The emerging spectrum of foetal acetylcholine receptor antibody-associated disorders (FARAD).
Allen NM., O'Rahelly M., Eymard B., Chouchane M., Hahn A., Kearns G., Kim D-S., Byun SY., Nguyen C-TE., Schara-Schmidt U., Kölbel H., Della Marina A., Schneider-Gold C., Roefke K., Thieme A., Van den Bergh P., Avalos G., Álvarez-Velasco R., Natera-de Benito D., Cheng MHM., Chan WK., Wan HS., Thomas MA., Borch L., Lauzon J., Kornblum C., Reimann J., Mueller A., Kuntzer T., Norwood F., Ramdas S., Jacobson LW., Jie X., Fernandez-Garcia MA., Wraige E., Lim M., Lin JP., Claeys KG., Aktas S., Oskoui M., Hacohen Y., Masud A., Leite MI., Palace J., De Vivo D., Vincent A., Jungbluth H.
In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). fAChR 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 multicenter cohort (n = 46 cases) associated with maternal fAChR antibodies, 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established MG diagnosis. All mothers (n = 30) had AChR antibodies, and where tested, against the fAChR (binding to fAChR was often much greater than that to the adAChR). 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/IVIG/PLEX) 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