Fetal acetylcholine receptor inactivation syndrome

Abstract

Background:Transient neonatal myasthenia gravis (TNMG) affects a proportion of infants born to mothers with myasthenia gravis (MG). Symptoms usually resolve completely within the first few months of life, but persistent myopathic features have been reported in a few isolated cases.Methods:Here we report 8 patients from 4 families born to mothers with clinically manifest MG or mothers who were asymptomatic but had elevated acetylcholine receptor (AChR) antibody levels.Results:Clinical features in affected infants ranged from a mild predominantly facial and bulbar myopathy to arthrogryposis multiplex congenita. Additional clinical findings included hearing impairment, pyloric stenosis, and mild CNS involvement. In all cases, antibodies against the AChR were markedly elevated, although not always specific for the fetal AChR γ subunit. There was a correlation between maternal symptoms; the timing, intensity, and frequency of maternal treatment; and neonatal outcome.Conclusions:These findings suggest that persistent myopathic features following TNMG may be more common than currently recognized. Fetal AChR inactivation syndrome should be considered in the differential diagnosis of infants presenting with unexplained myopathic features, in particular marked dysarthria and velopharyngeal incompetence. Correct diagnosis requires a high degree of suspicion if the mother is asymptomatic but is crucial considering the high recurrence risk for future pregnancies and the potentially treatable nature of this condition. Infants with a history of TNMG should be followed up for subtle myopathic signs and associated complications.

Maternal myasthenia gravis represents a risk for the child through autoantibody transfer, immunosuppressive therapy and genetic influence

“…This is much rarer than neonatal MG. Persistent myopathy can vary from a mild and isolated muscle weakness such as congenital facial paresis to generalized myopathy and severe arthrogryposis multiplex congenita with multiple joint contractures . In our unselected national cohort, five of 127 MG children (3.9%) had severe skeletal anomalies .…”

“…Neonatal MG in a sibling is a significant predictor for disease . AChR antibodies with high affinity for embryonic type AChR imply an increased risk for neonatal MG. Embryonic AChR is gradually replaced by the adult form from gestational week 33, but most MG antibodies can bind to both fetal and adult AChR (Fig.…”

“…Mutations in the gamma subunit encoding genes that cause AChR disruption lead to arthrogryposis . Luckily high titres of antibodies blocking the function of fetal AChR are rare in MG patients .…”

Serological and experimental studies in different forms of myasthenia gravis

“…Recent observations suggest that these antibodies are occasionally found in mothers whose babies have a less severe but persisting fetal inactivation syndrome with muscle weakness and long-term disability. 48 Using the mouse model of maternal-to-fetal transfer of these antibodies established earlier, 49 a potential drug was shown to reduce transfer of the AChR antibodies from mother to developing fetus; if further developed, this drug might provide a useful treatment for subsequent pregnancies in similar cases (Jacobson, Coutinho, and Vincent, unpublished findings).…”

Antibodies as Mediators of Brain Pathology

“…These antibodies can also lead to congenital heart block with a permanent structural heart defect [107]. Transient and/or permanent tissue injury secondary to maternal antibodies has also been reported in myasthenia gravis [108], antiphospholipid syndrome, and other autoimmune diseases [109]. …”