Abstract
Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.
Highlights
Introduction on Paroxysmal Movement Disorders andEpisodic AtaxiasParoxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements [1]
Two main categories of PMDs are recognized based on phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs) [2]
For the different diagnostic and management implications and for historical reasons, other hyperkinetic movement disorders are not considered PMDs, they have a limited time duration and their phenomenology is distinguishable from the baseline condition. This is the case of l-DOPA-induced dyskinesias, that are obviously excluded from PMDs because they are a common complication of Parkinson disease, their onset and cessation is related to l-DOPA administration and their treatment is highly specific and is part of the global management of the underlying disease [10]
Summary
Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements [1]. EA: Episodic Ataxia; GLUT1-DS: GLUT1 Deficiency syndrome; GTPCH: Guanosine Triphosphate cyclohydrolase I; MSA: multiple system atrophy; NIID: Neuronal intranuclear inclusion disease; NMDAr: N-methyl-D-aspartate receptor; PDH: Pyruvate dehydrogenase; PSP: Progressive supranuclear palsy; PTS: 6-Pyruvoyl Tetrahydrobiopterin Synthase; RDP: Rapid-Onset Dystonia-Parkinsonism; SR: sepiapterin reductase; TH: Tyrosine Hydroxylase; VGKC: voltage-gated potassium channel-complex; VMAT2: Vesicular monoamine transporter 2. For the different diagnostic and management implications and for historical reasons, other hyperkinetic movement disorders are not considered PMDs, they have a limited time duration and their phenomenology is distinguishable from the baseline condition This is the case of l-DOPA-induced dyskinesias, that are obviously excluded from PMDs because they are a common complication of Parkinson disease (limiting the diagnostic uncertainty), their onset and cessation is related to l-DOPA administration and their treatment is highly specific and is part of the global management of the underlying disease [10]. For this review of PMDs, we included both PxDs and EA, and developmental PMDs and other paroxysmal abnormal movements typically occurring in genetic neurological diseases, in order to provide a comprehensive review of these phenomena in both children and adults
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