TY - JOUR
T1 - Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease
T2 - functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome
AU - Kozycki, Christina Torres
AU - Kodati, Shilpa
AU - Huryn, Laryssa
AU - Wang, Hongying
AU - Warner, Blake M.
AU - Jani, Priyam
AU - Hammoud, Dima
AU - Abu-Asab, Mones S.
AU - Jittayasothorn, Yingyos
AU - Mattapallil, Mary J.
AU - Tsai, Wanxia Li
AU - Ullah, Ehsan
AU - Zhou, Ping
AU - Tian, Xiaoying
AU - Soldatos, Ariane
AU - Moutsopoulos, Niki
AU - Kao-Hsieh, Marie
AU - Heller, Theo
AU - Cowen, Edward W.
AU - Lee, Chyi Chia Richard
AU - Toro, Camilo
AU - Kalsi, Shelley
AU - Khavandgar, Zohreh
AU - Baer, Alan
AU - Beach, Margaret
AU - Priel, Debra Long
AU - Nehrebecky, Michele
AU - Rosenzweig, Sofia
AU - Romeo, Tina
AU - Deuitch, Natalie
AU - Brenchley, Laurie
AU - Pelayo, Eileen
AU - Zein, Wadih
AU - Sen, Nida
AU - Yang, Alexander H.
AU - Farley, Gary
AU - Sweetser, David A.
AU - Briere, Lauren
AU - Yang, Janine
AU - De Oliveira Poswar, Fabiano
AU - Schwartz, Ida Vanessa D.
AU - Alves, Tamires Silva
AU - Dusser, Perrine
AU - Koné-Paut, Isabelle
AU - Touitou, Isabelle
AU - Titah, Salah Mohamed
AU - Van Hagen, Petrus Martin
AU - Van Wijck, Rogier T.A.
AU - Van Der Spek, Peter J.
AU - Yano, Hiromi
AU - Benneche, Andreas
AU - Apalset, Ellen M.
AU - Jansson, Ragnhild Wivestad
AU - Caspi, Rachel R.
AU - Kuhns, Douglas Byron
AU - Gadina, Massimo
AU - Takada, Hidetoshi
AU - Ida, Hiroaki
AU - Nishikomori, Ryuta
AU - Verrecchia, Elena
AU - Sangiorgi, Eugenio
AU - Manna, Raffaele
AU - Brooks, Brian P.
AU - Sobrin, Lucia
AU - Hufnagel, Robert B.
AU - Beck, David
AU - Shao, Feng
AU - Ombrello, Amanda K.
AU - Aksentijevich, Ivona
AU - Kastner, Daniel L.
N1 - Publisher Copyright:
©
PY - 2022/7/22
Y1 - 2022/7/22
N2 - Objectives To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease. Methods This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling. Results The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys. Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients). Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation. Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow. Conclusion ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy.
AB - Objectives To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease. Methods This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling. Results The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys. Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients). Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation. Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow. Conclusion ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy.
KW - Amyloidosis
KW - Arthritis
KW - Immune System Diseases
KW - Inflammation
KW - Therapeutics
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U2 - 10.1136/annrheumdis-2022-222629
DO - 10.1136/annrheumdis-2022-222629
M3 - Article
C2 - 35868845
AN - SCOPUS:85135759296
SN - 0003-4967
VL - 81
SP - 1453
EP - 1464
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
IS - 10
ER -