A special issue on childhood-onset movement disorders.

Abstract

Sharing a common language, terminology, and taxonomy is essential to facilitate communication between clinicians and researchers in the fields of pediatric and adult movement disorders. This is crucial not only for ensuring best clinical practice and care for patients across the age spectrum, but also for developing research opportunities that may have important implications for the treatment of both pediatric and adult movement disorders. Although childhood-onset movement disorders have been at the core of our field from the very beginning, dating back centuries to Sydenham's description of chorea minor1 and Oppenheim's iconic description of DYT1 dystonia,2, 3 pediatric movement disorders is a relatively new field within child neurology. The spectrum of childhood-onset movement disorders is rapidly growing and complex owing to there being a large number of genetic and multisystem diseases that cause movement disorders. Complexity also stems from most movement disorders manifesting during a time of intense nervous system development. Transient developmental motor phenomena can resemble movements categorized as abnormal in adults. To define, assess, and treat movement disorders in the pediatric population at various ages is challenging and requires an approach that is naturally different from the approach to an adult. Consensus on phenomenology, terminology, disease definition, and, in some areas, treatment is available as the result of the work of several working groups and task forces.4-8 The International Parkinson and Movement Disorder Society's task forces on Rare Movement Disorders and on Pediatric Movement Disorders are expected to carry these efforts forward. The field of pediatric movement disorders is expanding because there is both a clinical need and new options for management. Advances in the fields of genetics and neuroscience have created unprecedented opportunities to tackle childhood-onset neurological diseases that once seemed completely resistant to therapy. In the field of pediatric movement disorders, genetic discoveries have been made possible by the advent and availability of next-generation sequencing technologies. Developing a framework to translate these genetic discoveries into clinical practice, research, and discovery is imperative. An important piece of this framework is the efficient communication of discoveries between pediatric and adult neurologists. Indeed, adult movement disorders specialists have to be increasingly aware of newly discovered conditions with childhood onset that may go undiagnosed until adulthood. This is particularly relevant for treatable disorders and may well be relevant for more disorders in the near future, given the intense research in the field. These considerations presented the impetus for this Special Series on Childhood-Onset Movement Disorders. Here, we focus on several important and timely issues by bringing together expert reviews covering 4 topics: challenges in identifying genetic disorders that mimic cerebral palsy, treatable inborn errors of metabolism that present with movement disorders, emerging overlaps between childhood-onset lysosomal diseases and adult-onset movement disorders, and finally an update on the management of pediatric movement disorders covering symptomatic and targeted treatments. We think that all of these topics bridge pediatric and adult neurology and have immediate relevance to clinical practice of both, but also implications for research. In the first article, “Genetic Mimics of Cerebral Palsy,” Pearson and colleagues9 address an important and evolving clinical question: How to distinguish cerebral palsy from genetic or metabolic disorders that mimic this condition? This is not an easy task and one that requires a careful approach. The authors decide to focus on conditions that satisfy the following criteria: onset before the age of 2 years, stable disease course with no development regression, and normal or nonspecific findings on brain imaging. Conditions that typically present with predominant intellectual disability, autism, encephalopathy, or epilepsy were excluded, allowing selection for a population that mainly presents with movement disorders. They provide a framework to a diagnostic approach and outline some specific clinical and imaging features, an approach that will be helpful to movement disorders specialists and general child neurologists alike. A precise etiological diagnosis has important implications for patients and families. There are disease-specific treatments for a small number of conditions that can improve symptoms and developmental outcomes. In addition, a precise genetic diagnosis opens opportunities for counseling, including genetic counseling for family members at risk, and can improve quality of life by relieving possible feelings of ambivalence or guilt. These important implications make it imperative for adult movement disorders specialists to challenge a preestablished diagnosis of cerebral palsy and to test, when appropriate, for newly discovered genes that may present as phenocopies of cerebral palsy. This has, for example, been recently described for ADCY5-associated movement disorders. In the second article, Ebrahimi-Fakhari, Van Karnebeek, and Münchau discuss “Movement Disorders in Treatable Inborn Errors of Metabolism.”9 The field of inborn errors of metabolism is rapidly expanding, now listing more than 1000 entities. Movement disorders are among the most common neurological manifestations in children with inborn errors of metabolism and account for a substantial part of the morbidity and mortality. The authors develop a phenomenology-based approach that can help to facilitate a diagnosis by guiding biochemical, molecular, and imaging testing. Over the last decades, new treatment approaches have changed the scope of inborn errors of metabolism from a group of rare, untreatable, and often fatal disorders to an important cause of potentially treatable diseases. It is thus imperative to recognize these conditions early. It is also increasingly established that many of these conditions, such as GTPCH1-related movement disorders or Wilson's disease, may present not only in childhood but also in adulthood and with a wide phenotypic spectrum. Adult neurologists thus need to be aware of these and other conditions. In the second part of the article, the authors lucidly discuss an approach to identifying the “top ten” of treatable inborn errors of metabolism presenting with movement disorders — diagnoses that should never be missed. This may hopefully serve as a helpful guide for everyone in the field. The third article, “Emerging Links Between Lysosomal Storage Diseases in Children and Adult-Onset Movement Disorders,” by Yseelstein, Shulman, and Krainc, highlights an important concept that has become apparent over the last years: The molecular and clinical overlap of several childhood-onset lysosomal diseases with often-degenerative diseases presenting with movement disorders in adults, including Parkinson's disease.10 Perhaps the strongest evidence comes from mutations in the glucocerebrosidase (GBA1) gene, which cause Gaucher's disease if present on both alleles, and were found to constitute a common and potent risk factor for Parkinson's disease. Such an association has recently extended to other lysosomal genes including ATP13A2 (Kufor-Rakeb syndrome), GALC (Krabbe disease), NPC1 (Niemann-Pick disease type C), SMPD1 (Niemann-Pick disease types A and B), and NAGLU (Sanfilippo syndrome). This exemplifies how monogenic diseases in children provide a unique window into the role of fundamental molecular mechanisms at play in adult-onset movement disorders. Precisely deciphering this association bears the potential to lead to novel and targeted therapies. In the fourth and final article, “Current Therapies And Therapeutic Decision Making for Childhood-Onset Movement Disorders,” Mohammad, Paget, and Dale cover existing and emerging treatments including pharmacologic, surgical, and gene therapy approaches.11 Faced with a broad task, the authors start out by outlining guiding principles for the treatment of movement disorders in children. From these principles that apply to all movement disorders the authors venture to discuss specific medications, physical therapies, invasive therapies, neuromodulation, and emerging targeted therapies. For each treatment, they feature the existing evidence and give pragmatic advice. Although this article will mainly guide neurologists in the clinic, it also highlights the need for well-designed clinical trials. Here, like in many areas of child neurology, we can learn from trials in adults, yet will have to address the challenges and opportunities that are unique to our pediatric patient population. We hope this Special Series will provide the reader with a resource for important scenarios in pediatric movement disorders and will foster discussion and collaboration. We thank Movement Disorders for supporting this endeavor and contributing authors for their expertise, time, and enthusiasm.