Approach to Myoclonus Dystonia Syndrome: A European Reference Network Survey.

A special issue on childhood-onset movement disorders.

200th ENMC International Workshop “European Reference Networks: Recommendations and Criteria in the Neuromuscular field”, 18–20 October 2013, Naarden, the Netherlands

This review aims to provide guidance on emerging concepts and policy related to European reference networks (ERNs) for rare diseases (RDs) and the development and management of RD patient registries. A major problem facing many RDs including rare renal disorders is that patients do not have a specialist centre that they can attend where clinicians, working as a multidisciplinary team, are experts in the particular disease. Furthermore, for most RDs, no single centre, and in many cases no single country, has sufficient numbers of patients and resources to fully understand the natural history or to conduct clinical and translational research. Therefore, the pooling of manpower and resources through the establishment of ERN and RD patient registries is a common and necessary area of collaboration. The concept of European networks for RDs dates back to the early 2000s and the Commission launch of a call for European pilot reference networks for RDs. These networks of expert centres have been brought together through the desire for further knowledge and innovation in RD areas. Networks demand a holistic approach and long-term vision with close collaboration between clinicians, diagnostic laboratories, scientists, patients and their families. The development of legal measures for ERNs is in progress at the Commission and these networks will be a shared responsibility of the Commission and member states. In the context of ERNs, an essential activity is the patient registries. Patient registries are organized databases where patient information, including demographic, medical and family history, are collected, stored and available for retrieval via standardized and secure methods. Patient registries are increasingly recognized as crucial tools for RD research for which international collaboration is absolutely essential to understand the pathogenesis of rare genotypes, achieve a unified collection of phenotypic data, foster natural history studies providing the foundation for successful orphan drug development, facilitate studies to identify appropriate clinical endpoints or biomarkers, identify participants for research and clinical trials and support discussions with regulators including the safety and efficacy evaluation of potential therapies. Furthermore, patient registries are often used as part of regulatory decisions and post-marketing surveillance requirements. Data can be entered into a registry by patients, clinicians, researchers or directly imported from patient's health records. The major concern in maintaining the dynamic of these networks and registries is sustainability, as the infrastructures and coordination have a cost.

Myoclonus dystonia syndrome (MDS) is an inherited movement disorder, and most MDS-related mutations have so far been found in the ε-sarcoglycan (SGCE) coding gene. By generating SGCE-knockout (KO) and human 237 C > T mutation knock-in (KI) mice, we showed here that both KO and KI mice exerted typical movement defects similar to those of MDS patients. SGCE promoted filopodia development in vitro and inhibited excitatory synapse formation both in vivo and in vitro. Loss of function of SGCE leading to excessive excitatory synapses that may ultimately contribute to MDS pathology. Indeed, using a zebrafish MDS model, we found that among 1700 screened chemical compounds, Vigabatrin was the most potent in readily reversing MDS symptoms of mouse disease models. Our study strengthens the notion that mutations of SGCE lead to MDS and most likely, SGCE functions to brake synaptogenesis in the CNS.

Movement disorders in children with congenital Zika virus syndrome

Objective: To explore the clinical characteristics and genotyping results of childhood-onset myoclonus dystonia syndrome caused by SGCE variants. Methods: The clinical data of 9 children with SGCE-related myoclonus dystonia syndrome admitted at either the Department of Neurology, Beijing Children's Hospital, Capital Medical University or the Department of Pediatrics, Peking University First Hospital from May 2018 to October 2019 were collected and the patients were followed up. The definite diagnosis was made on the basis of whole exome sequencing and multiple ligation-dependent probe amplification. The clinical features and gene test results were analyzed retrospectively. Results: Data of 9 patients (4 boys and 5 girls) diagnosed as myoclonus dystonia syndrome caused by SGCE variants were collected. The onset age ranged from 1 year to 3 years and 2 months. The first symptom was myoclonus in 4 cases, while dystonia in the remaining 5 cases. In the course of the disease, 9 cases had myoclonus and 8 had dystonia. Myoclonic jerks were characterized by involuntary jerks in both upper limbs in 8 patients. Six patients had involuntary jerks of lower limbs, resulting in gait instability or even falling. The myoclonus was exacerbated during the fine motor activities, emotional stress or fatigue. Dystonia was characterized by abnormal gait, including 5 cases with right leg dystonia, and 3 cases with the left leg dystonia. Three probands had a positive family history. Intellectual development was normal in all cases. There was no obvious abnormality in video-electroencephalogram (EEG) during both ictal and interictal periods. Electromyography (EMG) and brain magnetic resonance imaging (MRI) of 9 patients were normal. Nine patients carried SGCE gene variants, including 3 frame shift variants, 2 nonsense variants, 2 missense variants, 1 fragment deletion variant and 1 splice site variant. Seven variants were inherited paternally, and 2 variants were de novo. Madopar was used in 8 patients, and nitrazepam in 4 patients, leading to the decrease in the myoclonus jerks and improvement of gait in 6 and 2 patients, respectively. Conclusions: SGCE gene variants can cause myoclonus dystonia syndrome. The onset of the disease may occur at infancy or preschool age, with either myoclonic jerks or dystonia as the initial symptom. Non-epileptic myoclonus is the prominent symptom, with upper limb mainly involved. Most of the patients have the accompanying symptoms of dystonia, and some of them may have spontaneous symptom relief. SGCE gene is imprinted maternally, and the inherited variants of SGCE are paternal in origin.

Dear Sir, The European Organisation for Rare Diseases -EURORDIS- is a non-governmental patient-driven alliance of patient organisations and individuals active in the field of rare diseases. EURORDIS represents over 600 rare disease organisations in 58 countries (including 26 EU Member States) covering more than 4,000 rare diseases. More information is available on www.eurordis.org1. Since 2004, EURORDIS has been involved in different discussions at European and national levels on shaping Centres of Expertise and European Reference Networks (ERNs) for rare diseases with a view to improve timely access to appropriate diagnosis and care for people living with a rare disease. Over almost a decade, EURORDIS has gathered the opinions of its members on these topics through its Annual Membership Meetings as well as through surveys and workshops organised within the European co-funded projects RAPSODY and POLKA2. The opinions of our members have informed relevant EURORDIS position papers, which thus reflect the expectations of patients and their families regarding the organisation of care and delivery of treatments for their diseases. Why are ERNs important for patients with rare diseases? Due to the low prevalence of each rare disease, expertise is by essence scarce and scattered throughout Europe. The best way to accelerate access to a proper, timely diagnosis, as well as appropriate care, is to share expertise by linking at European level the national Centres of Expertise, healthcare providers, diagnostic laboratories, other relevant services and patients’ organisations. ERNs are also intended to gather a critical mass of patients and data to support rare disease registries and clinical research. The national Centres of Expertise are seen to constitute the nodes of ERNs for rare diseases. EURORDIS, through its representatives, contributed to the Recommendation of the European Committee of Experts on Rare Diseases (EUCERD) on the “quality criteria for Centres of Expertise for Rare Diseases in Member States”, which was adopted on 24 October 2011. To date, the EU Member States are developing criteria based on this Recommendation for designated Centres of Expertise for RDs in their territory within their national plans/strategies for rare diseases. The European Directive 2011/24/EU3 on the “application of patients’ rights in cross-border healthcare” has delineated for the first time the legal framework for European reference networks. This has been a success in translating a concept into a real healthcare framework with an added value for patients. In addition, Article 13 of this Directive is specifically dedicated to rare diseases: “The Commission shall support Member States in cooperating in the development of diagnosis and treatment capacity in particular by aiming to make health professionals aware of the tools available to them at Union level to assist them in the correct diagnosis of rare diseases, in particular the Orphanet database, and the European Reference Networks”. In this evolving context, EURORDIS adopted in May 2012 a position to outline its vision and strategy for ERNs for rare diseases; what they should comprise and how they should function based on the patient’s real life experience. EURORDIS rejects the logic of selecting priorities amongst rare diseases; all patients affected with a rare disease should be covered by at least one ERN in the long run. As it will not be possible to fund numerous ERNs, EURORDIS recommends that a limited number of ERNs for RDs (20 to 30) should be created by diagnostic and therapeutic areas in order to cover a wide range of rare diseases. EURORDIS also emphasises that a high-level of multi-disciplinarity and inter-operability among ERNs are absolutely necessary. The successful development of ERNs for RDs will rely on a step-wise approach aimed at establishing progressively the various activities of the ERN, such as experts’ opinions, good practice guidelines on medical care as well as social care, training, patient registries, e-health. The ERNS should remain flexible in order to evolve over time. The EURORDIS representatives in the EUCERD voiced the patients’ perspectives during the consultations on the elaboration of the Recommendation on European Reference Networks for Rare Diseases. This EUCERD Recommendation4 was adopted on 31 January 2013 and integrates many elements of the rare disease patients’ position. The new Health for Growth Programme of the European Commission, adopted in March, shall cover a period of seven years, from 2014 to 2020. We are aware that there will not be enough funding for European reference networks. Therefore, we need to be creative and seek other sources of funding, for instance from the Horizon 2020 programme and possibly structural funds for health. Tonio Borg, European Commissioner for Health, has recently emphasised that research on rare diseases is a priority for the European Commission and where there is an opportunity to offer a better service to citizens, the principle of subsidiarity applies; hence this principle applies to Cross-Border Healthcare for Rare Diseases.

Chromosome microarray (CMA) can determine copy number variants such as microdeletions or microduplications. Microdeletions of movement disorder genes including epsilon-sarcoglycan (SGCE) and thyroid transcription factor-1 (TITF1) have been described in patients with myoclonus dystonia and benign hereditary chorea respectively. We examined whether CMA is a valuable tool in the investigation of children with suspected genetic movement disorders. A genetic movement disorder was suspected if there was a positive first-degree family history, or two or more of the following factors: normal or near-normal magnetic resonance imaging, negative history of brain injury, and negative investigations for metabolic disorders. Tic disorders were excluded. Twenty-five patients (18 males, seven females) with a mean age at movement disorder onset of 4 years 5 month (range 1 mo-14 y) were prospectively recruited with the following primary movement disorders: dystonia (n=10), paroxysmal kinesigenic dyskinesia (n=5), tremor (n=4), chorea (n=3), myoclonus (n=2), and paroxysmal non-kinesigenic dyskinesia (n=1). Comorbid associated features were common, particularly developmental delay or intellectual disability (19 out of 25) and attention-deficit-hyperactivity disorder (six out of 25). CMA was performed using Agilent aCGH 60K array. Seven out of twenty-five patients had a microdeletion determined by CMA. None of the microdeletions were considered benign variants. Four patients had a deletion of a known movement disorder gene including paroxysmal kinesigenic dyskinesia (PRRT2; n=2), SGCE (myoclonus dystonia, n=1), and TITF1 (benign hereditary chorea, n=1). Three patients had novel microdeletions of unknown but potential significance including 14q13.3 (chorea, n=1), 19p13.12 (tremor, n=1), and 19q13.12 (progressive dystonia). All seven patients had associated neurodevelopmental or behavioural problems. Assays that determine copy number variants may be a valuable first-tier investigation in patients with suspected genetic movement disorders, particularly when associated with intellectual disability or developmental disorders. Microdeletion syndromes may help the search for new movement disorder genes.

IntroductionIn the current mobility and globalization context, there is a growing need to identify potential changes on the pattern of diseases in the European Union (EU)/European Economic Area (EEA) and provide accurate diagnosis and treatment for the population. The pattern of rare communicable diseases that can affect people returning to EU/EEA from travel abroad, visiting EU/EEA or establishing in the EU/EEA is of special relevance. The objective of this manuscript is to give an overview about the EURaDMoG study and discuss the feasibility of establishing a European network on rare communicable diseases and other rare conditions linked to mobility and globalization.MethodsWe undertook a three-steps process where we first conducted a narrative review to estimate the prevalence and incidence and to list rare communicable and non-communicable diseases linked to mobility and globalization in the EU/EEA; second, we organized an international consultation workshop with experts in the diseases previously selected; and finally, the feasibility study analysed how successful a European expert network on rare diseases linked to mobility and globalization focused on health care provision would be, accounting for different operational and also sustainability criteria.ResultsFirst, considering the areas or topics that the network should cover, it was concluded that communicable and non-communicable rare diseases linked to mobility and globalization should be differentiated. Second, since all non-communicable rare diseases linked to mobility and globalization identified are already covered by different European Reference Networks (ERNs), there is no need for them to be included in a new European network. Three scenarios were considered for establishing a potential European network for rare communicable diseases linked to Mobility and Globalisation with a focus on Health Care provision: 1) To maintain the current situation “Status Quo” scenario; 2) to create a specific European expert network (EEN) on rare communicable diseases linked to mobility and globalisation; 3) to develop a new ERN on communicable rare diseases linked to mobility and globalisation.ConclusionsSince the focus is the provision of health care, an ERN could have the potential to better boost the quality of care being facilitated by technological tools and online platforms that permit the safe and ethically acceptable exchange of data. However, this potential new network should not eclipse current existing networks and they should be complementary.

Myoclonus-dystonia syndrome (MDS) is a clinically and genetically heterogeneous movement disorder characterized by myoclonus and dystonia as its core features. While mutations in the epsilon-sarcoglycan gene (SGCE) account for most familial cases, heterozygous pathogenic variants in KCTD17 and KCNN2 have recently been described as novel genetic causes of MDS. We describe three patients from two Polish families presenting with progressive movement disorder combined with other features. Exome sequencing (ES) identified a novel heterozygous KCTD17 variant c.461 T > A, p.(Met154Lys) in a five-year-old girl with abnormal gait, postural instability, myoclonus, and tongue dyskinesia. In a 38-year-old woman and her 17-year-old daughter, both showing tremor, myoclonus, dystonia, and psychiatric symptoms, ES detected a heterozygous canonical splice-site c.1780-2A > G variant in KCNN2. Neuropsychological evaluation suggested a gene-specific effect of KCNN2 on psychiatric and cognitive functioning, including significant episodic memory impairment. This study broadens the clinical and molecular spectrum of KCTD17- and KCNN2-related MDS and highlights distinctive features compared with SGCE-MDS, focusing on disease progression, treatment response, and neuropsychiatric involvement. Recognition of these patterns may guide molecular diagnosis and the management of specific MDS types.

Aim: The European Reference Networks (ERNs) provide clinicians and patients the opportunity to collaborate at EU level to improve diagnosis, care and treatment for people living with rare and complex conditions. However, building a partnership culture to systematically involve patients in ERN activities and decision-making structures is challenging, partly because the role of patient representatives and the value of this collaboration are not always understood. The objective of this project was to develop an evaluation framework to assess the impact of patient engagement in the ERNs and to provide evidence on the value of patient-clinician partnership. Methods: The evaluation was developed by EURORDIS and patient representatives involved in the ERNs (ePAG advocates) through a participatory and iterative process. The work was organised in three different phases: (1) clarify roles and identify common goals for ePAG advocates’ engagement in the ERNs; (2) define a set of measures; and (3) test the measures in three different ePAGs (European Patient Advocacy Groups). Results: The project allowed developing a common understanding among ePAG advocates of their role and goals in the ERNs and defining a patient-driven evaluation framework to assess their level of engagement in the ERNs’ activities and how effectively they were working to fulfil their role. Conclusion: Engaging with ERN clinicians to refine the framework would probably render it more relevant to the reality and priorities of the specific ERNs and more valuable as a tool to build a strong partnership culture. Such an evaluation framework could be integrated into the ERNs’ quality improvement system to ensure that the networks’ activities are driven by and remain responsive to patients’ needs.

According to the European Union (EU), a disease is considered rare when it affects no more than one person in 2000. Rare diseases (RDs) are serious, chronic, and often life-threatening conditions. There are major problems with the diagnosis and treatment of RDs, such as lack of knowledge, lack of or delayed diagnosis, lack of treatment, and lack of or limited access to medical care. The aim of this article is to evaluate the European Reference Networks (ERNs) for rare diseases. Literature and document search. After undertaking many projects with regard to preparation of the national registries, the EU has established European Reference Networks (ERNs) to facilitate cooperation among national registries and to support more effectively the treatment of RDs throughout Europe. The first 24 ERNs were launched in 2017, involving more than 900 specialized healthcare units from over 300 hospitals in 26 Member States and healthcare providers across Europe. ERNs are virtual networks that bring all existing knowledge, experience, and resources together, using three e-health and telemedicine tools: the ERN Collaborative Platform, the ERN Clinical Patient Management System, and the ERN public website. With these tools, ERNs bring the best specialists together from all European countries and make the best treatment accessible for patients. ERNs can be considered a unique example of e-health and telemedicine implementation at a high level.

Although adult neurologists usually are keen to evaluate and treat movement disorders, some movement disorder specialists may not treat children, leaving the leading role to pediatricians who might feel inexperienced dealing with diseases of the nervous system.Movement Disorders in Childhood is primarily focused on tackling this problem by offering a practical and concise resource for clinicians.

Myoclonus dystonia syndrome (MDS) is a young-onset movement disorder. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. We assembled the largest cohort of MDS patients to date, and determined the frequency and type of SGCE mutations. The aim was to establish the motor phenotype in mutation carriers and utility of current diagnostic criteria. Eighty-nine probands with clinical features compatible with MDS were recruited from the UK and Ireland. Patients were phenotypically classified as "definite", "probable" or "possible" MDS according to previous guidelines. SGCE was analyzed using direct sequencing and copy number variant analysis. In those where no mutation was found, DYT1 (GAG deletion), GCH1, THAP1 and NKX2.1 genes were also sequenced. Nineteen (21.3%) probands had an SGCE mutation. Three patterns of motor symptoms emerged: (1) early childhood onset upper body myoclonus and dystonia, (2) early childhood onset lower limb dystonia, progressing later to more pronounced myoclonus and upper body involvement, and (3) later childhood onset upper body myoclonus and dystonia with evident cervical involvement. Five probands had large contiguous gene deletions ranging from 0.7 to 2.3 Mb in size with distinctive clinical features, including short stature, joint laxity and microcephaly. Our data confirms that SGCE mutations are most commonly identified in MDS patients with (1) age at onset ≤10 years and (2) predominant upper body involvement of a pure myoclonus-dystonia. Cases with whole SGCE gene deletions had additional clinical characteristics, which are not always predicted by deletion size or gene involvement.

Novel SGCE mutation in a patient with myoclonus-dystonia syndrome – Diagnostic delay of more than 40 years