Rapid-Onset Dystonia-Parkinsonism Phenotype Consistency for a Novel Variant of ATP1A3 in Patients Across 3 Global Populations

Abstract

Mutations in ATP1A3, which encodes the α3 subunit of Na, K-ATPase, produce various neurologic and psychological disorders that are increasingly believed to be on a continuum, from severe infantile presentations to adult-onset movement disorders. We present evidence that a single codon deletion can nonetheless produce a typical syndrome of rapid onset dystonia-parkinsonism (RDP, DYT/PARK-ATP1A3, OMIM 128235). 1 The novel heterozygous mutation p.Phe297del (c.889-891delTTC in NM_152296) was identified in 4 patients in 3 different countries with different genetic backgrounds, European, Japanese, and mixed. This supports the idea that there are discrete mutation-related syndromes underlying the continuum of ATP1A3 phenotypes.A 19-year-old Japanese man, 44-year-old and 37-year-old Portuguese siblings (older sister and younger brother), and a 29-year-old Brazilian woman were investigated clinically and genetically. Subjects underwent next-generation sequencing panel or Sanger sequencing under research protocols. All 4 cases had typical 1 and mild-to-moderate symptoms of RDP. Details are in table 1. All cases were familial according to family history and/or genetic testing. Rapid onset of oromandibular and upper extremity dystonia occurred in adolescence in 3 patients and at age 25 in 1. There were triggers in 3. Symptoms appeared immediately or over 3 weeks. Three developed mild parkinsonism within a decade. All had mild-to-moderate scores in the Burke-Fahn-Marsden dystonia scale; both the Japanese and Portuguese men work. None suffered from severe psychiatric disorders or intellectual disability. The Japanese man revealed abnormal SPECT, EEG, and memory-guided saccades (e-Methods case 1, figures e-1-5 and table e-1, links.lww.com/NXG/A392, and video 1). The Portuguese woman had normal muscle biopsy and metabolic screening. The Brazilian woman had normal brain tomography.The presence of consistent symptoms in independent patients with the same recurrent variant is itself strong evidence for pathogenicity. Supporting the pathogenicity of the shared variant, p.Phe297del in ATP1A3 corresponds to p.Phe305del in ATP1A2, which was reported in a case of hemiplegic migraine with symptoms typical of other mutations in that gene (FHM2, OMIM 602481). 2 In all 4 Na, K-ATPase catalytic subunit genes, there are 2 adjacent phenylalanines with the same codons, TTCTTC in ATP1A1, ATP1A2, and ATP1A3 and TTTTTT in ATP1A4. The deletion of 3 bases is so far the only mutation found at the site. p.Phe297del in ATP1A3 produced a uniform syndrome on different genetic backgrounds here, suggesting a *These authors contributed equally to this work. Prof. Sweadner connected these patients and studied the concept of this manuscript. Prof. Kawarai also investigated the gene of case 1.

ATP1A3 mutation in rapid-onset dystonia parkinsonism: New data and genotype-phenotype correlation analysis

“…A total of 95 patients with RDP and intermediate AHC/RDP, including 15 family and 36 sporadic patients with ATP1A3 mutations, were enrolled in our study. The manifestations and genetic information of all enrolled patients are summarized in Supplementary table 1 (Pittock et al, 2000 ; Wunderlich et al, 2002 ; de Carvalho Aguiar et al, 2004 ; Zaremba et al, 2004 ; Kamphuis et al, 2006 ; Brashear et al, 2007 , 2012 ; Lee et al, 2007 ; Kamm et al, 2008 ; Zanotti-Fregonara et al, 2008 ; Anselm et al, 2009 ; Blanco-Arias et al, 2009 ; Svetel et al, 2010 ; Tarsy et al, 2010 ; Barbano et al, 2012 ; Roubergue et al, 2013 ; Oblak et al, 2014 ; Rosewich et al, 2014a , b ; Sasaki et al, 2014 ; Tan et al, 2015 ; Termsarasab et al, 2015 ; Wilcox et al, 2015 ; Liu et al, 2016 ; Nicita et al, 2016 ; Pereira et al, 2016 ; Sampson et al, 2016 ; Sweadner et al, 2016 ; Sousa et al, 2017 ; Wenzel et al, 2017 ; Marrodan et al, 2018 ; Haq et al, 2019 ; Boonsimma et al, 2020 ; Yuan et al, 2020 ; Hoshino et al, 2021 ; Nomura et al, 2021 ). Due to the lack of clinical data of some patients, a total of 60 patients with typical RDP and 12 patients with intermediate AHC/RDP were finally included for further analysis ( Tables 1 , 2 ) (Anselm et al, 2009 ; Brashear et al, 2012 ; Rosewich et al, 2014a ; Sasaki et al, 2014 ; Termsarasab et al, 2015 ; Nicita et al, 2016 ; Pereira et al, 2016 ; Sousa et al, 2017 ; Boonsimma et al, 2020 ).…”