Spectrum of movement disorders in GNAO1 encephalopathy: in-depth phenotyping and case-by-case analysis
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RESEARCH
Spectrum of movement disorders in GNAO1 encephalopathy: in‑depth phenotyping and case‑by‑case analysis Soo Yeon Kim1,2, YoungKyu Shim1, Young Joon Ko1, Soojin Park1,3, Se Song Jang1, Byung Chan Lim1,2,4, Ki Joong Kim1,4 and Jong‑Hee Chae1,2,4*
Abstract Background: GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations. Results: Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Median follow-up duration was 41 months (range 7–78 months) and age at last examination was 7.4 years (range 3.3–16.9 years). Initial complaints were hypo‑ tonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at median age of 3 months (range 0–75 months). All patients showed global developmental delay and 4 had severely retarded devel‑ opment. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoatheto‑ sis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct and characteristics movement phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions: We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diag‑ nostic insight and practice guidelines. Keywords: GNAO1, GNAO1 encephalopathy, Movement disorder, Early-onset dystonia, Early-onset chorea Introduction Since the first identification of GNAO1 as a new causative gene of early-onset epileptic encephalopathy in 2013, variable phenotypes have been reported [1–3]. Epilepsy *Correspondence: [email protected] 1 Division of Pediatric Neurology, Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children’s Hospital, Seoul, Korea Full list of author information is available at the end of the article
itself varied from early onset epileptic encephalopathy including Ohtahara syndrome, and generalized and focal epilepsies of different ages [1, 4, 5]. Movement phenotypes were also reported since the first clinical report and have recently become major presenting symptoms: so far, chorea, dystonia, orofacial dyskinesia, and stereotyped hand movements have been reported i
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