Informace o publikaci

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

Autoři	SKORVANEK Matej REKTOROVÁ Irena MANDEMAKERS Wim WAGNER Matias STEINFELD Robert OREC Laura HAN Vladimir PAVELEKOVA Petra LACKOVA Alexandra KULCSAROVA Kristina OSTROZOVICOVA Miriam GDOVINOVA Zuzana PLECKO Barbara BRUNET Theresa BERUTTI Riccardo KUIPERS Demy J S BOUMEESTER Valerie HAVRANKOVA Petra TIJSSEN M A J KAIYRZHANOV Rauan RIZIG Mie HOULDEN Henry WINKELMANN Juliane BONIFATI Vincenzo ZECH Michael JECH Robert
Rok publikování	2022
Druh	Článek v odborném periodiku
Časopis / Zdroj	PARKINSONISM & RELATED DISORDERS
Fakulta / Pracoviště MU	Lékařská fakulta
Citace
www	https://www.sciencedirect.com/science/article/pii/S1353802021004375?via%3Dihub
Doi	http://dx.doi.org/10.1016/j.parkreldis.2021.11.030
Klíčová slova	WARS2; Early onset parkinsonism; Progressive myoclonus ataxia; Whole exome sequencing
Popis	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.