WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia

SKORVANEK, Matej, Irena REKTOROVÁ, Wim MANDEMAKERS, Matias WAGNER, Robert STEINFELD, Laura OREC, Vladimir HAN, Petra PAVELEKOVA, Alexandra LACKOVA, Kristina KULCSAROVA, Miriam OSTROZOVICOVA, Zuzana GDOVINOVA, Barbara PLECKO, Theresa BRUNET, Riccardo BERUTTI, Demy J S KUIPERS, Valerie BOUMEESTER, Petra HAVRANKOVA, M A J TIJSSEN, Rauan KAIYRZHANOV, Mie RIZIG, Henry HOULDEN, Juliane WINKELMANN, Vincenzo BONIFATI, Michael ZECH a Robert JECH. WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia. PARKINSONISM & RELATED DISORDERS. OXFORD: ELSEVIER SCI LTD, 2022, roč. 94, January 2022, s. 54-61. ISSN 1353-8020. Dostupné z: https://dx.doi.org/10.1016/j.parkreldis.2021.11.030.

Základní údaje

• Originální název: WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia
• Autoři: SKORVANEK, Matej (garant), Irena REKTOROVÁ (203 Česká republika, domácí), Wim MANDEMAKERS, Matias WAGNER, Robert STEINFELD, Laura OREC, Vladimir HAN, Petra PAVELEKOVA, Alexandra LACKOVA, Kristina KULCSAROVA, Miriam OSTROZOVICOVA, Zuzana GDOVINOVA, Barbara PLECKO, Theresa BRUNET, Riccardo BERUTTI, Demy J S KUIPERS, Valerie BOUMEESTER, Petra HAVRANKOVA, M A J TIJSSEN, Rauan KAIYRZHANOV, Mie RIZIG, Henry HOULDEN, Juliane WINKELMANN, Vincenzo BONIFATI, Michael ZECH a Robert JECH.
• Vydání: PARKINSONISM & RELATED DISORDERS, OXFORD, ELSEVIER SCI LTD, 2022, 1353-8020.

Další údaje

• Originální jazyk: angličtina
• Typ výsledku: Článek v odborném periodiku
• Obor: 30210 Clinical neurology
• Stát vydavatele: Velká Británie a Severní Irsko
• Utajení: není předmětem státního či obchodního tajemství
• WWW: URL
• Impakt faktor: Impact factor: 4.100
• Kód RIV: RIV/00216224:14110/22:00128075
• Organizační jednotka: Lékařská fakulta
• Doi: http://dx.doi.org/10.1016/j.parkreldis.2021.11.030
• UT WoS: 000748987300009
• Klíčová slova anglicky: WARS2; Early onset parkinsonism; Progressive myoclonus ataxia; Whole exome sequencing
• Štítky: 14110127, podil, rivok
• Příznaky: Mezinárodní význam, Recenzováno

Anotace

Introduction: Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia. Methods: Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed. Results: A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonusataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patientderived fibroblasts showed a markedly decreased expression of the full-length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity. Conclusions: This study expands the spectrum of the disease to later onset phenotypes of early-onset tremordominant parkinsonism and progressive myoclonus-ataxia phenotypes.