AOPEP variants as a novel cause of recessive dystonia: Generalized dystonia and dystonia-parkinsonism. (April 2022)

• Record Type: Journal Article
• Authors: Garavaglia, Barbara; Vallian, Sadeq; Romito, Luigi M.; Straccia, Giulia; Capecci, Marianna; Invernizzi, Federica; Andrenelli, Elisa; Kazemi, Arezu; Boesch, Sylvia; Kopajtich, Robert; Olfati, Nahid; Shariati, Mohammad; Shoeibi, Ali; Sadr-Nabavi, Ariane; Prokisch, Holger; Winkelmann, Juliane; Zech, Michael
• Is Part Of: Parkinsonism & related disorders. Volume 97(2022)
• Page Start: 52
• Page End: 56
• Publication Date: 2022-04
• Subjects: Recessive dystonia -- Isolated dystonia -- Dystonia-parkinsonism -- Exome sequencing -- AOPEP variants; Parkinson's disease -- Periodicals; Movement disorders -- Periodicals; Movement Disorders -- Periodicals; Nerve Degeneration -- Periodicals; Nervous System Diseases -- Periodicals; Parkinson Disease -- Periodicals; Tremor -- Periodicals; Parkinson, Maladie de -- Périodiques; Parkinson's disease; 616.833
• DOI: 10.1016/j.parkreldis.2022.03.007
• Languages: English
• ISSNs: 1353-8020

Abstract

Abstract: Introduction: The genetic basis of autosomal-recessive dystonia remains poorly understood. Our objective was to report identification of additional individuals with variants in AOPEP, a recently described gene for recessively inherited dystonic disorders (OMIM:619565 ). Methods: Ongoing analysis on a high-throughput genetic platform and international case-recruitment efforts were undertaken. Results: Novel biallelic, likely pathogenic loss-of-function alleles were identified in two pedigrees of different ethnic background. Two members of a consanguineous Iranian family shared a homozygous c.1917-1G>A essential splice-site variant and featured presentations of adolescence-onset generalized dystonia. An individual of Chinese descent, homozygous for the nonsense variant c.1909G>T (p.Glu637*), displayed childhood-onset generalized dystonia combined with later-manifesting parkinsonism. One additional Iranian patient with adolescence-onset generalized dystonia carried an ultrarare, likely protein-damaging homozygous missense variant (c.1201C>T [p.Arg401Trp]). Conclusions: These findings support the implication of AOPEP in recessive forms of generalized dystonia and dystonia-parkinsonism. Biallelic AOPEP variants represent a worldwide cause of dystonic movement-disorder phenotypes and should be considered in dystonia molecular testing approaches. Highlights: Recessively inherited dystonia syndromes are underreported. We confirm AOPEP biallelic variants as a new cause of recessive dystonia. The AOPEP -related condition includes generalized dystonia and dystonia-parkinsonism. In addition to loss-of-function mutations, rare AOPEP missense variants may also be disease-causing.