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Cortical Myoclonus and Complex Paroxysmal Dyskinesias in a Patient with NAA15 Variant

2024; Wiley; Volume: 39; Issue: 7 Linguagem: Inglês

10.1002/mds.29793

1531-8257

Elena Freri, Laura Canafoglia, Claudia Ciaccio, Davide Rossi Sebastiano, Davide Caputo, Roberta Solazzi, Francesca L. Sciacca, Maria Iascone, Ferruccio Panzica, Tiziana Granata, Silvana Franceschetti, Nardo Nardocci,

Glycogen Storage Diseases and Myoclonus

NAA15 gene encodes for a protein involved in amino-terminal acetylation of cytosolic proteins. Patients with NAA15 variants show variable levels of intellectual disability, dysmorphic features, cardiac and visual anomalies, and movement disorders, including pediatric-onset dystonia and dystonia parkinsonism.1-3 We report the clinical and neurophysiological characteristics observed in a young girl harboring a novel pathogenic NAA15 variant. The girl was born at term, from healthy parents, after a normal pregnancy; during adolescence, she reported episodes of tachycardia, without any significant findings on cardiac examinations. From the age of 12 years, she complained the appearance of stiffness and "tremor" in her right, dominant, hand that used to occur after a prolonged period (5–10 minutes) of writing and that disappeared after some minutes of rest. At the time of our first observation, at age 15, during upper-limb extension, we noticed irregular, arrhythmic, small-amplitude dyskinesias resembling myoclonus. The dyskinesias were absent at rest. Clinical examination did not detect somatic abnormalities, and cognitive evaluation reported IQ 72 on the Wechsler scale and specific learning disorder. Video electroencephalogram–electromyogram (EEG–EMG) recording identified short sequences of repetitive EMG bursts lasting less than 50 ms, intermingled with normal contraction (Fig. 1A). Coherence analysis indicated that the bursts were synchronous on the antagonist muscle couples (Fig. 1B); the study of cortico-muscular coherence showed a 17-Hz peak on contralateral central EEG derivation, consistent with a cortical origin of the myoclonic jerks (Fig. 1C).4 Cortical hyperexcitability was also proved by a mild increase in the peak-to-peak amplitude of somatosensory-evoked potentials (N20-P25: 8.2 μV). To determine the characteristics of the paroxysmal episodes reported to occur during writing, we recorded video EEG–EMG during drawing tasks (Siegfried spirals and parallel lines). During these tasks, we observed the gradual appearance of a complex movement disorder characterized by dystonia of the hand, and rapid hyperkinesias associated with bursts asynchronous on antagonist muscles on EMG, consistent with tremor (Fig. 1D,E), and by long-lasting (200–600 ms) jerky movements, involving the forearm (Fig. 1F; Video 1). After the interruption of the drawing tasks, the hyperkinesias continued for ~1 hour despite distracting maneuvers (conversation, execution of repetitive movements using the contralateral hand) and the administration of sublingual clonazepam. No EEG changes occurred during the movement disorders; the patient always remained alert and was able to respond verbally. Whole-exome sequencing analysis identified a heterozygous NAA15 variant: c.1492dup (p.Met498Asnfs*3), occurring de novo and classifiable as pathogenic, in agreement with American College of Medical Genetics and Genomics guidelines.5 A brain magnetic resonance imaging did not reveal any new information. To summarize, we observed a complex movement disorder characterized by cortical myoclonus, and paroxysmal dyskinesias. The clinical observation, together with the neurophysiological study, highlighted the complexity of movement disorder and the widespread involvement of cortical and subcortical structures in its generation. Our observation confirms that simple neurophysiological protocols based on EEG–EMG data are useful in defining the characteristics of movement disorders, particularly tremor and myoclonus.6 Finally, our findings broaden the spectrum of genes associated with paroxysmal dyskinesias7 and widen the phenotype associated with NAA15 variants. This case report was presented in the form of a poster at the Eighth International Symposium on Paediatric Movement Disorders, held in Barcelona. Open access funding provided by BIBLIOSAN. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. E.F. and L.C. were involved in design, execution, analysis, writing, and editing; S.F. and N.N. contributed to analysis and writing and editing of the manuscript; D.R.S. was involved in the interpretation of the evoked potentials and editing of the manuscript; C.C., F.L.S., and M.I. were involved in the execution and interpretation of genetic analyses, and editing of the manuscript; F.P. was involved in programming for neurophysiological analyses and editing of the manuscript; D.C., R.S., and T.G. assisted with writing and editing of the final version of the manuscript. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique E.F.: 1A, 1B, 1C, 2C, 3A, 3B L.C.: 1A, 1B, 1C, 2C, 3A, 3B C.C.: 1C, 2C, 3B D.R.S: 1C, 2C, 3B D.C.: 1C, 2C, 3B R.S.: 2C, 3B F.L.S.: 1C, 2C, 3B M.I.: 1C, 2C, 3B F.P.: 2C, 3B T.G.: 2C, 3B S.F.: 1A, 2C, 3B N.N.: 1A,2C, 3B Patients' guardians gave their written informed consent to publication of anonymized patients' data and video. The data that support the findings of this study are available from the corresponding author upon reasonable request.