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Andersen Tawil Syndrome (ATS) is a neurological channelopathy caused by mutations in the KCNJ2 gene that encodes the ubiquitously expressed Kir2.1 potassium channel. The syndrome is characterised by episodic weakness, cardiac arrythmias and dysmorphic features. However, the full extent of the multi-system phenotype is not well described. In-depth, multi-system phenotyping is required to inform diagnosis, and guide management. We report our findings following deep multimodal phenotyping across all systems in a large case series of 69 total patients, with comprehensive data for 52. As a national referral centre, we assessed point prevalence and showed it is higher than previously reported, at 0.105 per 100 000 population in England. While the classical phenotype of episodic weakness is recognised, we found that a quarter of our cohort have fixed myopathy and 13.5% required a wheelchair or gait aid. We identified frequent fatty infiltration on MRI and tubular aggregates on muscle biopsy emphasising the active myopathic process underpinning the potential for severe neuromuscular disability. Long exercise testing (LET) was not reliable in predicting neuromuscular symptoms. A normal LET was seen in five patients of whom four had episodic weakness. 67% of patients treated with acetazolamide reported a good neuromuscular response. 13% of the cohort required cardiac defibrillator or pacemaker insertion. An additional 23% reported syncope. Baseline electrocardiograms were not helpful in stratifying cardiac risk, but holter monitoring was. A subset of patients had no cardiac symptoms, but had abnormal holter monitor recordings which prompted medication treatment. We describe the utility of loop recorders to guide management in two such asymptomatic patients. Micrognathia was the most commonly reported skeletal feature, however 8% of patients did not have dysmorphic features and one third of patients had only mild dysmorphic features. We describe novel phenotypic features including abnormal echocardiogram in nine patients, prominent pain, fatigue and fasciculations. Five patients exhibited executive dysfunction and slowed processing which may be linked to central expression of KCNJ2. We report eight new KCNJ2 variants with in vitro functional data. Our series illustrates that ATS is not benign. We report marked neuromuscular morbidity and cardiac risk with multi-system involvement. Our key recommendations include proactive genetic screening of all family members of a proband. This is required, given the risk of cardiac arrhythmias among asymptomatic individuals, and a significant subset of ATS patients have no (or few) dysmorphic features or negative LET. We discuss recommendations for increased cardiac surveillance and neuropsychometry testing.

High throughput DNA sequencing is increasingly employed to diagnose single gene neurological and neuromuscular disorders. Large volumes of data present new challenges in data interpretation and its useful translation into clinical and genetic counselling for families. Even when a plausible gene is identified with confidence, interpretation of the clinical significance and inheritance pattern of variants can be challenging. We report our approach to evaluating variants in the skeletal muscle chloride channel ClC-1 identified in 223 probands with myotonia congenita (MC) as an example of these challenges. Sequencing of CLCN1, the gene that encodes CLC-1, is central to the diagnosis of MC. However, interpreting the pathogenicity and inheritance pattern of novel variants is notoriously difficult as both dominant and recessive mutations are reported throughout the channel sequence, ClC-1 structure-function is poorly understood and significant intra- and interfamilial variability in phenotype is reported. Heterologous expression systems to study functional consequences of CIC-1 variants are widely reported to aid the assessment of pathogenicity and inheritance pattern. However, heterogeneity of reported analyses does not allow for the systematic correlation of available functional and genetic data. We report the systematic evaluation of 95 CIC-1 variants in 223 probands, the largest reported patient cohort, in which we apply standardised functional analyses and correlate this with clinical assessment and inheritance pattern. Such correlation is important to determine if functional data improves the accuracy of variant interpretation and likely mode of inheritance. Our data provide an evidence-based approach that functional characterisation of ClC-1 variants improves clinical interpretation of their pathogenicity and inheritance pattern and serve as reference for 34 previously unreported and 28 previously uncharacterised CLCN1 variants. In addition, we identify novel pathogenic mechanisms and find that variants that alter voltage dependence of activation cluster in the first half of the transmembrane domains and variants that yield no currents cluster in the second half of the transmembrane domain. None of the variants in the intracellular domains were associated with dominant functional features or dominant inheritance pattern of MC. Our data help provide an initial estimate of the anticipated inheritance pattern based on the location of a novel variant and shows that systematic functional characterisation can significantly refine the assessment of risk of an associated inheritance pattern and consequently the clinical and genetic counselling.

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant neuromuscular disorder due to mutations in the KCNJ2 gene. The classical phenotype of ATS consists of a triad of periodic paralysis, cardiac conduction abnormalities and dysmorphic features. Episodes of either muscle weakness or cardiac arrhythmia may predominate however, and dysmorphic features may be subtle, masking the true breadth of the clinical presentation, and posing a diagnostic challenge. The severity of cardiac involvement varies but includes reports of life-threatening events or sudden cardiac death, usually attributed to ventricular tachyarrhythmias. We report the first case of advanced atrioventricular (AV) block in ATS and highlight clinical factors that may delay diagnosis.

Hadron therapy is a novel treatment against cancer. The main advantage of this therapy causes less side effect in comparison to X-ray irradiation methods. Hadron therapy is just ahead of a significant breakthrough since this technique can be more precise, applying proton computer tomograph (pCT) to map the stopping power in the tissues. The research and development of a pCT require a fast detector to measure the energy of hadrons behind the patient. The best detector option is called hadron-tracking calorimeter, which consists of sandwich layers of silicon tracking detectors and absorber layers. The combination of measuring the trajectory (tracking process), and, in parallel, the energy of relativistic particles, can provide high-resolution hadron imaging. This semiconductor-based technology requires stable temperature and homogeneous cooling. I have worked in the development of this detector in the Bergen pCT Collaboration for two years. Last year my work was to investigate the temperature distribution in the calorimeter and examine two cooling concepts in detail. I performed both analytical and numerical calculations to analyze the temperature distribution of the calorimeter. The final decision about the design takes into account many engineering aspects, such as reliability, flexibility, and performance., BSc thesis of \'Akos Sud\'ar at Budapest University of Technology and Economics

OBJECTIVE: To characterize the phenotype of patients with symptoms of periodic paralysis (PP) and ryanodine receptor (RYR1) gene mutations.METHODS: Cases with a possible diagnosis of PP but additional clinicopathologic findings previously associated with RYR1-related disorders were referred for a tertiary neuromuscular clinical assessment in which they underwent detailed clinical evaluation, including neurophysiologic assessment, muscle biopsy, and muscle MRI. Genetic analysis with next-generation sequencing and/or targeted Sanger sequencing was performed.RESULTS: Three cases with episodic muscle paralysis or weakness and additional findings compatible with a RYR1-related myopathy were identified. The McManis test, used in the diagnosis of PP, was positive in 2 of 3 cases. Genetic analysis of known PP genes was negative. RYR1 analysis confirmed likely pathogenic variants in all 3 cases.CONCLUSIONS: RYR1 mutations can cause late-onset atypical PP both with and without associated myopathy. Myalgia and cramps are prominent features. The McManis test may be a useful diagnostic tool to indicate RYR1-associated PP. We propose that clinicopathologic features suggestive of RYR1-related disorders should be sought in genetically undefined PP cases and that RYR1 gene testing be considered in those in whom mutations in SCN4A, CACNA1S, and KCNJ2 have already been excluded.