The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD)
Authors: Allen Nicholas M , O’Rahelly Mark , Eymard Bruno , Chouchane Mondher , Hahn Andreas , Kearns Gerry , Kim Dae-Seong , Byun Shin Yun , Nguyen Cam-Tu Emilie , Schara-Schmidt Ulrike , Kölbel Heike , Marina Adela Della , Schneider-Gold Christiane , Roefke Kathryn , Thieme Andrea , Van den Bergh Peter , Avalos Gloria , Álvarez-Velasco Rodrigo , Natera-de Benito Daniel , Cheng Man Hin Mark , Chan Wing Ki , Wan Hoi Shan , Thomas Mary Ann , Borch Lauren , Lauzon Julie , Kornblum Cornelia , Reimann Jens , Mueller Andreas , Kuntzer Thierry , Norwood Fiona , Ramdas Sithara , Jacobson Leslie W , Jie Xiaobo , Fernandez-Garcia Miguel A , Wraige Elizabeth , Lim Ming , Lin Jean Pierre , Claeys Kristl G , Aktas Selma , Oskoui Maryam , Hacohen Yael , Masud Ameneh , Leite M Isabel , Palace Jacqueline , De Vivo Darryl , Vincent Angela , Jungbluth Heinz 
Published: May 2023

Abstract
In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies.
Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%).
Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P &lt; 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective.
We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose ‘fetal acetylcholine receptor antibody-related disorders’ (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.