Disease characteristics of SEPSECS deficiency: An international, retrospective, multicenter cohort study.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Killam Benjamin Y, Knol Maria J, Fradejas-Villar Noelia, Chillon Thilo S, Ruijter George J G, Bonte Ramon, Abdulwahab Firdous, Aldhalaan Hesham, Alfaifi Abdullah, Alkuraya Fowzan S, Alsaif Hessa S, Kiernan Kaitlyn A, Puppala Anupama K, Baker Laura, Batten Leigh, Chedrawi Aziza, Dempsey Jennifer C, Doherty Dan, Faivre Laurence, Gowda Vykuntaraju K, Hashem Mais O, Heidari Erfan, Garshasbi Masoud, Inaba Yuji, Iwama Kazuhiro, Kinali Maria, Korinthenberg Rudolf, Lesca Gaetan, Maroofian Reza, Matsumoto Naomichi, Mazel Benoît, Nelson Stanley F, Neuteboom Rinze F, Nicolescu C Ramona, Olson Heather, Poduri Annapurna, Sasaki Masayuki, Schorling David, Signer Rebecca H, Srinivasan Varunvenkat M, Tamim Abdullah, Tavasoli Ali Reza, Tous Ehab, Tyynismaa Henna, Visser W Edward, Vitobello Antonio, Vlachou Victoria, Wilke Martina, Adams Hieab H H, Schomburg Lutz, Schweizer Ulrich, Simonović Miljan, Demirdas Serwet
Аннотация
METHODS: We studied 27 individuals with biallelic SEPSECS variants and identified 13 unreported gene variants. To better understand and diagnose the disorder, broad biochemical correlations of neurological symptoms, focused metabolomics, and structural and in vitro activity analyses were deployed.
RESULTS: Our results suggest 3 general clinical courses: (i) severe early onset with cerebellar or cerebral atrophy, (ii) milder early onset with gradual deterioration, and (iii) late-onset, mild disease. SEPSECS variants primarily affect the brain. In only 1 individual out of 8, thyroid hormone measurements suggested a defect in T4 to T3 conversion. An accompanied increase in glutathione and sulfur metabolites in plasma indicates elevated oxidative stress. Variants mapping to conserved N- and C-termini and the catalytic site elicit SEPSECS misfolding, aggregation, thermal instability, and loss of function, which could ultimately lead to ferroptosis of neurons and perhaps oligodendrocytes. For differential diagnosis and monitoring therapeutic attempts, we recommend measuring the levels of plasma selenium, glutathione, and sulfur metabolites, GPX activity, and SELENOP. Given the pontine involvement in less than half of the cases, we suggest renaming the syndrome from pontocerebellar hypoplasia type 2D to SEPSECS-related neurodevelopmental disorder.
CONCLUSION: Our study expands the understanding of SEPSECS-related neurodevelopmental disorders, highlighting the need for updated diagnostic criteria and potential treatment strategies.