Distinct phenotypes of congenital acetylcholine receptor deficiency

Abstract

We contrast the phenotypes associated with hereditary acetylcholine receptor deficiency arising from mutations in either the acetylcholine receptor ε subunit or the endplate acetylcholine receptor clustering protein rapsyn. Mutational screening was performed by amplification of promoter and coding regions by PCR and direct DNA sequencing. We identified mutations in 37 acetylcholine receptor deficiency patients; 18 had acetylcholine receptor-ε mutations, 19 had rapsyn mutations. Mutated acetylcholine receptor-ε associated with bulbar symptoms, ptosis and ophthalmoplegia at birth, and generalized weakness. Mutated rapsyn caused either an early onset (rapsyn-EO) or late onset (rapsyn-LO) phenotype. Rapsyn-EO associated with arthrogryposis and life-threatening exacerbations during early childhood. Rapsyn-LO presented with limb weakness in adolescence or adulthood resembling seronegative myasthenia gravis. Awareness of distinct phenotypic features of acetylcholine receptor deficiency resulting from acetylcholine receptor-ε or rapsyn mutations should facilitate targeted genetic diagnosis, avoid inappropriate immunological therapy and, in some infants, prompt the rapid introduction of treatment that could be life saving.

Introduction

Congenital myasthenic syndromes (CMS) comprise a heterogeneous group of rare disorders arising from genetic defects in pre-synaptic, synaptic or post-synaptic proteins at the neuromuscular junction [1]. They are characterized by impaired neuromuscular transmission, which results in fatigable muscle weakness. Most CMS involve mutations of the muscle acetylcholine receptor (AChR), which consists of five transmembrane subunits arranged around a central ion pore. In humans there are two forms of the AChR; foetal and adult [2]. The foetal form of the receptor consists of α₂βδγ subunits but late in gestation the γ subunit is replaced by the adult ε subunit [3]. Mutations in any one of the adult subunits can result in a deficiency and/or kinetic abnormality of the AChR [1].

The majority of post-synaptic syndromes result from a deficiency of muscle AChR at the endplate, usually due to mutations within the AChR-ε gene [4]. Persistent low-level expression of the AChR containing the γ subunit [5] may compensate for absence of the ε subunit [6]. In general most of the AChR ε-subunit mutations are restricted to a few families, although the ε1267delG mutation is relatively common in patients of Gypsy origin [7].

In around 25% of AChR deficiency patients, AChR mutations are not detected. Recent advances have shown that many of these patients harbour mutations in rapsyn [8], [9], [10], [11], [12] and a detailed study of 16 such patients demonstrated two distinct phenotypes; early- and late-onset [12]. Rapsyn is a 43 kDa post-synaptic protein involved in development and maintenance of the specialized post-synaptic structures at the neuromuscular junction, and specifically in AChR clustering [13].

Mutations in either the AChR-ε or rapsyn can result in a loss of AChR at the muscle endplate, with similar histopathological and electrophysiological properties [6] and cause an AChR deficiency congenital myasthenic syndrome. We have previously reported clinical features of 16 patients with rapsyn mutations [12]. Here, we confirm AChR deficiency by functional analysis of rapsyn and ε-subunit mutations and contrast the clinical features of AChR deficiency due to AChR-ε mutations with those of AChR deficiency due to rapsyn mutations. The clinical features associated with these mutations comprise distinct syndromes that have implications for diagnosis and management.