An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.
Background Preterm infants are at risk of germinal matrix haemorrhage‐intraventricular haemorrhage (GMH‐IVH) which leads to post‐haemorrhagic hydrocephalus (PHH) in 30% of infants; this is associated with moderate‐severe neurodevelopmental impairment and confers significant risk of cerebral palsy. There are however no predictive indicators of the severity or long‐term outcome after GMH‐IVH. In recent years, endosome‐derived extracellular vesicles (EVs) or exosomes have been isolated from biofluids and shown to mediate intercellular communication via selective enrichment in proteins and micro‐RNAs. Methods This study aimed to isolate and characterise EVs from the cerebrospinal fluid (CSF) of 3 preterm infants with PHH using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) with immunogold protein labelling, and micro‐RNA analysis. Results NTA of unaltered CSF revealed a heterogeneous and dynamic population of EVs. Exosomal‐sized EVs were isolated by differential ultracentrifugation and TEM confirmed the presence of CD63+ and CD81+ exosomes. The micro‐RNAs miR‐9, miR‐17, miR‐26a, miR‐124 and miR‐1911 were detected within the exosome‐enriched fraction and profiled over time. Conclusion This is the first reported characterisation of exosomes from the CSF of preterm infants with post‐haemorrhagic hydrocephalus.
Objective:To explore the phenotypic spectrum of RHOBTB2-related disorders, and specifically to determine whether patients fulfil criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals.Methods:Individuals with RHOBTB2-related disorders were identified through a movement disorder clinic at a specialist paediatric centre, with additional cases identified through collaboration with other centres internationally. Clinical data was acquired through retrospective case-note review.Results:11 affected patients were identified. All had heterozygous missense variants involving exon 9 of RHOBTB2, confirmed as de novo in nine cases. All had a complex motor phenotype, including at least two different kinds of movement disorder, e.g. ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements and eight experienced hemiplegic episodes. In contrast to classical AHC, commonly caused by mutations in ATP1A3, these events were only reported later in RHOBTB2-mutation-positive patients, from twenty months of age. Seven patients had epilepsy, but of these, four achieved seizure-freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin colour change and gastrointestinal symptoms, each in four patients.Conclusion:Although heterozygous RHOBTB2 mutations were originally described in early infantile epileptic encephalopathy (EIEE64), our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. RHOBTB2 testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for ATPA1A3 mutations.
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