Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea

Am J Hum Genet. 2016 Sep 1;99(3):753-761. doi: 10.1016/j.ajhg.2016.06.033. Epub 2016 Aug 25.


The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMSs), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Apnea / complications
  • Apnea / genetics*
  • Apnea / metabolism
  • Apnea / pathology
  • Arthrogryposis / complications
  • Arthrogryposis / genetics
  • Butyrylcholinesterase / metabolism
  • Child
  • Child, Preschool
  • Cholinergic Neurons / metabolism
  • Cholinergic Neurons / pathology
  • DNA Mutational Analysis
  • Exome / genetics
  • Female
  • Genes, Recessive / genetics
  • HEK293 Cells
  • Heterozygote
  • Homozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Muscle Hypotonia / genetics
  • Muscle Weakness / complications
  • Muscle Weakness / genetics
  • Muscle Weakness / pathology
  • Mutation / genetics*
  • Mutation, Missense / genetics
  • Myasthenia Gravis / complications
  • Myasthenia Gravis / genetics*
  • Myasthenia Gravis / metabolism
  • Myasthenia Gravis / pathology
  • Neuromuscular Junction / enzymology
  • Neuromuscular Junction / metabolism
  • Neuromuscular Junction / pathology
  • Presynaptic Terminals / metabolism*
  • Presynaptic Terminals / pathology
  • Symporters / deficiency
  • Symporters / genetics*
  • Symporters / metabolism*
  • Synaptic Transmission


  • SLC5A7 protein, human
  • Symporters
  • Butyrylcholinesterase

Supplementary concepts

  • Congenital myasthenic syndrome with episodic apnea