Background: Patients with CHAT mutations can develop life-threatening episodic apneic events, a rare subtype of Congenital Myasthenic Syndromes. CMS-EA was initially described along with a CHAT gene mutation. The number of associated genetic mutations continues to expand. The episodic apneic events are potentially treatable and treatment response varies based on the genetic subtype.

Clinical Case:

A newborn male born at 33.4 weeks gestational age was delivered via Cesarean-section for non-reassuring fetal heart tones with APGARS of 1 and 2, at 1 and  5 minutes, respectively. He was intubated at 15 minutes of life for respiratory failure. Exam revealed minimal spontaneous movements and diffuse arthrogryposis.  MRI brain and C-spine on DOL 2 were unremarkable, and extensive genetic evaluation including CGH array, myotonic dystrophy panel, Prader-Willi/Angelman testing, and a congenital myasthenia panel were all normal. He underwent Whole Genome Sequencing which revealed two novel variants in the CHAT gene. The compound heterozygous variants include a maternally inherited novel missense variant, c.152T>C (p.Phe51Ser), in exon 3 and a missense variant c.857C>T (p.Ala286Val) in exon 8.  The patient was 3 months old when these results returned, at which time he had remained on mechanical ventilation with severe and diffuse hypotonia, minimal movements, and frequent intermittent apneic/desaturation episodes. He was started on pyridostigmine at 10 mg/kg/day divided four times daily. After starting pyridostigmine, he had subtle improvement in distal extremity movements, spontaneous eye opening, and improvement of apneic/desaturation episodes.

Conclusion:

We report a neonate with congenital arthrogryposis, severe generalized weakness, respiratory failure, and episodes of apnea/desaturation with two variants in the CHAT gene not previously reported as pathogenic. Furthermore, the patient was treated with pyridostigmine and demonstrated clear improvement of episodic apneic / desaturation events.  

References:

McMacken, G., Whittaker, R.G., Evangelista, T. et al. J Neurol (2018) 265: 194.