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

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.

Ketogenic Diet in Patients with GLUT1 Deficiency Syndrome.

Background:The ketogenic diet (KD) is a high fat, low carbohydrate diet considered to be the treatment of choice for GLUT1deficiency syndrome, a metabolic disorder affecting the nervous system. Aim:To present our experience in four patients with GLUT1 deficiency syndrome who were treated with KD. Methods:Retrospective data from case series. Phenotypical features, mainly movement disorder and seizures, are being described for each patient. All four cases are currently following the Modified Atkins Diet. Results:The response to ketogenic diet in our four patients was significant with improvement of movement disorder or seizures control. Conclusion:The ketogenic diet is the treatment of choice for GLUT1deficiency syndrome. Recognition of the disorder is the key for appropriate management among clinicians. Diet compliance is an important issue in school age children.

Neurofibromatosis type 1 associated with moyamoya syndrome. Case report and review of the literature.

Neurofibromatosis type 1 (NF1) is a genetic disorder with a very heterogeneous clinical picture, affecting central nervous system, skin and bone system. Cerebrovascular lesions, such as moyamoya syndrome, are rarely seen in NF1. Approximately 250 children with NF1 and moyamoya syndrome have been reported. The clinical picture includes hemiparesis, hemianopsia, paresthesia, seizures, speech disorders, and intellectual disability. In this paper, we report on a 6-year-old girl with NF1 and moyamoya syndrome, with a brief review of the existing literature.