Reply: Lysosomal storage disorder gene variants in multiple system atrophy

Reply: Lysosomal storage disorder gene variants in multiple system atrophy doi:10.1093/brain/awy125 BRAIN 2018: 141; 1 | e54 LETTER TO THE EDITOR 1,2 Joshua M. Shulman 1 Departments of Neurology, Molecular and Human Genetics, and Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA 2 Jan and Dan Duncan Neurologic Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA Correspondence to: Joshua M. Shulman, MD, PhD Jan and Dan Duncan Neurological Research Institute 1250 Moursund St., Suite N.1150 Houston, TX 77030, USA E-mail: Joshua.Shulman@bcm.edu Sir, examine for a broader contribution of LSD gene variants Pihlstrøm et al. (2018) examined the intriguing hypoth- to heterogeneous Parkinson’s disease phenotypes. Evidence esis that variation in genes causing lysosomal storage dis- for association with Parkinson’s disease features that also orders (LSDs) might increase risk for multiple system overlap with DLB (e.g. cognitive impairment, hallucin- atrophy (MSA). They adopted the same analytic strategy ations) and/or MSA (e.g. dysautonomia, early falls, dyspha- that we used successfully to demonstrate an aggregate gia, dysarthria) may provide clues of a shared genetic burden among 54 LSD genes and Parkinson’s disease sus- architecture underlying synucleinopathies more broadly. ceptibility (Robak et al., 2017). Since MSA is rare, with a prevalence of 2.5 per 100 000 (Stefanova et al., 2009), the investigators’ effort to assemble a whole-exome sequen- cing cohort of more than 350 cases, including 264 with References pathological confirmation, is commendable. Although the results were negative, it will be important to repeat the Mitsui J, Matsukawa T, Sasaki H, Yabe I, Matsushima M, Durr A, et al. Variants associated with Gaucher disease in multiple system analysis in the future when even larger sample sizes are atrophy. Ann Clin Transl Neurol 2015; 2: 417–26. available. The underlying hypothesis is supported not Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, only by emerging evidence for a connection between LSD Chinnery PF, et al. A multicenter study of glucocerebrosidase mu- gene variants and Parkinson’s disease risk, but also studies tations in dementia with Lewy bodies. JAMA Neurol 2013; 70: implicating GBA variants in both MSA (Mitsui et al., 727–35. O’Regan G, deSouza R-M, Balestrino R, Schapira AH. 2015; Sklerov et al., 2017) and dementia with Lewy Glucocerebrosidase mutations in Parkinson disease. J Parkinsons bodies (DLB) (Nalls et al., 2013). Indeed, substantial Dis 2017; 7: 411–22. phenotypic overlap is recognized among synucleinopathies. Pihlstrøm L, Schottlaender L, Chelban V, MSA Exome Consortium, For example, cognitive impairment and autonomic dysfunc- Meissner WG, Federoff M, et al. Lysosomal storage disorder gene tion, which are core features of DLB and MSA, respect- variants in multiple system atrophy. Brain 2018; 141: e53. ively, are also common and disabling non-motor Robak LA, Jansen IE, van Rooij J, Uitterlinden AG, Kraaij R, Jankovic J, et al. Excessive burden of lysosomal storage disorder gene variants complications of Parkinson’s disease. Besides its association in Parkinson’s disease. Brain 2017; 140: 3191–203. with Parkinson’s disease risk, genetic evidence suggests that Sklerov M, Kang UJ, Liong C, Clark L, Marder K, Pauciulo M, et al. GBA variants may modify Parkinson’s disease clinical Frequency of GBA variants in autopsy-proven multiple system atro- manifestations, including incidence of dementia and rate phy. Mov Disord Clin Pract 2017; 4: 574–81. of progression (O’Regan et al., 2017). Thus, one promising Stefanova N, Bu¨ cke P, Duerr S, Wenning GK. Multiple system atro- future approach is to apply aggregate burden tests to phy: an update. Lancet Neurol 2009; 8: 1172–8. Advance Access publication May 7, 2018 The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com Downloaded from https://academic.oup.com/brain/article-abstract/141/7/e54/4993385 by Ed 'DeepDyve' Gillespie user on 03 July 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Oxford University Press

Reply: Lysosomal storage disorder gene variants in multiple system atrophy

Brain , Volume Advance Article (7) – May 7, 2018
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doi:10.1093/brain/awy125 BRAIN 2018: 141; 1 | e54 LETTER TO THE EDITOR 1,2 Joshua M. Shulman 1 Departments of Neurology, Molecular and Human Genetics, and Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA 2 Jan and Dan Duncan Neurologic Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA Correspondence to: Joshua M. Shulman, MD, PhD Jan and Dan Duncan Neurological Research Institute 1250 Moursund St., Suite N.1150 Houston, TX 77030, USA E-mail: Joshua.Shulman@bcm.edu Sir, examine for a broader contribution of LSD gene variants Pihlstrøm et al. (2018) examined the intriguing hypoth- to heterogeneous Parkinson’s disease phenotypes. Evidence esis that variation in genes causing lysosomal storage dis- for association with Parkinson’s disease features that also orders (LSDs) might increase risk for multiple system overlap with DLB (e.g. cognitive impairment, hallucin- atrophy (MSA). They adopted the same analytic strategy ations) and/or MSA (e.g. dysautonomia, early falls, dyspha- that we used successfully to demonstrate an aggregate gia, dysarthria) may provide clues of a shared genetic burden among 54 LSD genes and Parkinson’s disease sus- architecture underlying synucleinopathies more broadly. ceptibility (Robak et al., 2017). Since MSA is rare, with a prevalence of 2.5 per 100 000 (Stefanova et al., 2009), the investigators’ effort to assemble a whole-exome sequen- cing cohort of more than 350 cases, including 264 with References pathological confirmation, is commendable. Although the results were negative, it will be important to repeat the Mitsui J, Matsukawa T, Sasaki H, Yabe I, Matsushima M, Durr A, et al. Variants associated with Gaucher disease in multiple system analysis in the future when even larger sample sizes are atrophy. Ann Clin Transl Neurol 2015; 2: 417–26. available. The underlying hypothesis is supported not Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, only by emerging evidence for a connection between LSD Chinnery PF, et al. A multicenter study of glucocerebrosidase mu- gene variants and Parkinson’s disease risk, but also studies tations in dementia with Lewy bodies. JAMA Neurol 2013; 70: implicating GBA variants in both MSA (Mitsui et al., 727–35. O’Regan G, deSouza R-M, Balestrino R, Schapira AH. 2015; Sklerov et al., 2017) and dementia with Lewy Glucocerebrosidase mutations in Parkinson disease. J Parkinsons bodies (DLB) (Nalls et al., 2013). Indeed, substantial Dis 2017; 7: 411–22. phenotypic overlap is recognized among synucleinopathies. Pihlstrøm L, Schottlaender L, Chelban V, MSA Exome Consortium, For example, cognitive impairment and autonomic dysfunc- Meissner WG, Federoff M, et al. Lysosomal storage disorder gene tion, which are core features of DLB and MSA, respect- variants in multiple system atrophy. Brain 2018; 141: e53. ively, are also common and disabling non-motor Robak LA, Jansen IE, van Rooij J, Uitterlinden AG, Kraaij R, Jankovic J, et al. Excessive burden of lysosomal storage disorder gene variants complications of Parkinson’s disease. Besides its association in Parkinson’s disease. Brain 2017; 140: 3191–203. with Parkinson’s disease risk, genetic evidence suggests that Sklerov M, Kang UJ, Liong C, Clark L, Marder K, Pauciulo M, et al. GBA variants may modify Parkinson’s disease clinical Frequency of GBA variants in autopsy-proven multiple system atro- manifestations, including incidence of dementia and rate phy. Mov Disord Clin Pract 2017; 4: 574–81. of progression (O’Regan et al., 2017). Thus, one promising Stefanova N, Bu¨ cke P, Duerr S, Wenning GK. Multiple system atro- future approach is to apply aggregate burden tests to phy: an update. Lancet Neurol 2009; 8: 1172–8. Advance Access publication May 7, 2018 The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com Downloaded from https://academic.oup.com/brain/article-abstract/141/7/e54/4993385 by Ed 'DeepDyve' Gillespie user on 03 July 2018

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BrainOxford University Press

Published: May 7, 2018

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