Acetylcholine Receptor Pathway Mutations Explain Various Fetal Akinesia Deformation Sequence Disorders

Abstract

Impaired fetal movement causes malformations, summarized as fetal akinesia deformation sequence (FADS), and is triggered by environmental and genetic factors. Acetylcholine receptor (AChR) components are suspects because mutations in the fetally expressed gamma subunit (CHRNG) of AChR were found in two FADS disorders, lethal multiple pterygium syndrome (LMPS) and Escobar syndrome. Other AChR subunits alpha1, beta1, and delta (CHRNA1, CHRNB1, CHRND) as well as receptor-associated protein of the synapse (RAPSN) previously revealed missense or compound nonsense-missense mutations in viable congenital myasthenic syndrome; lethality of homozygous null mutations was predicted but never shown. We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype. To elucidate disease-associated malformations such as frequent abortions, fetal edema, cystic hygroma, or cardiac defects, we studied Chrna1, Chrnb1, Chrnd, Chrng, and Rapsn in mouse embryos and found expression in skeletal muscles but also in early somite development. This indicates that early developmental defects might be due to somite expression in addition to solely muscle-specific effects. We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life.

Congenital Myasthenic Syndromes - Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction

“…If a null mutation resides in the other AChR subunit genes, the affected individual will have no substituting subunit and cannot survive. Indeed, two homozygous missense low expressor or null mutations in CHRNA1 and CHRND caused lethal fetal akinesia (Michalk et al, 2008).…”

Genetic heterogeneity and pathophysiological mechanisms in congenital myasthenic syndromes

“…The foetal AChR seems to play a pivotal role in neuromuscular organogenesis by acting as a guide for the primary encounter of axon and muscle in utero. [35][36] Escobar syndrome is an antenatal congenital myasthenic disorder in which neuromuscular organogenesis is flawed due to mutation in the γ subunit, encoded by CHRNG gene. Although clinically variable, this syndrome typically presents with arthrogryposis multiplex congenital with joint contractures, pterygia, cryptochism in males and respiratory distress.…”

Anesthetic Management for Escobar Syndrome: A Case Report

“…However, it has been suggested that mutations within the gamma subunit of the cholinergic receptor nicotinic gamma gene of the acetylcholine receptor (AChR), which has a role in the muscle relaxant effect, is responsible for muscle contractures observed in patients with this disorder (12). Complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome, whereas milder alterations result in fetal hypokinesia with congenital contractures or a myasthenic syndrome later in life (13). The increased frequency of hyperthermia is a condition that must be taken into consideration in determining the anesthetic management (14).…”