BACKGROUND: Multiple system atrophy (MSA) is marked by abnormal inclusions of alpha-synuclein in oligodendrogliocytes. Etiology remains unknown. Variants in the glucocerebrosidase gene have been associated with other synucleinopathies, dementia with Lewy bodies and Parkinson disease. It is unclear whether glucocerebrosidase variants are associated with MSA. OBJECTIVES: To analyze the frequency of glucocerebrosidase gene variants among autopsy-proven cases of MSA at a brain bank in New York City. METHODS: The glucocerebrosidase gene was fully sequenced in the 17 autopsy-proven MSA cases with extractable DNA at the Columbia University New York Brain Bank from 2002 to 2016. To test if the MSA cases in the brain bank are enriched for GBA variants, we compared the GBA variant frequency in MSA to all brain bank cases with pure Alzheimer's disease (AD) at Columbia University for whom GBA genotype was available (n=82). RESULTS: 4/17 (23.5%) MSA cases carried glucocerebrosidase gene variants, including an individual homozygous for N370S, and one each who were heterozygous carriers of N370S, T369M and R496H. Among the comparator cases with pure AD, 3 of the 82 autopsies (3.7%) carried GBA variants (P = 0.0127, Fisher exact test), including one case each of N370S homozygote, and R496H and T369M heterozygous variant. CONCLUSION: We found a higher frequency of glucocerebrosidase variants among pathologically diagnosed MSA cases in our brain bank compared to AD autopsies. This study demonstrates the need for further investigation into the role of glucocerebrosidase and lysosomal dysfunction in the etiology of MSA.
BACKGROUND:Multiple system atrophy (MSA) is marked by abnormal inclusions of alpha-synuclein in oligodendrogliocytes. Etiology remains unknown. Variants in the glucocerebrosidase gene have been associated with other synucleinopathies, dementia with Lewy bodies and Parkinson disease. It is unclear whether glucocerebrosidase variants are associated with MSA. OBJECTIVES: To analyze the frequency of glucocerebrosidase gene variants among autopsy-proven cases of MSA at a brain bank in New York City. METHODS: The glucocerebrosidase gene was fully sequenced in the 17 autopsy-proven MSA cases with extractable DNA at the Columbia University New York Brain Bank from 2002 to 2016. To test if the MSA cases in the brain bank are enriched for GBA variants, we compared the GBA variant frequency in MSA to all brain bank cases with pure Alzheimer's disease (AD) at Columbia University for whom GBA genotype was available (n=82). RESULTS: 4/17 (23.5%) MSA cases carried glucocerebrosidase gene variants, including an individual homozygous for N370S, and one each who were heterozygous carriers of N370S, T369M and R496H. Among the comparator cases with pure AD, 3 of the 82 autopsies (3.7%) carried GBA variants (P = 0.0127, Fisher exact test), including one case each of N370S homozygote, and R496H and T369M heterozygous variant. CONCLUSION: We found a higher frequency of glucocerebrosidase variants among pathologically diagnosed MSA cases in our brain bank compared to AD autopsies. This study demonstrates the need for further investigation into the role of glucocerebrosidase and lysosomal dysfunction in the etiology of MSA.
Authors: K Srulijes; A-K Hauser; I Guella; R Asselta; K Brockmann; C Schulte; G Soldà; R Cilia; W Maetzler; L Schols; G K Wenning; W Poewe; P Barone; U Wüllner; W Oertel; D Berg; S Goldwurm; T Gasser Journal: Eur J Neurol Date: 2013-04 Impact factor: 6.089
Authors: Roy N Alcalay; Elise Caccappolo; Helen Mejia-Santana; Ming Xin Tang; Llency Rosado; Barbara M Ross; Miguel Verbitsky; Sergey Kisselev; Elan D Louis; Cynthia Comella; Amy Colcher; Danna Jennings; Martha A Nance; Susan B Bressman; William K Scott; Caroline Tanner; Susan Mickel; Howard Andrews; Cheryl Waters; Stanley Fahn; Lucien Cote; Steven Frucht; Blair Ford; Michael Rezak; Kevin Novak; Joseph H Friedman; Ronald Pfeiffer; Laura Marsh; Bradley Hiner; Andrew Siderowf; Ruth Ottman; Karen Marder; Lorraine N Clark Journal: Arch Neurol Date: 2010-09
Authors: Nadia Stefanova; Markus Reindl; Manuela Neumann; Christian Haass; Werner Poewe; Philipp J Kahle; Gregor K Wenning Journal: Am J Pathol Date: 2005-03 Impact factor: 4.307
Authors: L N Clark; B M Ross; Y Wang; H Mejia-Santana; J Harris; E D Louis; L J Cote; H Andrews; S Fahn; C Waters; B Ford; S Frucht; R Ottman; K Marder Journal: Neurology Date: 2007-09-18 Impact factor: 9.910
Authors: Nathan Pankratz; Jemma B Wilk; Jeanne C Latourelle; Anita L DeStefano; Cheryl Halter; Elizabeth W Pugh; Kimberly F Doheny; James F Gusella; William C Nichols; Tatiana Foroud; Richard H Myers Journal: Hum Genet Date: 2008-11-06 Impact factor: 4.132
Authors: Jose Bras; Rita Guerreiro; Lee Darwent; Laura Parkkinen; Olaf Ansorge; Valentina Escott-Price; Dena G Hernandez; Michael A Nalls; Lorraine N Clark; Lawrence S Honig; Karen Marder; Wiesje M Van Der Flier; Afina Lemstra; Philip Scheltens; Ekaterina Rogaeva; Peter St George-Hyslop; Elisabet Londos; Henrik Zetterberg; Sara Ortega-Cubero; Pau Pastor; Tanis J Ferman; Neill R Graff-Radford; Owen A Ross; Imelda Barber; Anne Braae; Kristelle Brown; Kevin Morgan; Walter Maetzler; Daniela Berg; Claire Troakes; Safa Al-Sarraj; Tammaryn Lashley; Yaroslau Compta; Tamas Revesz; Andrew Lees; Nigel Cairns; Glenda M Halliday; David Mann; Stuart Pickering-Brown; Dennis W Dickson; Andrew Singleton; John Hardy Journal: Hum Mol Genet Date: 2014-06-27 Impact factor: 6.150
Authors: Johannes Brettschneider; EunRan Suh; John L Robinson; Lubin Fang; Edward B Lee; David J Irwin; Murray Grossman; Vivianna M Van Deerlin; Virginia M-Y Lee; John Q Trojanowski Journal: J Neuropathol Exp Neurol Date: 2018-11-01 Impact factor: 3.685
Authors: Anna I Wernick; Ronald L Walton; Alexandra I Soto-Beasley; Shunsuke Koga; Michael G Heckman; Rebecca R Valentino; Lukasz M Milanowski; Dorota Hoffman-Zacharska; Dariusz Koziorowski; Anhar Hassan; Ryan J Uitti; William P Cheshire; Wolfgang Singer; Zbigniew K Wszolek; Dennis W Dickson; Phillip A Low; Owen A Ross Journal: Clin Auton Res Date: 2021-01-27 Impact factor: 5.625
Authors: Mary B Makarious; Monica Diez-Fairen; Lynne Krohn; Cornelis Blauwendraat; Sara Bandres-Ciga; Jinhui Ding; Lasse Pihlstrøm; Henry Houlden; Sonja W Scholz; Ziv Gan-Or Journal: Brain Date: 2019-12-01 Impact factor: 13.501