ABSTRACT
Hereditary sensory and autonomic neuropathy type 1 is an autosomal dominant neuropathy caused by the SPTLC1 or SPTLC2 variants. These variants modify the preferred substrate of serine palmitoyl transferase, responsible for the first step of de novo sphingolipids synthesis, leading to accumulation of cytotoxic deoxysphingolipids. Diagnosis of HSAN1 is based on clinical symptoms, mainly progressive loss of distal sensory keep, and genetic analysis. Aim: Identifying new SPTLC1 or SPTLC2 "gain-of-function" variants raises the question as to their pathogenicity. This work focused on characterizing six new SPTLC1 variants using in silico prediction tools, new meta-scores, 3D modeling, and functional testing to establish their pathogenicity. Methods: Variants from six patients with HSAN1 were studied. In silico, CADD and REVEL scores and the 3D modeling software MITZLI were used to characterize the pathogenic effect of the variants. Functional tests based on plasma sphingolipids quantification (total deoxysphinganine, ceramides, and dihydroceramides) were performed by tandem mass spectrometry. Results: In silico predictors did not provide very contrasting results when functional tests discriminated the different variants according to their impact on deoxysphinganine level or canonical sphingolipids synthesis. Two SPTLC1 variants were newly described as pathogenic: SPTLC1 NM_006415.4:c.998A>G and NM_006415.4:c.1015G>A. Discussion: The combination of the different tools provides arguments to establish the pathogenicity of these new variants. When available, functional testing remains the best option to establish the in vivo impact of a variant. Moreover, the comprehension of metabolic dysregulation offers opportunities to develop new therapeutic strategies for these genetic disorders.
Subject(s)
Hereditary Sensory and Autonomic Neuropathies , Mutation, Missense , Serine C-Palmitoyltransferase , Sphingolipids , Humans , Serine C-Palmitoyltransferase/genetics , Serine C-Palmitoyltransferase/metabolism , Hereditary Sensory and Autonomic Neuropathies/genetics , Hereditary Sensory and Autonomic Neuropathies/diagnosis , Male , Female , Sphingolipids/metabolism , Adult , Middle AgedABSTRACT
BACKGROUND: Teamwork is an essential factor in reducing workflow disruption (WD) in the operating room. Team familiarity (TF) has been recognized as an antecedent to surgical quality and safety. To date, no study has examined the link between team members' role and expertise, TF and WD in surgical setting. This study aimed to examine the relationships between expertise, surgeon-scrub nurse familiarity and WD. METHODS: We observed a convenience sample of 12 elective neurosurgical procedures carried out by 4 surgeons and 11 SN with different levels of expertise and different degrees of familiarity between surgeons and SN. We calculated the number of WD per unit of coding time to control for the duration of operation. We explored the type and frequency of WD, and the differences between the surgeons and SN. We examined the relationships between duration of WD, staff expertise and surgeon-scrub nurse familiarity. RESULTS: 9.91% of the coded surgical time concerned WD. The most frequent causes of WD were distractions (29.7%) and colleagues' interruptions (25.2%). This proportion was seen for SN, whereas teaching moments and colleagues' interruptions were the most frequent WD for surgeons. The WD was less high among expert surgeons and less frequent when surgeon was familiar with SN. CONCLUSIONS: The frequency of WD during surgical time can compromise surgical quality and patient safety. WD seems to decrease in teams with high levels of surgeon-scrub nurse familiarity and with development of surgical expertise. Favoring TF and giving feedback to the team about WD issues could be interesting ways to improve teamwork.
