Quality of life and upper limb disability in Charcot-Marie-Tooth disease: A pilot study

Charcot-Marie-Tooth (CMT) patients present mainly lower limbs disability, with slowly progressive distal muscle weakness and atrophy, but hands impairment is a relevant problem affecting the quality of life (QoL). The evaluation of the upper limb is of primary importance. Often these patients present subclinical disorders or report difficulties in manipulating objects, with little evidence in the most used outcome measures. We aim to investigate the impact of hand impairment in the perceived QoL of CMT persons and secondly whether the Disability of Arm, Shoulder and Hand (DASH) scale can be useful in assessing upper limb abilities in CMT. We recruited 23 patients with confirmed genetic diagnosis of CMT. We performed a clinical evaluation with Sollerman Hand Function Test (SHFT), Thumb Opposition Test (TOT) and CMT examination score (CMTES). We completed the clinical assessment with DASH scale and the Short form 36 (SF36) questionnaire for a subjective evaluation of upper limb disability and quality of life. All patients also underwent an instrumental evaluation with a hand-held dynamometer measuring hand grip and tripod pinch and a sensor-engineered glove test (SEGT) to evaluate finger opposition movements in a quantitative spatial-temporal way. As expected, we found significant differences between CMT and control group performances in both clinical and instrumental assessment. Concerning QoL, we found that total score of SF36 and the SF36 Physical Composite Score (PCS) correlate with all clinical and instrumental Outcome Measures (OMs), particularly with Tripod pinch strength and TOT, which are considered major determinants of manual dexterity in CMT. DASH scale correlates with most clinical and instrumental OMs. Not surprisingly, we also found a correlation with DASH work, because CMT affects young patients engaged in work activities. However, we found a low correlation with the TOT and the dynamometer suggesting that DASH may not be the best scale for remote monitoring of upper limb disorders in CMT patients. Nevertheless, the results of our study confirm the usefulness of SF36 in recognizing the impact of upper limb disability in these subjects suggesting its use even in the remote monitoring of physical functioning

Respiratory involvement and sleep-related disorders in CMT1A: case report and review of the literature

Sleep-disordered breathing has been reported in Charcot–Marie–Tooth disease (CMT) type 1A in association with diaphragmatic weakness and sleep apnea syndrome, mainly of the obstructive type (OSA). Improvement has been observed not only in sleep quality but also in neuropathy symptoms in CMT1A patients with OSA following the initiation of continuous positive airway pressure. We report the cases of two siblings affected by CMT1A associated with hemidiaphragm relaxatio necessitating nocturnal non-invasive ventilation (NIV). Two twins, now 42 years old, with a family history of CMT1A, received a genetic diagnosis of CMT1A at the age of 16. Over the years, they developed a slowly worsening gait disorder and a decline in fine motor hand movements, currently presenting with moderate disability (CMTES:13). At the age of 40, they both started complaining of daytime sleepiness, orthopnea, and exertional dyspnea. They received a diagnosis of relaxatio of the right hemidiaphragm associated with impairment of nocturnal ventilation and they both have benefited from nocturnal NIV. Disorders of breathing during sleep may be underestimated in CMT1A since routine investigations of sleep quality are rarely performed. Our two clinical cases and a literature review suggest the importance of inquiring about symptoms of excessive daytime sleepiness and respiratory disturbances in individuals with CMT1A, even in the absence of severe neuropathy. In the presence of compatible symptoms, a pneumological assessment, along with an overnight polysomnogram and lung function tests, should be performed. Recognizing sleep-related symptoms is essential for providing accurate treatment and improving the quality of life for patients with CMT1A

Hand Rehabilitation Treatment for Charcot-Marie-Tooth Disease: An Open Label Pilot Study

Charcot-Marie-Tooth neuropathy affects mainly and early the lower limbs, but hands deformities are a relevant problem, which involves the quality of life of the patients. Unfortunately, there are few studies about the evaluation of the upper limbs and very rare works about the rehabilitation. A treatment study at the moment is missing and it is important to search rehabilitation exercises to improve the dexterity and the quality of life of the patients. METHODS: We recruited 9 patients with clinical and genetic diagnosis of CMT and we proposed a rehabilitation protocol which includes muscle recruitment, stretching and proprioceptive exercises for the hand with the duration of 4 weeks (two sessions for week). We evaluated the patients before and one week after the treatment with Thumb Opposition Test, Sollerman Hand Function Scale, dynamometry (tripod pinch and hand grip). RESULTS: The rehabilitation protocol has been well tolerated and there were not dropouts. We did not observe any worsening in every scale we used. Every parameter tested showed an improvement especially in the right/dominant hand. CONCLUSION: This study demonstrates that this three phases treatment is well tolerated by patients, it is not detrimental for the hands status and perfectly reproducible by professionals. Moreover, this could be the basis for future randomized single blind projects

a grid enabled web platform for integrated digital biobanking in paediatrics

Motivation and Objectives A solid and integrated biobanking framework is an absolute requirement for high quality investigation in paediatric tumours. The overall goal of our activity is to design and develop a centralized Digital Biobank prototype able to integrate and interconnect an increasing number of local biobanks situated in various centres across Europe. As a first step, we are designing a web-based repository to store all tissue and genomic data from paediatric tumours collected by the G. Gaslini Children's Hospital, in Genoa. The repository satisfies flexibility and extensibility criteria, and is being deployed on a data Grid architecture (Bote-Lorenzo et al., 2004). Methods The repository is designed to contain data from all the tissue and blood samples obtained from infants and children affected by paediatric tumours, such as primary bone tumour and neuroblastoma. Many samples may be extracted from the same patient in a single visit or surgical operation; moreover from a single sample, nucleic acids (i.e. DNA and RNA) may be extracted for further analysis. These extractions could happen more than once, even at a distance of months or even years, if required. In order to satisfy the strict requirements above and ensure the extensibility of the repository, we have adopted a process/event model, already used for designing data and image repositories in Neuroscience (Corradi et al., 2012). The process/event model is a multipurpose taxonomic schema composed by two main generic objects: processes and events. An event can be any 'atomic' operation that is performed on patients or samples, or any processing of data or everything else related to the repository administration and management. A process is defined as a group of sequential events or sub-processes related to an activity, allowing the creation of a sort of hierarchical structure. As an example, the storage of a DNA sample in a specified location within a -80°C freezer and a post-processing step (such as differential expression, survival or correlation/anti-correlation analysis on microarray data) are single events, pertaining respectively to the more general 'Nucleic Acid Extraction' and 'Data Mining' processes. Platform Architecture The repository has a client-server architecture and it is composed by three main components, as shown in Figure 1: Repository portal Database Grid storage The repository portal is designed to make the storage and the navigation of data and information easy, through a simple and transparent web interface. It is a Java Enterprise Edition web application based on several existing open source tools for the development of web applications. The basis of the portal consists in a framework that relies on an Apache Tomcat web application container. It incorporates a database interface layer built through MyBatis, a persistence framework that automates the mapping between SQL databases and objects in Java. To provide users with highly interactive interfaces, some components are designed using the Asynchronous Javascript and XML (AJAX) programming technique. Wherever possible information is exchanged in XML or JavaScript Object Notation (JSON) format. The web portal represents the main access point to all the functionalities available through the overall integration platform, and exposes both user and administrator interfaces. T he repository itself is based on a MySQL database. The database design is fundamental in order to make the repository highly flexible and easily extensible. The core of the database is formed by the two previously described entities: processes and events and their relationships to data and metadata. Existing processes and events are contained in two homonymous tables. Each element in the event table refers to an element in the data table. The information inside the latter represents all the data inserted in the repository. These data can be associated with one or more files accordingly to their data type. The file table contains the logical path of all the stored files. The repository can be configured to store the metadata totally or partially within the database. In this latter case, the metadata are stored as XML descriptions inside the data table, to display the data in a rapid and dynamic way using XSL Transformations, and as records of specific metadata tables, to perform complex queries in an easier way. All data files are contained in the Grid storage, so the database doesn't really have to deal with hundreds of GB of data. Moreover, the number of operators should be quite small, thus making MySQL a reasonable choice as a database. The storage subsystem has been built around the iRODS data grid software (Rajasketar et al., 2010), chosen among others because it allows building a federated and distributed data storage system without the need of central components. Being able to deal with a huge amount of metadata, iRODS is widely used by the research community, also for Next Generation Sequencing Projects (Chiang et al., 2011). Careful attention has been given to security and privacy issues. All data are anonymised and cannot be linked in any way to patients' names, since the connection between clinical and personal data is done using unique identifiers managed exclusively by clinicians. Administrators are able to control users' access by creating groups and their association with pages and functions, define processes, events and all their relationships, define new data types and related metadata, associate them with the related events and manage available ontologies. Normal users, according to their assigned permissions, can insert new data, retrieve patients' information and view all the related data, download stored information, explore processes together with all the related events, data and metadata to have a global picture. The integrated system we envision at a European level will take advantage of the data Grid features provided by iRODS. Each hospital or biobank involved in the virtual community may have a local database and a dedicated separated iRODS system (called iRODS zone) where its own metadata and files can be saved. All the iRODS zones in the community will be federated. Federated iRODS zones are administered separately, but the users in the multiple zones, if given permission, will be able to access data stored in the other zones. If more hospital or research groups are working on the same project or using the same data structure, they may share a single iRODS zone and database. To provide access to the various local databases, federated database systems will be taken into account. Results and Discussion A first prototype of the repository is currently being tested at the Giannina Gaslini Institute, in Genoa. Information on over 1300 tissue samples, with their related DNA and RNA purified samples, have been stored together with administrative and clinical data from more than 700 patients. Three kinds of genomic analyses (i.e. event types) are currently provided, two for DNA samples - Comparative Genomic Hybridization (CGH) array and Multiplex Ligation-dependent Probe Amplification (MLPA) - and one for RNA - microarray analysis. For each analysis it is possible to store one or more files and user customized metadata. New data types can be configured via administrator interface, without additional programming, when new types of analyses or processing are required. The extensibility of our data model with user-defined data types and metadata is a crucial aspect of our implementation. As mentioned before, future developments will comprise the integration of our local biobank at the Gaslini Institute, with similar digital structures located across Europe. We are currently testing a distributed storage configuration, implementing data management policies expressed as rules that are interpreted by the iRODS Rule Engine. Acknowledgements Our research activity is performed in the framework of the 'European Network for Cancer Research in Children and Adolescents' (ENCCA) European project. References Bote-Lorenzo ML, Dimitriadis YA and Gomez-Sanchez E (2004) Grid characteristics and uses: a grid definition, Proceedings of the First European Across Grids Conference, ACG'03, Springer-Verlag, LNCS 2970, 291-298. doi:10.1007/978-3-540-24689-3_36 Chiang GT, Clapham P, Qi G, Sale K and Coates G (2011) Implementing a genomic data management system using iRODS in the Wellcome Trust Sanger Institute BMC Bioinformatics 2011, 12:361. doi:10.1186/1471-2105-12-361 Corradi L, Porro I, Schenone A, Momeni P, Ferrari , Nobili F, Ferrara M, Arnulfo G and Fato MM (2012) A repository based on a dynamically extensible data model supporting multidisciplinary research in neuroscience, BMC Medical Informatics and Decision Making (in press). JSON (JavaScript Object Notation), [online], http://www.json.org/. MyBatis, [online], http://www.mybatis.org. Rajasketar A, Moore R, Hou C et al. (2010) iRODS Primer: Integrated Rule-Oriented Data Systems. Morgan & Claypool. doi:10.2200/S00233ED1V01Y200912ICR012 XSL Transformations [online], http://www.w3.org/TR/xslt. Note: Figures and tables are available in PDF version only

A novel mutation in the N-terminal acting-binding domain of Filamin C protein causing a distal myofibrillar myopathy

Variants in Filamin C (FLNC) gene may cause either cardiomyopathies or different myopathies. We describe a family affected by a distal myopathy with autosomal dominant inheritance. The onset of the disease was in the third decade with gait impairment due to distal leg weakness. Subsequently, the disease progressed with an involvement of proximal lower limbs and hand muscles. Muscle biopsy, performed in one subject,identified relevant myofibrillar abnormalities. We performed a target gene panel testing for myofibrillar myopathies by NGS approach which identified a novel mutation in exon 3 of FLNC gene (c.A664G:p.M222V), within the N-terminal actin-binding (ABD) domain. This variant has been identified in all affected members of the family, thus supporting its pathogenic role. Differently from previously identified variants, our family showed a predominant leg involvement and myofibrillar aggregates, thus further expanding the spectrum of Filamin C related myopathies

Detection of influenza A(H1N1)pdm09 virus in a patient travelling from Shanghai to Italy in July 2018: an uncommon clinical presentation in a non-seasonal period

Influenza is one of the most common infectious diseases in travellers, especially in those returning from subtropical and tropical regions.In late June 2018 an influenza A(H1N1)pdm09 virus infection was diagnosed in a 36-years-old man, returned from a travel in Shanghai and hospitalized at the Ospedale Policlinico San Martino, Genoa, Italy, with a diagnosis of fever and an uncommon clinical presentation characterised by a persistent leukopenia. Phylogenetic analysis revealed a closeness with influenza A(H1N1)pdm09 strains circulating in the US in May-June 2018.Prompt recognition of influenza infection led to a proper case management, demonstrating the crucial role of the continuous influenza surveillance programme

Psychological treatments and psychotherapies in the neurorehabilitation of pain. Evidences and recommendations from the italian consensus conference on pain in neurorehabilitation

BACKGROUND: It is increasingly recognized that treating pain is crucial for effective care within neurological rehabilitation in the setting of the neurological rehabilitation. The Italian Consensus Conference on Pain in Neurorehabilitation was constituted with the purpose identifying best practices for us in this context. Along with drug therapies and physical interventions, psychological treatments have been proven to be some of the most valuable tools that can be used within a multidisciplinary approach for fostering a reduction in pain intensity. However, there is a need to elucidate what forms of psychotherapy could be effectively matched with the specific pathologies that are typically addressed by neurorehabilitation teams. OBJECTIVES: To extensively assess the available evidence which supports the use of psychological therapies for pain reduction in neurological diseases. METHODS: A systematic review of the studies evaluating the effect of psychotherapies on pain intensity in neurological disorders was performed through an electronic search using PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews. Based on the level of evidence of the included studies, recommendations were outlined separately for the different conditions. RESULTS: The literature search yielded 2352 results and the final database included 400 articles. The overall strength of the recommendations was medium/low. The different forms of psychological interventions, including Cognitive-Behavioral Therapy, cognitive or behavioral techniques, Mindfulness, hypnosis, Acceptance and Commitment Therapy (ACT), Brief Interpersonal Therapy, virtual reality interventions, various forms of biofeedback and mirror therapy were found to be effective for pain reduction in pathologies such as musculoskeletal pain, fibromyalgia, Complex Regional Pain Syndrome, Central Post-Stroke pain, Phantom Limb Pain, pain secondary to Spinal Cord Injury, multiple sclerosis and other debilitating syndromes, diabetic neuropathy, Medically Unexplained Symptoms, migraine and headache. CONCLUSIONS: Psychological interventions and psychotherapies are safe and effective treatments that can be used within an integrated approach for patients undergoing neurological rehabilitation for pain. The different interventions can be specifically selected depending on the disease being treated. A table of evidence and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation is also provided in the final part of the pape

Diagnosing mucopolysaccharidosis IVA

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian consensus conference on pain in neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy

Predicting Response to Neoadjuvant Therapy in Colorectal Cancer Patients the Role of Messenger-and Micro-RNA Profiling

Colorectal cancer patients' responses to neoadjuvant therapy undergo broad inter-individual variations. The aim of this systematic review is to identify a molecular signature that is predictive of colon cancer downstaging and/or downgrading after neoadjuvant therapy. Among the hundreds analysed in the available studies, only 19 messenger-RNAs (mRNAs) and six micro-RNAs (miRNAs) were differentially expressed in responders versus non-responders in two or more independent studies. Therefore, a mRNA/miRNA signature can be designed accordingly, with limitations caused by the retrospective nature of these studies, the heterogeneity in study designs and the downgrading/downstaging assessment criteria. This signature can be proposed to tailor neoadjuvant therapy regimens on an individual basis