TY - JOUR
T1 - GNAQ/GNA11 Mosaicism Is Associated with Abnormal Serum Calcium Indices and Microvascular Neurocalcification
AU - Knöpfel, Nicole
AU - Zecchin, Davide
AU - Richardson, Hanna
AU - Polubothu, Satyamaanasa
AU - Barberan-Martin, Sara
AU - Cullup, Thomas
AU - Gholam, Karolina
AU - Heales, Simon
AU - Krywawych, Steve
AU - López-Balboa, Pablo
AU - Muwanga-Nanyonjo, Noreen
AU - Ogunbiyi, Olumide
AU - Puvirajasinghe, Clinda
AU - Solman, Lea
AU - Swarbrick, Katherine
AU - Syed, Samira B.
AU - Tahir, Zubair
AU - Tisdall, Martin M.
AU - Allgrove, Jeremy
AU - Chesover, Alexander D.
AU - Aylett, Sarah E.
AU - Jacques, Thomas S.
AU - Hannan, Fadil M.
AU - Löbel, Ulrike
AU - Semple, Robert K.
AU - Thakker, Rajesh V.
AU - Kinsler, Veronica A.
N1 - We gratefully acknowledge the participation of the patients and families in this research and research coordination by Jane White. VK and NK are funded by the UK NIHR (grant NIHR300774). This work was supported by the GOSHCC Livingstone Skin Research Centreand by the UK National Institute for Health Research (NIHR) through the Biomedical Research Centre at Great Ormond St Hospital for Children NHS Foundation Trust and the UCL GOS Institute of Child Health. R.V.T. was funded by a grant (106995/Z/15/Z) from the Wellcome Trust, a grant from the Oxford Biomedical Research Centre Program of the National Institute for Health Research (NIHR), a grant (NF-SI-0514–10091) from the NIHR. R.K.S. was funded by a grant (210752/Z/18/Z) from the Wellcome Trust. A.I. was funded by Japan Society for the Promotion of Science (JSPS) KAKENHI grants 21H04791 and 21H05113; Moonshot Research and Development Program JPMJMS2023 from Japan Science and Technology 16Agency (JST); the the LEAP JP20gm0010004 and the BINDS JP20am0101095 from the Japan Agency for Medical Research and Development (AMED); Daiichi Sankyo Foundation of Life Science; Takeda Science Foundation; The Uehara Memorial Foundation; The Tokyo Biochemical Research Foundation.
PY - 2023/10/4
Y1 - 2023/10/4
N2 - Mosaic mutations in genes GNAQ or GNA11 lead to a spectrum of diseases including Sturge-Weber syndrome and phakomatosis pigmentovascularis with dermal melanocytosis. The pathognomonic finding of localized “tramlining” on plain skull radiography, representing medium-sized neurovascular calcification and associated with postnatal neurological deterioration, led us to study calcium metabolism in a cohort of 42 children. In this study, we find that 74% of patients had at least one abnormal measurement of calcium metabolism, the commonest being moderately low serum ionized calcium (41%) or high parathyroid hormone (17%). Lower levels of ionized calcium even within the normal range were significantly associated with seizures, and with specific antiepileptics despite normal vitamin D levels. Successive measurements documented substantial intrapersonal fluctuation in indices over time, and DEXA scans were normal in patients with hypocalcemia. 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 a nonspecific sign of damage as was previously thought, but may instead reflect the central postnatal pathological process in this disease spectrum.
AB - Mosaic mutations in genes GNAQ or GNA11 lead to a spectrum of diseases including Sturge-Weber syndrome and phakomatosis pigmentovascularis with dermal melanocytosis. The pathognomonic finding of localized “tramlining” on plain skull radiography, representing medium-sized neurovascular calcification and associated with postnatal neurological deterioration, led us to study calcium metabolism in a cohort of 42 children. In this study, we find that 74% of patients had at least one abnormal measurement of calcium metabolism, the commonest being moderately low serum ionized calcium (41%) or high parathyroid hormone (17%). Lower levels of ionized calcium even within the normal range were significantly associated with seizures, and with specific antiepileptics despite normal vitamin D levels. Successive measurements documented substantial intrapersonal fluctuation in indices over time, and DEXA scans were normal in patients with hypocalcemia. 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 a nonspecific sign of damage as was previously thought, but may instead reflect the central postnatal pathological process in this disease spectrum.
U2 - 10.1016/j.jid.2023.09.008
DO - 10.1016/j.jid.2023.09.008
M3 - Article
SN - 0022-202X
VL - 144
SP - 820-832.e9
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 4
ER -