Congenital myasthenic syndrome with episodic apnoea: clinical, neurophysiological and genetic features in the long-term follow-up of 19 patients

Abstract

Background: Congenital myasthenic syndrome with episodic apnoea (CMS-EA) is a rare but potentially treatable cause of apparent life-threatening events in infancy. The underlying mechanisms for sudden and recurrent episodes of respiratory arrest in these patients are unclear. Whilst CMS-EA is most commonly caused by mutations in CHAT, the list of associated genotypes is expanding.

Methods: We reviewed clinical information from 19 patients with CMS-EA, including patients with mutations in CHAT, SLC5A7 and RAPSN, and patients lacking a genetic diagnosis.

Results: Lack of genetic diagnosis was more common in CMS-EA than in CMS without EA (56% n = 18, compared to 7% n = 97). Most patients manifested intermittent apnoea in the first 4 months of life (74%, n = 14). A degree of clinical improvement with medication was observed in most patients (74%, n = 14), but the majority of cases also showed a tendency towards complete remission of apnoeic events with age (mean age of resolution 2 years 5 months). Signs of impaired neuromuscular transmission were detected on neurophysiology studies in 79% (n = 15) of cases, but in six cases, this was only apparent following specific neurophysiological testing protocols (prolonged high-frequency stimulation).

Conclusions: A relatively large proportion of CMS-EA remains genetically undiagnosed, which suggests the existence of novel causative CMS genes which remain uncharacterised. In light of the potential for recurrent life-threatening apnoeas in early life and the positive response to therapy, early diagnostic consideration of CMS-EA is critical, but without specific neurophysiology tests, it may go overlooked.

Keywords: Congenital myasthenic syndrome; Neuromuscular disease; Neuromuscular junction; Neurophysiology.

Fig. 1

Heterogeneity of genetic defects in CMS: Mutations are described in genes encoding pre-synaptic, synaptic and post-synaptic proteins, proteins of the extracellular matrix and dystrophin-associated glycoprotein complex and in ubiquitously expressed proteins involved in glycosylation (GFPT1, DPAGT1, ALG2, ALG14, GHMPPB) and mitochondrial function (SLC25A1) which may act at multiple sites. Genes in which mutations have been previously described in patients with EA are highlighted in red

Fig. 2

Proportion of CMS-EA subtypes in our patient cohort (n=32)

Fig. 3

Resolution of apnoeic events over time: For the majority of cases, the period of recurrent EAs (orange) during a patient’s life span (gray) began in the first months of life and resolved in early childhood. Cases marked * are deceased