Cortical Myoclonus-Dystonia and Intellectual disability: A Case of IRF2BPL defect

Introduction Pathogenic variants in the IRF2BPL (interferon regulatory factor 2 binding-like protein) cause a complex and progressive neurological disorder, including neurodevelopmental disorder with regression (loss of speech), movement disorders (typically dystonia and ataxia), and seizures (NEDAMSS). IRF2BPL has been more recently associated with progressive myoclonus epilepsy. We report on a young patient with IRF2BPL defect presenting with myoclonus and neurodevelopmental disorders (NDD). Methods We performed an extensive examinations, including EEG/EMG polygraphy to characterize her movement disorder, brain MRI, metabolic studies, and genetic analysis. Results This 14-year-old girl was diagnosed with West syndrome at 9 months without further epileptic manifestation after the age of 4 years. At the age of 10, she presented with a sudden onset of auditory and visual hallucinations. Neuropsychological evaluation detected a moderate intellectual disability (WAIS-IV: IQ 49, VCI 74, PRI 58, WMI 58, PSI 50). On examination, she was hypomimic and exhibited mild dystonic posturing of the hands with contralateral mirroring diffusion and spontaneous and stimulus-evoked jerky movements of upper limbs at rest, exacerbated by action. EEG detected an excessive expression of theta rhythm for the age without epileptic discharges. EMG recorded short-length (<30 milliseconds) and irregular muscular bursts with agonist-antagonist co-activation. Jerk-locked back-averaging disclosed a small amplitude EEG wave time-locked to EMG discharges, confirming the cortical generator of the myoclonus. Brain MRI detected bilateral white matter T2 hyperintensity in the peritrigonal region, associated with dilatation of the lateral ventricles. Array CGH analysis was uninformative. WES demonstrated the presence of a likely pathogenic c.2139_2140dupCT variant in IRF2BPL (p.Cys714SerfsTer54). Conclusions We report on an unusual association of cortical myoclonus and dystonia in our patient. Dystonia and non-cortical myoclonus has been described in several early-onset genetic conditions such as epsilon-sarcoglycan (SGCE) (as the principal genetic cause), KCTD17, KCNN2. In contrast, we detected the cortical origin of myoclonus associated with dystonia in IRF2BPL defect. Moderate intellectual disability and a previous diagnosis of West syndrome are not usually part of the phenotypical spectrum of the classical myoclonus-dystonia genes and should address the diagnostic work-up towards this condition. This case suggests that IRF2BPL variants should be considered in those cases with myoclonus-dystonia phenotype that include atypical features such as a cortical rather than a subcortical myoclonus, a moderate intellectual disability, and a concomitant or a previous epileptic syndrome.