The Francis Crick Institute
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GNAQ/GNA11 mosaicism is associated with abnormal serum calcium indices and microvascular neurocalcification

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journal contribution
posted on 2024-03-21, 09:40 authored by Nicole Knöpfel, Davide Zecchin, Hanna Richardson, Satyamaanasa Polubothu, Sara Barberan-Martin, Thomas Cullup, Karolina Gholam, Simon Heales, Steve Krywawych, Pablo López-Balboa, Noreen Muwanga-Nanyonjo, Olumide Ogunbiyi, Clinda Puvirajasinghe, Lea Solman, Katherine Swarbrick, Samira B Syed, Zubair Tahir, Martin M Tisdall, Jeremy Allgrove, Alexander D Chesover, Sarah E Aylett, Thomas S Jacques, Fadil M Hannan, Ulrike Löbel, Robert K Semple, Rajesh V Thakker, Veronica A Kinsler
Mosaic mutations in genes GNAQ or GNA11 lead to a spectrum of diseases including Sturge-Weber syndrome (SWS) and phakomatosis pigmentovascularis with dermal melanocytosis (PPV-DM). The pathognomonic finding of localised “tramlining” on plain skull radiography, representing medium-sized neurovascular calcification and associated with post-natal neurological deterioration, led us to study calcium metabolism in a cohort of 42 children. We find here that 74% of patients had at least one abnormal measurement of calcium metabolism, the commonest being moderately low serum ionised calcium (41%) or high PTH (17%). Lower levels of ionised calcium even within the normal range were significantly associated with seizures, and with specific anti-epileptics despite normal vitamin D levels. Successive measurements documented substantial intrapersonal fluctuation in indices over time, and DEXA scans were normal in hypocalcaemic patients. Neurohistology from epilepsy surgery in five patients revealed not only intravascular, but perivascular and intraparenchymal mineral deposition and intraparenchymal microvascular disease in addition to previously reported findings. Neuroradiology review clearly demonstrated progressive calcium deposition in individuals over time. These findings and those of the adjoining paper suggest that calcium deposition in the brain of patients with GNAQ/GNA11 mosaicism may not be the non-specific sign of damage it was previously thought, but may instead reflect the central post-natal pathological process in this disease spectrum.