<i>PURA-</i>
            Related Developmental and Epileptic Encephalopathy

Johannesen, Katrine M; Gardella, Elena; Gjerulfsen, Cathrine E; Bayat, Allan; Rouhl, Rob P.W.; Reijnders, Margot R.F.; Whalen, Sandra; Keren, Boris; Buratti, Julien; Courtin, Thomas; Wierenga, Klaas J.; Isidor, Bertrand; Piton, Amélie; Faivre, Laurence; Garde, Aurore; Moutton, Sébastien; Mau-Them, Frédéric Tran; Denommé‐Pichon, Anne‐Sophie; Coubes, Christine; Larson, Austin; Esser, Michael J.; Appendino, Juan Pablo; Al-Hertani, Walla; Gamboni, Beatriz; Mampel, Alejandra; Mayorga, Lía; Orsini, Alessandro; Bonuccelli, Alice; Suppiej, Agnese; Van-Gils, Julien; Vogt, Julie; Damioli, Simona; Giordano, Lucio; Moortgat, Stéphanie; Wirrell, Elaine; Hicks, Sarah; Kini, Usha; Noble, Nathan; Stewart, Helen; Asakar, Shailesh; Cohen, Julie S.; Naidu, Sakkubai; Collier, Ashley; Brilstra, Eva H.; Li, Mindy H.; Brew, Casey; Bigoni, Stefania; Ognibene, Davide; Ballardini, Elisa; Ruivenkamp, Claudia; Faggioli, Raffaella; Afenjar, Alexandra; Rodriguez, Diana; Bick, David; Segal, Devorah; Coman, David; Gunning, Boudewijn; Devinsky, Orrin; Demmer, Laurie A.; Grebe, Theresa A.; Pruna, Dario; Cursio, Ida; Greenhalgh, Lynn; Graziano, Claudio; Singh, Rahul; Cantalupo, Gaetano; Willems, Marjolaine; Yoganathan, Sangeetha; Góes, Fernanda Veiga de; Leventer, Richard J.; Colavito, Davide; Olivotto, Sara; Scelsa, Barbara; Andrade, Andrea; Ratke, Kelly; Tokarz, F; Khan, Atiya; Ormières, Clothilde; Benko, William; Keough, Karen; Keros, Sotirios; Hussain, Shanawaz; Franques, Ashlea; Varsalone, Felicia; Grønborg, Sabine; Mignot, Cyril; Héron, Delphine; Nava, Caroline; Isapof, Arnaud; Borlot, Felippe; Whitney, Robyn; Ronan, Anne; Foulds, Nicola; Somorai, Marta; Brandsema, John F.; Helbig, Katherine L.; Helbig, Ingo; Ortiz-González, Xilma R.; Dubbs, Holly; Vitobello, Antonio; Anderson, Mel; Spadafore, Dominic; Hunt, David; Møller, Rikke S.; Rubboli, Guido

doi:10.1212/nxg.0000000000000613

Cited by 29 publications

(44 citation statements)

References 41 publications

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“…In a cohort of 142 patients with PURA syndrome, 60% had drug-resistant epilepsy, and the most common epilepsy syndrome reported was Lennox-Gastaut. Although many different variants were detected in the PURA -gene, the authors did not observe overt genotype-phenotype associations ( 59 ).…”

Section: Discussionmentioning

confidence: 97%

Monogenic developmental and epileptic encephalopathies of infancy and childhood, a population cohort from Norway

Stenshorne

Syvertsen²,

Ramm-Pettersen³

et al. 2022

Front. Pediatr.

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IntroductionDevelopmental and epileptic encephalopathies (DEE) is a group of epilepsies where the epileptic activity, seizures and the underlying neurobiology contributes to cognitive and behavioral impairments. Uncovering the causes of DEE is important in order to develop guidelines for treatment and follow-up. The aim of the present study was to describe the clinical picture and to identify genetic causes in a patient cohort with DEE without known etiology, from a Norwegian regional hospital.MethodsSystematic searches of medical records were performed at Drammen Hospital, Vestre Viken Health Trust, to identify patients with epilepsy in the period 1999–2018. Medical records were reviewed to identify patients with DEE of unknown cause. In 2018, patients were also recruited consecutively from treating physicians. All patients underwent thorough clinical evaluation and updated genetic diagnostic analyses.ResultsFifty-five of 2,225 patients with epilepsy had DEE of unknown etiology. Disease-causing genetic variants were found in 15/33 (45%) included patients. Three had potentially treatable metabolic disorders (SLC2A1, COQ4 and SLC6A8). Developmental comorbidity was higher in the group with a genetic diagnosis, compared to those who remained undiagnosed. Five novel variants in known genes were found, and the patient phenotypes are described.ConclusionThe results from this study illustrate the importance of performing updated genetic investigations and/or analyses in patients with DEE of unknown etiology. A genetic cause was identified in 45% of the patients, and three of these patients had potentially treatable conditions where available targeted therapy may improve patient outcome.

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Section: Discussionmentioning

confidence: 97%

Monogenic developmental and epileptic encephalopathies of infancy and childhood, a population cohort from Norway

Stenshorne

Syvertsen²,

Ramm-Pettersen³

et al. 2022

Front. Pediatr.

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“…While the above-mentioned potential links are highly suggestive, it should be considered that the spectrum of symptoms of PURA Syndrome patients is broad and variable ( 6 , 7 ). Furthermore, the understanding of the medical condition of patients has only begun to be investigated, rendering it very difficult to directly and safely correlate molecular PURA-dependent events to symptoms of patients with haploinsufficiency in the PURA gene.…”

Section: Discussionmentioning

confidence: 99%

“…In 2014, mutations in the PURA gene have been linked to the neurodevelopmental disorder PURA Syndrome ( 4 , 5 ). Patients with heterozygous de novo mutations in PURA show a range of symptoms including neurodevelopmental delay, intellectual disability, hypotonia, and epilepsy ( 6 , 7 ). For unknown reasons, the phenotypes of patients with PURA Syndrome vary considerably.…”

Section: Introductionmentioning

confidence: 99%

Depletion of the RNA-binding protein PURA triggers changes in posttranscriptional gene regulation and loss of P-bodies

Klostermann

Bacher

Merl-Pham

et al. 2023

Nucleic Acids Research

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The RNA-binding protein PURA has been implicated in the rare, monogenetic, neurodevelopmental disorder PURA Syndrome. PURA binds both DNA and RNA and has been associated with various cellular functions. Only little is known about its main cellular roles and the molecular pathways affected upon PURA depletion. Here, we show that PURA is predominantly located in the cytoplasm, where it binds to thousands of mRNAs. Many of these transcripts change abundance in response to PURA depletion. The encoded proteins suggest a role for PURA in immune responses, mitochondrial function, autophagy and processing (P)-body activity. Intriguingly, reduced PURA levels decrease the expression of the integral P-body components LSM14A and DDX6 and strongly affect P-body formation in human cells. Furthermore, PURA knockdown results in stabilization of P-body-enriched transcripts, whereas other mRNAs are not affected. Hence, reduced PURA levels, as reported in patients with PURA Syndrome, influence the formation and composition of this phase-separated RNA processing machinery. Our study proposes PURA Syndrome as a new model to study the tight connection between P-body-associated RNA regulation and neurodevelopmental disorders.

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“…Hypsarrhythmia and burst suppression were observed in three patients presented with excessive activation of the epileptic abnormalities during sleep. Patients without epilepsy showed poorly organized or slowed background activity of the EEG (21.6%), diffuse spikes in 2.7% of patients, and focal spikes in (5.4%) of patients (Johannesen et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

A new case with the recurrent PURA p.(Phe233del) pathogenic variant: Expansion of the phenotype and review of the literature

Ben Issa,

Ben Ayed,

Jallouli

et al. 2023

Intl J of Devlp Neuroscience

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In the process of neuronal development, the protein Purα (encoded by the PURA gene) is essential for neuronal proliferation, dendritic maturation, and the transportation of mRNA to translation sites. Mutations in the PURA gene may alter normal brain development and impair neuronal function, contributing to developmental delays and seizures. Recently, PURA syndrome is described as developmental encephalopathy with or without epilepsy, neonatal hypotonia, feeding difficulties, global developmental delay, and severe intellectual disability. In our study, we aimed to perform a genetic analysis by whole exome sequencing (WES) in a Tunisian patient presented with developmental and epileptic encephalopathy to provide a molecular explanation for the developed phenotype. We collected, also, clinical data of all PURA p.(Phe233del) patients reported yet and compared the clinical features with those of our patient. Results revealed the presence of the known PURA c.697_699del, p.(Phe233del) variant. Our studied case shares some clinical features including hypotonia, feeding difficulties, severe developmental delay, epilepsy, and language delay (nonverbal) but presents a radiological finding undescribed before. Our finding defines and expands the phenotypic and genotypic spectrum of the PURA syndrome supporting the absence of reliable genotype–phenotype correlations and the existence of a highly variable, wide‐ranging clinical spectrum.

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PURA- Related Developmental and Epileptic Encephalopathy

Cited by 29 publications

References 41 publications

Monogenic developmental and epileptic encephalopathies of infancy and childhood, a population cohort from Norway

Monogenic developmental and epileptic encephalopathies of infancy and childhood, a population cohort from Norway

Depletion of the RNA-binding protein PURA triggers changes in posttranscriptional gene regulation and loss of P-bodies

A new case with the recurrent PURA p.(Phe233del) pathogenic variant: Expansion of the phenotype and review of the literature

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