Abstract
Autosomal recessive cerebellar ataxias are a group of rare neurological diseases with a genetic origin. Recently, the mutations in the PNPLA6 gene were suggested to lead to ataxia and also to other specific syndromes such as Boucher-Neuhauser (ataxia, hypogonadism, and chorioretinal dystrophy) or Gordon-Holmes Syndromes (ataxia, hypogonadism, and brisk reflexes) within a broad spectrum of neurodegenerative diseases. Here we report three patients from a single-family with a novel pathogenic mutation in the PNPLA6 gene which led to predominantly spastic-ataxia, and intractable Holmes tremor. The PNPLA6-related disease should be considered in the differential diagnosis of spastic-ataxias even in the absence of chorioretinal dystrophy, and hypogonadotropic hypogonadism. Further studies should unravel the factors which account for the phenotypic variability present in patients with PNPLA6 gene mutations.
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Acknowledgments
ANB is grateful to Suna and İnan Kıraç Foundation and Koç University for their invaluable support and the stimulating working environment created. GŞ is an İnan Kıraç Fellow.
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BB and ANB designed the study, and ASE, BS, and GS assembled the data. All authors wrote and approved the final article.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent form for genetic analysis and consent to publish were obtained from all participants. Ethics committee approval was not applicable as the data was analyzed retrospectively and had no effect on treatment.
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Online Resource 2
Family tree of the patients and validation of the variant (c.940C>T) in the family: All affected sisters are, as expected, homozygous while the asymptomatic parents and the brother are heterozygous for the variant (PNG 495 kb)
Online Resource 3
(A) The position of Arg314Trp in the CNBD1 domain of PNPLA6 and (B) its conservation across species. PNPLA6 protein domains taken from http://www.ebi.ac.uk/interpro/protein/UniProt/Q8IY17/ and https://www.uniprot.org/uniprot/Q8IY17. Our mutation, located in the CNBD1 domain, is indicated in red. Other mutations were taken from OMIM (https://omim.org/entry/603197). TD: Transmembrane domain (aa positions: 58-80); CNBD1: Cyclic nucleotide-binding domain 1 (aa positions: 195-322); CNBD2: Cyclic nucleotide-binding domain 2 (aa positions: 511-631); CNBD3: Cyclic nucleotide-binding domain 3 (aa positions: 634-750); PLPD: Patatin-like phospholipase domain (aa positions: 981 – 1147) (PNG 924 kb)
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Emekli, A.S., Samanci, B., Şimşir, G. et al. A novel PNPLA6 mutation in a Turkish family with intractable Holmes tremor and spastic ataxia. Neurol Sci 42, 1535–1539 (2021). https://doi.org/10.1007/s10072-020-04869-6
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DOI: https://doi.org/10.1007/s10072-020-04869-6