Involvement of mTOR pathway in neurodegeneration in NSF-related developmental and epileptic encephalopathy.

Membrane fusion is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. During neurotransmitter exocytosis, SNARE proteins on a synaptic vesicle and the target membrane form a complex, resulting in neurotransmitter release. N-ethylmaleimide-sensitive factor (NSF), a homohexameric ATPase, disassembles the complex, allowing individual SNARE proteins to be recycled. Recently, the association between pathogenic NSF variants and developmental and epileptic encephalopathy (DEE) was reported; however, the molecular pathomechanism of NSF-related DEE remains unclear. Here, three patients with de novo heterozygous NSF variants were presented, of which two were associated with DEE and one with a very mild phenotype. One of the DEE patients also had hypocalcemia from parathyroid hormone deficiency and neuromuscular junction impairment. Using PC12 cells, a neurosecretion model, we show that NSF with DEE-associated variants impaired the recycling of vesicular membrane proteins and vesicle enlargement in response to exocytotic stimulation. In addition, DEE-associated variants caused neurodegenerative change and defective autophagy through overactivation of the mammalian/mechanistic target of rapamycin (mTOR) pathway. Treatment with rapamycin, an mTOR inhibitor or overexpression of wild-type NSF ameliorated these phenotypes. Furthermore, neurons differentiated from patient-derived induced pluripotent stem cells showed neurite degeneration, which was also alleviated by rapamycin treatment or gene correction using genome editing. Protein structure analysis of NSF revealed that DEE-associated variants might disrupt the transmission of the conformational change of NSF monomers and consequently halt the rotation of ATP hydrolysis, indicating a dominant negative mechanism. In conclusion, this study elucidates the pathomechanism underlying NSF-related DEE and identifies a potential therapeutic approach.

Isolated sixth nerve palsy as an initial presentation of primary angiitis of the central nervous system.

BACKGROUND: Primary angiitis of the central nervous system (PACNS) is a newly-emerging disease, and it is known that early diagnosis with treatment is important for the improvement of prognosis. CASE DESCRIPTION: Here, we report the case of a previously healthy 13-year-old girl who presented with right eye abduction failure, attributed to isolated right sixth nerve palsy, as the initial symptom of PACNS. Magnetic resonance angiography (MRA) showed stenosis in the distal portion of the right internal carotid artery, and delay alternating with nutation for tailored excitation (DANTE)-prepared contrast-enhanced magnetic resonance imaging confirmed vasculitis at the same site. The patient was subsequently treated with three courses of pulse corticosteroid therapy (methylprednisolone intravenously 30 mg/kg/day for three consecutive days). Diplopia completely resolved within 3 months after three course of steroid pulse therapy, and when taking 10 mg PSL daily. Follow-up MRA confirmed complete resolution of the arterial narrowing, and no relapse was observed after 2 months of steroid cessation. DISCUSSION: This case report illustrates an unusual presentation of PACNS with isolated sixth nerve palsy. PACNS was thought to cause insults on a single cranial nerve either through local spread of inflammation or hypoxic-ischemic insults on the nerve root due to involvement of feeding microvessels. The decision to perform imaging studies in cases of isolated sixth nerve palsy remains controversial because of the possibility of spontaneous recovery. Our case supports the existing literature that recommends that even an isolated symptom of unilateral abducens nerve palsy requires timely imaging studies.