Inborn errors of metabolism presenting with movement disorders: how should they be recognized, diagnosed and treated?

Administrator: Juan Dario Ortigoza-Escobar, Spain

Dr. Juan Dario Ortigoza-Escobar
Movement Disorder Unit, Hospital Sant Joan de Déu and European Reference Network for Rare Neurological Disorders (ERN-RND). Barcelona, Spain.
juandario.ortigoza@sjd.es
Diagnostic algorithm for inborn errors of metabolism presenting with movements disorders.
Inborn errors of metabolism (IEMs) encompass a large group of single gene disorders that can affect all organs and lead to a variety of symptoms. Most of the IEMs are multisystemic diseases with neurological and non-neurological manifestations. Commonly, the initial symptoms and signs are somewhat nonspecific. Movement disorders (MD) are among the most usual neurological symptoms and account for a significant part of the morbidity and mortality. MD manifests in IEMs that cause diffuse CNS or selective basal ganglia involvement and can be both hyperkinetic (dystonia, chorea, myoclonus, ataxia, tremor, etc.) and hypokinetic (rigid-akinetic syndrome). A MD does not always predict the type of IEM because an MD in the context of IEMs is often a combination of different MDs. The International Classification of Inherited Metabolic Disorders (ICIMD) recently defined 1450 IEMs. A recent review by Ortigoza-Escobar, 2020, describes two hundred and thirty-one IEMs presenting with MD. The great number and variety of IEMs associated with MD, as well as the lack of awareness of these disorders, make it difficult for the pediatric neurologist to decide on the initial evaluation, resulting in a delay in diagnosis and timely treatment. 

Dr. Michèl AAP Willemsen
Department of Child Neurology, Amalia Children's Hospital, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
michel.willemsen@radboudumc.nl
Biochemical investigation and radiological patterns in movement disorders associated with Inborn errors of metabolism.
IEMs account for less than a quarter of all diagnoses in children with MD, according to several studies. In addition, there are IEMs with MD as a primary or predominant feature caused by treatable IEMs that should be kept in mind at all times. As a result, early detection of these underlying IEMs is critical, as it frequently allows for disease-specific therapy and the best possible prognosis for the affected child. Biochemical tests in blood, urine, feces, fibroblasts, or CSF can detect 88 percent of the 231 IEMs with MD. It is quite difficult for general neuropediatricians to decide which tests to order in each situation. In this symposium, we will provide a list of tests to request taking into account the type of movement disorder and other clinical characteristics. Along with this baseline biochemical testing, neuroimage can identify patterns of treatable inborn errors of metabolism and help to exclude other secondary causes of MD, guiding further testing. Consequently, neuroimage should be considered part of the initial diagnostic evaluation. This segment will look at the minimal biochemical investigation required to diagnosis treatable disorders, radiological patterns, and genetic testing. We acknowledge that resources to investigate patients are not the same all over the world, thus we will provide a summary of the investigations required for the successful diagnosis of treatable disorders.

Dr. Shekeeb Mohammad
Paediatric Neurologist Discipline of Child and Adolescent Health, Children's Hospital at Westmead Clinical School. Sidney Australia.
shekeeb.mohammad@health.nsw.gov.au
Treatment approach to childhood-onset movement disorders associated with Inborn errors of metabolism
MDs are a major medical problem. Treatment of children with IEM-associated MD may include both symptomatic treatment of MDs and disease-specific management of the underlying IEM. Pharmacologic treatments for IEMs may comprise specialized dietary modifications, cofactor, vitamin, or supplement addition, enzyme replacement therapy, hematopoietic stem cell transplantation, and gene therapy. Successful treatment and better outcomes frequently take place with early recognition of an underlying treatable IEM. Therefore, there should be an increased awareness of these IEMs. Mohammad et al., 2019 has recently summarized several practical applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions, and offered a current summary of therapeutic options for childhood-onset movement disorders. IEMs associated with movement disorders in children are amenable to disease-specific precision treatments. In addition, symptomatic treatments with conventional agents such as dopaminergic and cholinergic therapies are still the most accessible around the world.