Tom J. de Koning

North Sea‐Progressive Myoclonus Epilepsy (NS‐PME) is a progressive neurological disorder, initially only associated with the homozygous GOSR2 founder mutation (c.430G>T; p.Gly144Trp). Clinical symptoms include untreatable early‐onset ataxia, cortical myoclonus and epilepsy. Recently, the spectrum of GOSR2 mutations and associated phenotypic variability has expanded. To improve care and to facilitate genotype–phenotype predictions for NS‐PME patients, we systematically reviewed all reported GOSR2 mutations, clinical phenotypes, and pathophysiological findings. A narrative review literature search was conducted in PubMed, EMBASE, and Web of Science (1985—August 2024) using the keywords “GOSR2”, “GS27 protein”, “Bos1”, and “Membrin”. Only studies in English and specifically studies on GOSR2 function, pathogenic variants, clinical manifestations, and potential therapies were included. A total of 42 patients with 11 different GOSR2 mutations were identified. Three main phenotypes were observed: progressive myoclonus ataxia/epilepsy (PMA/PME), congenital muscular dystrophy, and hearing loss. Orthopedic abnormalities were frequently reported. Intercurrent infections or fever often led to a worsening of symptoms. Glycosylation defects were reported in several compound heterozygous GOSR2 variants. Molecularly, GOSR2 mutations result in (partial) loss of function of the GOSR2/SNARE complex, with mutation severity and the involvement of specific isoforms contributing to phenotypic variability. GOSR2 mutations lead to progressive neurological disorders, primarily characterized by myoclonus ataxia/epilepsy, muscular dystrophy, and hearing loss. The genotypic background of NS‐PME has expanded with pathogenic biallelic GOSR2 variants beyond the original homozygous founder mutation. Understanding the clinical spectrum and molecular mechanisms of GOSR2‐related diseases may facilitate more targeted treatment strategies as well as better‐informed phenotype predictions.

Movement disorders are common in inherited metabolic diseases (IMDs) and significantly impact quality of life. Unfortunately, they are often underrecognised by metabolic physicians. This study investigated whether a new screening tool improves recognition of movement disorders in IMD patients by non‐neurologists. Internists and paediatricians specialized in IMDs assessed videos of 44 IMD patients who perform four specific neurological tests, to evaluate the presence and phenotype of a movement disorder. Initially, baseline assessments were performed without the tool. Eight months later, the same videos were assessed using an instructional video demonstrating the four neurological tests, and a screening tool including these tests with 14 yes/no questions regarding observed abnormalities. One hundred and forty‐nine assessments were conducted by 15 metabolic internists and paediatricians. At baseline, 70% (105/149) of assessments correctly determined the presence of a movement disorder. Sensitivity of the tool was 68%. In the second measurement, when the outcome of the tool was considered decisive (with at least one positive answer indicating a movement disorder), 79% (117/149) of assessments were correct. Sensitivity of the tool increased to 87% (Chi‐square = 15.75, p < 0.001). All severe and moderately severe movement disorders were recognized in the second measurement. The tool and instructional video did not enhance recognition of specific movement disorder phenotypes. However, the tool did improve the accuracy of treatment indications (chi‐square = 4.000, p < 0.05). The correct use of the screening tool significantly increased the sensitivity and thereby the recognition of movement disorders in IMD patients, though referral to a neurologist remains necessary for phenotype identification.

Objectives: North Sea–Progressive Myoclonus Epilepsy (NS‐PME) is a rare, childhood‐onset disorder primarily characterized by movement disorders including progressive myoclonus and ataxia; subsequently accompanied by varying degrees of epilepsy. While motor symptoms are clearly defined, quality of life (QoL) has never been investigated in NS‐PME. Additionally, nonmotor symptoms (NMS) including anxiety, depression, and cognitive problems are known to impact QoL and are increasingly being reported in other movement disorders. Hence, we examined the presence of anxiety and depression symptoms and the degree of QoL in NS‐PME. Materials and Methods: Data were collected from multiple cross‐sectional, survey‐based studies conducted between 2014 and 2020 at the University Medical Center Groningen (UMCG), the Netherlands. First, data on QoL, anxiety, and depression symptoms were collected from 11 persons with NS‐PME. Second, to compare outcomes in NS‐PME with controls ( n = 21) and other hyperkinetic movement disorders (HMDs; n = 146), data from previously conducted studies in the UMCG were reused. The surveys used include the SF‐36/RAND‐36, the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory (BDI). Results: Symptoms of anxiety and depression were not present in the majority of persons with NS‐PME. Compared to QoL scores of controls and other HMDs, persons with NS‐PME scored significantly worse on physical functioning domains and, although nonsignificant, rendered the highest scores on emotional functioning domains. Conclusion: Firstly, we did not find indications for significantly increased anxiety or depression symptoms in NS‐PME. Secondly, our findings on QoL in NS‐PME reveal the following: (1) a floor effect of the SF‐36 questionnaire and (2) suggest a disability paradox in NS‐PME, in which persons with NS‐PME reported good emotional well‐being, despite physical challenges. To explore the presence of a disability paradox further and generate more suitable QoL measures for movement disorders such as NS‐PME, future studies should elaborate on personal perspectives, including the exploration of coping mechanisms.

Background Transition from child-centered to adult-centered healthcare is a gradual process that addresses the medical, psychological, and educational needs of young people in the management of their autonomy in making decisions about their health and their future clinical assistance. This transfer is challenging across all chronic diseases but can be particularly arduous in rare neurological conditions. Aim To describe the current practice on the transition process for young patients in centers participating in the European Reference Network for Rare Neurological Diseases (ERN-RND). Methods Members of the ERN-RND working group developed a questionnaire considering child-to-adult transition issues and procedures in current clinical practice. The questionnaire included 20 questions and was sent to members of the health care providers (HCPs) participating in the network. Results Twenty ERN-RND members (75% adult neurologists; 25% pediatricians; 5% nurses or study coordinators) responded to the survey, representing 10 European countries. Transition usually occurs between 16 and 18 years of age, but 55% of pediatric HCPs continue to care for their patients until they reach 40 years of age or older. In 5/20 ERN-RND centers, a standardized procedure managing transition is currently adopted, whereas in the remaining centers, the transition from youth to adult service is usually assisted by pediatricians as part of their clinical practice. Conclusions This survey demonstrated significant variations in clinical practice between different centers within the ERN-RND network. It provided valuable data on existing transition programs and highlighted key challenges in managing transitions for patients with rare neurological disorders.

Biallelic variants in the Golgi SNAP receptor complex member 2 gene (GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the GOSR2 founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic–clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype–phenotype spectrum of GOSR2-related disorders and suggest that GOSR2 should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures.

Background: Movement disorders are frequent in patients with inborn errors of metabolism (IEMs) but poorly recognized, particularly by nonmovement disorder specialists. We propose an easy‐to‐use clinical screening tool to help recognize movement disorders.Objective: The aim is to develop a user‐friendly rapid screening tool for nonmovement disorder specialists to detect moderate and severe movement disorders in patients aged ≥4 years with IEMs.Methods: Videos of 55 patients with different IEMs were scored by experienced movement disorder specialists (n = 12). Inter‐rater agreements were determined on the presence and subtype of the movement disorder. Based on ranking and consensus, items were chosen to be incorporated into the screening tool.Results: A movement disorder was rated as present in 80% of the patients, with a moderate inter‐rater agreement (κ =0.420, P < 0.001) on the presence of a movement disorder. When considering only moderate and severe movement disorders, the inter‐rater agreement increased to almost perfect (κ = 0.900, P < 0.001). Dystonia was most frequently scored (27.3%) as the dominant phenotype. Treatment was mainly suggested for patients with moderate or severe movement disorders. Walking, observations of the arms, and drawing a spiral were found to be the most informative tasks and were included in the screening tool.Conclusions: We designed a screening tool to recognize movement disorders in patients with IEMs. We propose that this screening tool can contribute to select patients who should be referred to a movement disorder specialist for further evaluation and, if necessary, treatment of the movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dystonia is a movement disorder in which patients have involuntary abnormal movements or postures. Non-motor symptoms, such as psychiatric symptoms, sleep problems and fatigue, are common. We hypothesise that the gut microbiome might play a role in the pathophysiology of the (non-)motor symptoms in dystonia via the gut–brain axis. This exploratory study investigates the composition of the gut microbiome in dystonia patients compared to healthy controls. Furthermore, the abundance of neuro-active metabolic pathways, which might be implicated in the (non-)motor symptoms, was investigated. We performed both metagenomic and 16S rRNA sequencing on the stool samples of three subtypes of dystonia (27 cervical dystonia, 20 dopa-responsive dystonia and 24 myoclonus-dystonia patients) and 25 controls. While microbiome alpha and beta diversity was not different between dystonia patients and controls, dystonia patients had higher abundances of Ruminococcus torques and Dorea formicigenerans, and a lower abundance of Butyrivibrio crossotus compared to controls. For those with dystonia, non-motor symptoms and the levels of neurotransmitters in plasma explained the variance in the gut microbiome composition. Several neuro-active metabolic pathways, especially tryptophan degradation, were less abundant in the dystonia patients compared to controls. This suggest that the gut–brain axis might be involved in the pathophysiology of dystonia. Further studies are necessary to confirm our preliminary findings.

Background: With advances in clinical genetic testing, associations between genetic neurodevelopmental disorders and parkinsonism are increasingly recognized. In this review, we aimed to provide a comprehensive overview of reports on parkinsonism in genetic neurodevelopmental disorders and summarize findings related to genetic diagnosis, clinical features and proposed disease mechanisms.Methods: A systematic literature review was conducted in PubMed and Embase on June 15, 2021. Search terms for parkinsonism and genetic neurodevelopmental disorders, using generic terms and the Human Phenotype Ontology, were combined. Study characteristics and descriptive data were extracted from the articles using a modified version of the Cochrane Consumers and Communication Review Group's data extraction template. The protocol was registered in PROSPERO (CRD42020191035).Results: The literature search yielded 208 reports for data‐extraction, describing 69 genetic disorders in 422 patients. The five most reported from most to least frequent were: 22q11.2 deletion syndrome, beta‐propeller protein‐associated neurodegeneration, Down syndrome, cerebrotendinous xanthomatosis, and Rett syndrome. Notable findings were an almost equal male to female ratio, an early median age of motor onset (26 years old) and rigidity being more common than rest tremor. Results of dopaminergic imaging and response to antiparkinsonian medication often supported the neurodegenerative nature of parkinsonism. Moreover, neuropathology results showed neuronal loss in the majority of cases. Proposed disease mechanisms included aberrant mitochondrial function and disruptions in neurotransmitter metabolism, endosomal trafficking, and the autophagic‐lysosomal and ubiquitin‐proteasome system.Conclusion: Parkinsonism has been reported in many GNDs. Findings from this study may provide clues for further research and improve management of patients with GNDs and/or parkinsonism.

Mutations in either mitochondrial DNA (mtDNA) or nuclear genes that encode mitochondrial proteins may lead to dysfunctional mitochondria, giving rise to mitochondrial diseases. Some mitochondrial myopathies, however, present without a known underlying cause. Interestingly, methylation of mtDNA has been associated with various clinical pathologies. The present study set out to assess whether mtDNA methylation could explain impaired mitochondrial function in patients diagnosed with myopathy without known underlying genetic mutations. Enhanced mtDNA methylation was indicated by pyrosequencing for muscle biopsies of 14 myopathy patients compared to four healthy controls, at selected cytosines in the Cytochrome B (CYTB) gene, but not within the displacement loop (D-loop) region. The mtDNA methylation patterns of the four healthy muscle biopsies were highly consistent and showed intriguing tissue-specific differences at particular cytosines with control skin fibroblasts cultured in vitro. Within individual myopathy patients, the overall mtDNA methylation pattern correlated well between muscle and skin fibroblasts. Despite this correlation, a pilot analysis of four myopathy and five healthy fibroblast samples did not reveal a disease-associated difference in mtDNA methylation. We did, however, detect increased expression of solute carrier family 25A26 (SLC25A26), encoding the importer of S-adenosylmethionine, together with enhanced mtDNA copy numbers in myopathy fibroblasts compared to healthy controls. To confirm that pyrosequencing indeed reflected DNA methylation and not bisulfite accessibility, mass spectrometry was employed. Although no myopathy-related differences in total amount of methylated cytosines were detected at this stage, a significant contribution of contaminating nuclear DNA (nDNA) was revealed, and steps to improve enrichment for mtDNA are reported. In conclusion, in this explorative study we show that analyzing the mitochondrial genome beyond its sequence opens novel avenues to identify potential molecular biomarkers assisting in the diagnosis of unexplained myopathies.