the c-arm in 2 different projection angles. We hypothesized that the 2D image acquisition for vessel roadmap development would result in a significant reduction in patient radiation dose in comparison to the 3D CT registration without compromising image quality or increasing procedural length. METHODS: This single-center, retrospective study included FEVARs performed from January 2015 to May 2019. For patient data, the cumulative reference air kerma (RAK) was presented as geometric mean and standard deviation. A general linear model with log-normal distribution was used to test the difference in patient RAK between 2D X-ray and 3D CT VesselNavigator registration after adjusting for BMI and the number of vessel fenestrations (1 to 2 vs. 3 to 4). Fluoroscopy time was recorded and used as a surrogate for case complexity. All analyses were done in SAS 9.4 (SAS Institute, Inc., Cary, North Carolina). RESULTS: One hundred and sixty four FEVARs were performed on a Philips Allura Xper FD 20 fluoroscopy system equipped with clarity technology. The VesselNavigator registration was completed using 3D CT mapping in 99 cases and 2D X-rays in 65 procedures. On average, utilization of 2D mapping versus 3D mapping for the VesselNavigator resulted in a 20.4% reduction in patient RAK after controlling for BMI and number of vessel fenestrations, P = 0.0135. There was no significant difference in fluoroscopy time between the 2 study groups (P= 0.81) suggesting that image quality was not compromised by the use of 2D mapping leading to the need for additional fluoroscopy. CONCLUSION: Acquisition of 2D films rather than a 3D CT scan for VesselNavigator registration allows for a significant reduction in patient radiation dose during FEVAR without increasing the case complexity or compromising image quality.

[Newborn screening program for spinal muscular atrophy]. / Neugeborenenscreeningprogramm für die spinale Muskelatrophie.

BACKGROUND: The introduction of a comprehensive newborn screening program for spinal muscular atrophy (SMA), specifically for 5q-SMA, is planned for the end of 2021 in Germany. Several targeted treatment options have become available for all patients with SMA. MATERIAL AND METHODS: Newborn screening for 5q-SMA is based on the detection of a homozygous deletion of exon 7 in the SMN1 gene by molecular genetic analysis from the dried blood card. In all cases a second blood sample must be drawn as a part of confirmation diagnostics including the determination of the SMN2 copy numbers. RESULTS: Insights from pilot projects performed in parts of Germany are presented. Advantages and disadvantages of the screening project are discussed. CONCLUSION: Consultation and treatment should be carried out in a department of neuropediatrics with experience in the treatment of children with 5q-SMA, which is able to provide all current treatment options for the child, so that, when necessary, the treatment can be started within the first month of life.

Novel modification to leaded eyewear results in significant operator eye radiation dose reduction.

OBJECTIVE: Ocular radiation exposure from fluoroscopically guided interventions (FGIs) can cause cataracts. Standard lead eyewear may not significantly reduce eye radiation dose as the majority of scattered radiation penetrates the operator's eye obliquely. Our aim was to evaluate the efficacy of standard leaded eyewear and a customized eyewear design in lowering eye radiation dose to vascular surgeons. METHODS: The attenuating efficacy of three forms of leaded eyewear (standard eyewear, eyewear with built-in leaded side shields, and our modified eyewear) was tested in both a simulated setting and clinical practice. The modified design consisted of safety eyewear with 0.75 mm of added lead shielding attached to the lateral and inferior borders of the eyewear frame to attenuate oblique radiation. We performed simulated experiments using an anthropomorphic head phantom (ATOM model 701; CIRS, Norfolk, Va) positioned to represent a primary operator performing right femoral access. Optically stimulated, luminescent nanoDot detectors (Landauer, Glenwood, Ill) were placed inside the phantom's ocular spaces and at the surface of the left eye within and outside the leaded glasses to measure the eye radiation dose reduction provided by each eyewear type. All three eyewear types were also tested during clinical FGIs by placing nanoDots below the operator's left eye, inside and outside of the eyewear coverage. Means and standard errors were calculated using a pooled linear mixed model with repeated measurements. RESULTS: This prospective, single-center study included 60 FGIs, 30 with traditional eyewear and 30 with our modified design. There was no significant eye radiation dose reduction (P > .05) with the standard eyewear or leaded side shield eyewear in both the simulated and clinical settings. In the simulated environment, our modified design resulted in an 86% radiation dose reduction to the surface of the left eye and an 80% reduction in left lens radiation dose (P < .0001). In the clinical FGIs, the modified eyewear led to a 62% left ocular radiation dose reduction (P < .0001). CONCLUSIONS: Standard lead-equivalent glasses are ineffective at reducing ocular radiation dose during FGIs. Eyewear modification with lateral and inferior lead shielding molded to the operator's face significantly decreases radiation exposure to the eye closest to the X-ray source.

IQ predictors in pediatric opsoclonus myoclonus syndrome: a large international cohort study.

AIM: To determine predictors of full-scale IQ (FSIQ) in an international pediatric opsoclonus myoclonus syndrome (OMS) cohort. METHOD: In this retrospective and prospective cohort study at three academic medical centers (2006-2013), the primary outcome measure, FSIQ, was categorized based on z-score: above average (≥+1), average (+1 to -1), mildly impaired (-1 to -2), and impaired (<-2). Univariate analysis and multivariable linear regression modeling using stepwise selection with Akaike's information criterion was performed to understand the relationship between exposures and FSIQ. RESULTS: Of 81 participants, 37 with sufficient data had mean FSIQ 84.38 (SD 20.55) and median 90 (40-114) at latest available evaluation (mean age 8y 5mo). Twenty (54%), nine (24.3%), and eight (21.6%) had normal, mildly impaired, and impaired FSIQ respectively. The final multivariable linear regression model included 34 participants with evaluable data: number of relapses occurring before neuropsychological testing (p<0.001) and OMS severity score at last follow-up (p<0.001) predicted FSIQ (adjusted R2 =0.64). There was a mean decrease of 2.4 FSIQ points per OMS relapse. INTERPRETATION: Number of relapses negatively correlates with FSIQ in pediatric OMS. Demographic and clinical measures available at OMS onset did not predict FSIQ. Strategies to reduce OMS relapses may improve intellectual outcomes.

The Effects of Gender on Radiation Dose during Fenestrated Endovascular Aneurysm Repair.

BACKGROUND: Female gender is considered a risk factor for worse perioperative outcomes after fenestrated endovascular aneurysm repair (FEVAR). We hypothesized that women would have more unfavorable anatomy, increasing case complexity and leading to higher radiation doses. Our aim was to evaluate the effect of gender on radiation dose during FEVARs. METHODS: This single-center retrospective study was performed from 1/2015 to 2/2018. For patient data, linear model and stepwise variable selection algorithm were used. All dose measurements were log transformed before analysis. Significance level for parameter estimates and corresponding 95% confidence intervals were all transformed back using an exponential function. P-value of <0.05 was considered statistically significant. All analyses were performed in SAS 9.4 (SAS Institute Inc., Cary, NC). RESULTS: A total of 169 FEVARs (45 women) were performed on a Philips Allura Xper FD 20 fluoroscopy system equipped with clarity technology. There was no difference in body mass index (BMI) or operative time between genders, P = 0.9. The median reference air kerma for women was significantly lower than that for men (1,672 mGy vs. 2,496 mGy), P < 0.001. Women had on average a 28% total dose reduction after controlling for BMI, number of vessels fenestrated, operative time, and type of device, P < 0.001. The median fluorography and fluoroscopy doses for women were significantly lower than those for men (973 mGy vs. 1,401 mGy and 659 mGy vs. 1,008 mGy), resulting in a 24% fluorography dose reduction and a 38% fluoroscopy dose reduction for women, P < 0.001. CONCLUSIONS: FEVARs can be performed successfully in women with comparatively lower radiation doses.

Clinical, radiological, and genetic characteristics of 16 patients with ACO2 gene defects: Delineation of an emerging neurometabolic syndrome.

Mitochondrial aconitase is the second enzyme in the tricarboxylic acid (TCA) cycle catalyzing the interconversion of citrate into isocitrate and encoded by the nuclear gene ACO2. A homozygous pathogenic variant in the ACO2 gene was initially described in 2012 resulting in a novel disorder termed "infantile cerebellar retinal degeneration" (ICRD, OMIM#614559). Subsequently, additional studies reported patients with pathogenic ACO2 variants, further expanding the genetic and clinical spectrum of this disorder to include milder and later onset manifestations. Here, we report an international multicenter cohort of 16 patients (of whom 7 are newly diagnosed) with biallelic pathogenic variants in ACO2 gene. Most patients present in early infancy with severe truncal hypotonia, truncal ataxia, variable seizures, evolving microcephaly, and ophthalmological abnormalities of which the most dominant are esotropia and optic atrophy with later development of retinal dystrophy. Most patients remain nonambulatory and do no acquire any language, but a subgroup of patients share a more favorable course. Brain magnetic resonance imaging (MRI) is typically normal within the first months but global atrophy gradually develops affecting predominantly the cerebellum. Ten of our patients were homozygous to the previously reported c.336C>G founder mutation while the other six patients were all compound heterozygotes displaying 10 novel mutations of whom 2 were nonsense predicting a deleterious effect on enzyme function. Structural protein modeling predicted significant impairment in aconitase substrate binding in the additional missense mutations. This study provides the most extensive cohort of patients and further delineates the clinical, radiological, biochemical, and molecular features of ACO2 deficiency.

Histoplasmosis Infection of Aortobifemoral Graft Treated with a Neoaortoiliac System.

Aortic graft infections are a feared complication of aortic bypass operations and impart significant morbidity and mortality when they occur. The most common etiology is bacterial, with a presentation ranging from subclinical to acutely symptomatic depending on the organism. Fungal infections of prosthetic grafts are rare, especially in immunocompetent patients. Graft infections remain a clinical diagnosis. We report a rare case of an aortobifemoral graft infection with Histoplasma capsulatum that was diagnosed on surgical pathology, as the preoperative infectious evaluation was negative. The neoaortoiliac system operation was successfully used to solve this patient's highly morbid condition.

Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.

OBJECTIVE: To determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms. METHODS: Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG- and AQP4-antibodies using live cell-based assays. RESULTS: 45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016). CONCLUSIONS: 67% of all children presenting with NMO or limited forms tested positive for MOG- or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes.

A severe congenital myasthenic syndrome with "dropped head" caused by novel MUSK mutations.

INTRODUCTION: Congenital myasthenic syndromes are rare. Mutations in MUSK were first described in 2004. Thirteen patients have been reported to date, mostly with a relatively mild course. The molecular diagnosis has implications for choice of treatment and genetic counseling. METHODS: Clinical course and electrophysiological, pathological, and genetic findings were assessed. RESULTS: We describe the case of a boy with prenatal onset and severe respiratory symptoms with a persisting need for ventilation. The patient had severe bulbar symptoms, marked axial weakness causing a "dropped head," and some facial and proximal weakness. Ophthalmoparesis developed during the first year of life. Salbutamol led to improvement, 3,4-diaminopyridine had a modest effect, but pyridostigmine produced deterioration. Two novel mutations in MUSK were found by whole exome sequencing. CONCLUSIONS: We expand the phenotype of congenital myasthenic syndromes with MUSK mutations, describing a more severe clinical course with prenatal onset. Predominant bulbar and respiratory weakness with facial and axial weakness and ophthalmoparesis are diagnostic clues.

Guiding healthier food choice: systematic comparison of four front-of-pack labelling systems and their effect on judgements of product healthiness.

Different front-of-pack (FOP) labelling systems have been developed in Europe by industry and organisations concerned with health promotion. A study (n 2068) was performed to establish the extent to which inclusion of the most prevalent FOP systems--guideline daily amounts (GDA), traffic lights (TL), GDA+TL hybrid (HYB) and health logos (HL)--impact consumer perceptions of healthiness over and above the provision of a FOP basic label (BL) containing numerical nutritional information alone. The design included within- and between-subjects factors. The within-subjects factors were: food (pizzas, yogurts and biscuits), healthiness of the food (high health, medium health and low health) and the repeated measurements under BL and test FOP label conditions. The between-subjects factors were: the system (GDA, TL, GDA+TL hybrid, HL), portion size (typical portion size and a 50% reduction of a typical portion) and country (the UK, Germany, Poland and Turkey). Although the FOP systems tested did result in small improvements for objective understanding under some conditions, there was little difference between the provision of an FOP label containing basic numerical nutritional information alone or between the various systems. Thus, any structured and legible presentation of key nutrient and energy information on the FOP label is sufficient to enable consumers to detect a healthier alternative within a food category when provided with foods that have distinctly different levels of healthiness. Future research should focus on developing greater understanding of the psychological and contextual factors that impact motivation and the opportunity to use the various FOP systems in real-world shopping settings.

Ataxia, intellectual disability, and ocular apraxia with cerebellar cysts: a new disease?

Cerebellar cysts are rare findings in pediatric neuroimaging and rather characteristic for dystroglycanopathies and GPR56-related encephalopathy. We aim to report on seven children with cerebellar cysts showing absence of weakness and ruling out mutations within eight dystroglycanopathy genes and GPR56. Data about neurological and ophthalmological features, outcome, and creatine kinase values were collected from clinical histories and follow-up examinations. All MR images were qualitatively evaluated for infra- and supratentorial abnormalities. A SNP 6.0-Array was performed in three children. The POMT1, POMT2, POMGnT1, FKRP, FKTN, LARGE, ISPD, B3GALNT2, and GPR56 genes were screened in all patients by Sanger sequencing. Seven children from five families were studied. Ataxia, intellectual disability, and language impairment were found in all patients, ocular motor apraxia in five, and severe myopia in three. None of the patients had weakness, only three a minimally increased creatine kinase value. Qualitative neuroimaging evaluation showed cerebellar cysts and dysplasia in the cerebellar hemispheres and vermis in all children. Additional findings were an enlarged fourth ventricle in all children, vermian hypoplasia and brain stem morphological abnormalities in five. The SNP array showed no pathogenetic imbalances in all children evaluated. In all patients, no mutations were found in POMT1, POMT2, POMGnT1, FKRP, FKTN, LARGE, ISPD, B3GALNT2, and GPR56. The peculiar combination of the same clinical and neuroimaging findings in our patients highly suggests that this phenotype may represent a novel entity, possibly falling within the spectrum of dystroglycanopathies.

Muscle magnetic resonance imaging of the lower limbs: valuable diagnostic tool in the investigation of childhood neuromuscular disorders.

Children presenting with neuromuscular symptoms are subject to exhaustive investigations. As it is noninvasive, muscle magnetic resonance imaging (MRI) is an important diagnostic tool in children, yet its impact has so far been mainly studied in small groups of genetically defined diseases, where specific MRI patterns are known. To assess the contribution of muscle MRI of the lower limbs in a diverse cohort of patients, we reviewed the diagnostic findings in 39 patients with a suspected neuromuscular disorder that underwent muscle MRI (28/39), biopsy (26/39), or both (18/39). MRI was performed without sedation in 26 of 28 patients at a mean age of 10 years (range, 1-27 years). In 10 of 28 cases (35%), MRI significantly contributed to the final diagnosis, and in 7 of 28 cases (25%), muscle MRI directly instructed genetic testing. These cases included Bethlem myopathy, laminopathy, calpainopathy, and RYR1-related myopathies. Muscle MRI serves as a valuable additional tool to guide diagnosis in suspected neuromuscular disorders in children, especially in cases with nonspecific biopsy findings.

Neurofibromatosis type 1 (NF1) with an unusually severe phenotype due to digeny for NF1 and ryanodine receptor 1 associated myopathy.

UNLABELLED: We describe a 5-year-old girl with marked hypotonia, poor feeding and reduced facial expression since birth. Congenital myopathy was suspected; muscle biopsy showed unspecific type 1 fibre predominance. The possibility of a ryanodine receptor 1 gene (RYR1)-associated myopathy was considered, but not further investigated. At the age of 2 years, she presented with exophthalmos. Brain MRI revealed optic pathway glioma. On clinical examination, she had six café-au-lait spots, thus fulfilling the diagnostic criteria for neurofibromatosis type 1 (NF1). The hypotonia was then attributed to NF1. At the age of 3 years, she developed scoliosis and had an unusually severe motor delay for NF1, as she was not able to walk independently. Dual pathology was suspected, and muscle MRI showed the typical pattern for RYR1-related myopathy. This was genetically confirmed with the discovery of two heterozygous mutations. CONCLUSION: NF1 is one of the most frequent genetic diseases in children. RYR1-related myopathy is one of the most frequent causes of congenital myopathy. The combination of these two pathologies has not yet been described. In cases of unusual presentations or clinical course, the possibility of genetic "double trouble" should be considered.