University of Mississippi eGrove Health, Exercise Science, and Recreation Faculty and Student Publications Management, Department of 3-1-2019 Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias Shanshan Zhong Peking University People's Hospital Shumeng Wen Wenzhou Medical University Yusen Qiu Nanchang University Yanyan Yu Nanchang University Ling Xin University of Mississippi Follow this and additional works at: https://egrove.olemiss.edu/hesrm_facpubs See next page for additional authors Part of the Exercise Physiology Commons, Leisure Studies Commons, Recreation Business Commons, Sports Management Commons, Sports Sciences Commons, and the Sports Studies Commons Recommended Citation Zhong, S., Wen, S., Qiu, Y., Yu, Y., Xin, L., He, Y., Gao, X., Fang, H., Hong, D., & Zhang, J. (2019). Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias. Molecular Genetics & Genomic Medicine, 7(3), e541. https://doi.org/10.1002/ mgg3.541 This Article is brought to you for free and open access by the Health, Exercise Science, and Recreation Management, Department of at eGrove. It has been accepted for inclusion in Faculty and Student Publications by an authorized administrator of eGrove. For more information, please contact [email protected]. Authors Shanshan Zhong, Shumeng Wen, Yusen Qiu, Yanyan Yu, Ling Xin, Yang He, Xuguang Gao, Hezhi Fang, Daojun Hong, and Jun Zhang This article is available at eGrove: https://egrove.olemiss.edu/hesrm_facpubs/27 Received: 24 September 2018 | Revised: 9 November 2018 | Accepted: 2 December 2018 DOI: 10.1002/mgg3.541 ORIGINAL ARTICLE Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias Shanshan Zhong1* | Shumeng Wen2* | Yusen Qiu3 | Yanyan Yu3 | Ling Xin4 | Yang He1 | Xuguang Gao1 | Hezhi Fang2 | Daojun Hong1 | Jun Zhang1 1Department of Neurology, Peking University People’s Hospital, Beijing, China Abstract 2Key Laboratory of Laboratory Medicine, Background: Heteroplasmic mitochondrial 3697G>A mutation has been associated College of Laboratory Medicine and Life with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lac- Science, Wenzhou Medical University, tic acidosis and stroke‐like episodes (MELAS), and LHON/MELAS overlap syn- Wenzhou, China drome. However, homoplasmic m.3697G>A mutation was only found in a family 3Department of Neurology, The First Affiliated Hospital of Nanchang University, with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic Nanchang, China mutation still need to be investigated in new patients. 4 Department of Health, Exercise Science, Methods: The clinical interviews were conducted in 12 individuals from a multiple‐ and Recreation Management, University of generation inherited family. Mutations were screened through exome next‐genera- Mississippi, University, Mississippi tion sequencing and subsequently confirmed by PCR‐restriction fragment length Correspondence polymorphism. Mitochondrial complex activities and ATP production rate were Daojun Hong and Jun Zhang, Department of Neurology, Peking University People’s measured by biochemical analysis. Hospital, Beijing, China. Results: The male offspring with bilateral striatal necrosis (BSN) were characterized Emails: [email protected] (DH); by severe spastic dystonia and complete penetrance, while the female offspring pre- [email protected] (JZ) sented with mild symptom and low penetrance. All offspring carried homoplasmic mutation of NC_012920.1: m.3697G>A, p.(Gly131Ser). Biochemical analysis re- Funding information This work was supported by the National vealed an isolated defect of complex I, but the magnitude of the defect was higher in Natural Science Foundation of China the male patients than that in the female ones. The ATP production rate also exhib- (81460199 and 81870996); and Peking University People’s Hospital Research and ited a similar pattern. However, no possible modifier genes on the X chromosome Development Funds (RDX 2018‐08). were identified. Conclusion: Homoplasmic m.3697G>A mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G>A. Our preliminary investiga- tions had not found the underlying modifiers to support the double hit hypothesis, while the high level of estrogens in the female patients might exert a potential com- pensatory effect on mutant cell metabolism. KEYWORDS bilateral striatal necrosis, homoplasmy, mitochondrial DNA mutation, sex bias *The authors had equal contribution to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Mol Genet Genomic Med. 2019;7:e541. wileyonlinelibrary.com/journal/mgg3 | 1 of 9 https://doi.org/10.1002/mgg3.541 2 of 9 | ZHONG ET AL. 1 | INTRODUCTION provided by every examined individual according to the Declaration of Helsinki. The study was approved by the Bilateral striatal necrosis (BSN) is a heterogeneous group of institutional ethical review board of the Peking University neurodegenerative diseases named after the distinctive neu- People's Hospital. roradiological features (Lim, 2009). The main neurological findings are characterized by symmetrical degeneration of putamen, caudate nucleus, and globus pallidus occasionally. 2.2 | Patients The pathogenesis of BSN is heterogeneous and has been asso- The index patient was a 20‐year‐old man (III3) from a non- ciated with various acquired and hereditary causes (Chokshi, consanguineous family (Figure 1). He had rigidity on the left Aygun, & Mullins, 2014). Hereditary striatal degeneration can limbs since he was 6 years old. The dystonia insidiously pro- be inherited as an autosomal dominant, autosomal recessive, or gressed and resulted in clumsy movements of the left limbs, mitochondrial disorder (Tonduti et al., 2016). Adult‐onset auto- but the symptoms maintained a stable condition since the age somal‐dominant BSN is caused by mutations in the phosphodi- of eight. Eight months ago, the right limbs started exhibiting esterase 8B (PDE8B, OMIM #603390) gene on chromosome similar rigidity. He presented with dysarthria, dysphagia, and 5q13 (Appenzeller et al., 2010). Autosomal‐recessive BSNs are difficulty of standing steadily. The patient had no complaints associated with mutations in several genes such as solute carrier about muscle weakness, myalgia, or numbness. Mini‐mental family 25 member 19 (SLC25A19, OMIM #606521) (Spiegel state examination (MMSE) revealed a moderate cognitive et al., 2009), nucleoporin 62 (NUP62, OMIM #605815) disability (17/30). Physical examination revealed scoliosis, (Bianciardi et al., 2016), adenosine deaminase RNA specific finger joint contracture, left ankle deformity, and an in- (ADAR1, OMIM: 146920) (La Piana et al., 2014), and protein creased muscle tone of the neck and all of the limbs. Muscle Vac14 homolog (VAC14, OMIM #604632) (Stutterd et al., strength graded 5/5 in the right limbs and 4/5 in the left limbs 2017). Mitochondrial BSNs are caused by mutations in both mi- (Medical Research Council Scale). The deep tendon reflexes tochondrial and nuclear genes associated with the maintenance of the lower limbs were enhanced. The Babinski sign was of mitochondrial function (Binder et al., 2003; Thyagarajan, positive on the left side. His visual acuity and auditory ability Shanske, Vazquez‐Memije, Vivo, & DiMauro, 1995). were unimpaired. The pinprick, position, and vibration sen- Several mitochondrial DNA (mtDNA) mutations associ- sations were normal. ated with defects of oxidative respiratory chain enzymes were The elder aunt's son (III2) was 23 years old, and he dis- linked with infantile‐onset BSNs (Hirayanagi et al., 2017; played spastic gait at the age of five. He developed upper limb Tarnopolsky, Meaney, Robinson, Sheldon, & Boles, 2013). spasticity, lower limb tightness, and walking difficulty at the The heteroplasmic mutation of NC_012920.1: m.3697G>A, age of 10. He was wheelchair‐bound when he was referred p.(Gly131Ser) in the mitochondrial NADH dehydrogenase to our clinic at the age of 26. His cognitive performance was subunit 1 (MTND1, OMIM #516000) gene was identified in mildly decreased (MMSE: 20/30). Physical examination re- patients with mitochondrial encephalomyopathy, lactic aci- vealed enhanced muscle tone. The sensations were intact, and dosis and stroke‐like episodes (MELAS) (Kirby et al., 2004), the optic neuropathy was not detected. Leber's hereditary optic neuropathy (LHON) (Spruijt et al., The index patient's young brother (III5) was 16 years 2007), LHON/MELAS overlap syndrome (Blakely et al., old. He had similar symptoms with the index patient. The 2005), and Stüve‐Wiedemann syndrome (Morava, Hamel, Hol, age of onset was four. Clinical symptoms included moder- Rodenburg, & Smeitink, 2006). In contrast, the homoplas- ate cognitive ability (MMSE: 17/30), scoliosis, finger joint mic m.3697G>A mutation was found as a causation of Leigh syndrome (LS) in a Japanese family (Negishi et al., 2014), in which the affected individuals exhibited early childhood‐onset rigidity of the upper and lower limbs due to bilateral basal ganglion and brainstem degeneration. Herein, we investigated the clinical features, brain MRI changes,