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Hepatic inflammation is commonly identified in Wilson disease (WD), a genetic disease of hepatic and brain copper accumulation. Copper accumulation is associated with increased oxidative stress and reactive oxygen species generation which may result in non-enzymatic oxidation of membrane-bound polyunsaturated fatty acids (PUFA). PUFA can be oxidized enzymatically via lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 monooxygenases (CYP). Products of PUFA oxidation are collectively known as oxylipins (OXL) and are bioactive lipids that modulate hepatic inflammation. We examined hepatic OXL profiles at early stages of WD in two mouse models, the toxic milk mouse from The Jackson Laboratory (tx-j) and the Atp7b knockout on a C57Bl/6 background (Atp7b-/-B6). Targeted lipidomic analysis performed by ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry showed that in both tx-j and Atp7b-/-B6 mice, hepatic OXL profiles were altered with higher thromboxane and prostaglandins levels. The levels of oxidative stress marker, 9-HETE were increased more markedly in tx-j mice. However, both genotypes showed upregulated transcript levels of many genes related to oxidative stress and inflammation. Both genotypes showed higher prostaglandins, thromboxin along with higher PUFA-derived alcohols, diols, and ketones with altered epoxides; the expression of Alox5 was upregulated and many CYP-related genes were dysregulated. Pathway analyses show dysregulation in arachidonic acid and linoleic acid metabolism characterizes mice with WD. Our findings indicate alterations in hepatic PUFA metabolism in early-stage WD and suggest the upregulation of both, non-enzymatic ROS-dependent and enzymatic PUFA oxidation, which could have implications for hepatic manifestations in WD and represent potential targets for future therapies.

(1) Background: Clinical results on the effects of excess sugar consumption on insulin sensitivity are conflicting, possibly due to differences in sugar type and the insulin sensitivity index (ISI) assessed. Therefore, we compared the effects of consuming four different sugars on insulin sensitivity indices derived from oral glucose tolerance tests (OGTT). (2) Methods: Young adults consumed fructose-, glucose-, high-fructose corn syrup (HFCS)-, sucrose-, or aspartame-sweetened beverages (SB) for 2 weeks. Participants underwent OGTT before and at the end of the intervention. Fasting glucose and insulin, Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), glucose and insulin area under the curve, Surrogate Hepatic Insulin Resistance Index, Matsuda ISI, Predicted M ISI, and Stumvoll Index were assessed. Outcomes were analyzed to determine: (1) effects of the five SB; (2) effects of the proportions of fructose and glucose in all SB. (3) Results: Fructose-SB and the fructose component in mixed sugars negatively affected outcomes that assess hepatic insulin sensitivity, while glucose did not. The effects of glucose-SB and the glucose component in mixed sugar on muscle insulin sensitivity were more negative than those of fructose. (4) Conclusion: the effects of consuming sugar-SB on insulin sensitivity varied depending on type of sugar and ISI index because outcomes assessing hepatic insulin sensitivity were negatively affected by fructose, and outcomes assessing muscle insulin sensitivity were more negatively affected by glucose.

Abstract Defects at the neuromuscular junction (NMJ) are among the earliest hallmarks of amyotrophic lateral sclerosis (ALS). According to the “dying-back” hypothesis, NMJ disruption not only precedes but also triggers the subsequent degeneration of motoneurons in both sporadic (sALS) and familial (fALS) ALS. Using human induced pluripotent stem cells (iPSCs), we show that the RNA-binding protein HuD (ELAVL4) contributes to NMJ defects and apoptosis in FUS-ALS. HuD overexpression mimics the severe FUSP525L mutation, while its knockdown rescues the FUSP525L phenotypes. In Drosophila, neuronal overexpression of the HuD ortholog, elav, induces motor dysfunction, and its knockdown improves motor function in a FUS-ALS model. Finally, we report increased HuD levels upon oxidative stress in human motoneurons and in sALS patients with an oxidative stress signature. Based on these findings, we propose that HuD plays a role downstream of FUS mutations in fALS and in sALS related to oxidative stress.

Abstract Background The Steno Type 1 Risk Engine (ST1RE) was developed to aid clinical decisions in primary prevention for individuals with type 1 diabetes (T1D), as existing cardiovascular (CV) risk models for the general population and type 2 diabetes tend to underestimate CV risk in T1D. However, the applicability of ST1RE in different populations remains uncertain, as prediction models developed for one population may not accurately estimate risk in another. This study aimed to evaluate the performance of the ST1RE in predicting CV events among ethnically mixed T1D individuals and its association with the progression of microangiopathy complications. Methods A retrospective survey of 435 adults with T1D who were free of CV events at baseline was assessed by ST1RE and chronic diabetes complications at 5 and 10 years of follow-up. The estimated CV risk rates were compared with the observed rates at 5 and 10 years using statistical analyses, including Receiver Operating Characteristic (ROC) curve analysis, Hosmer-Lemeshow test, Kaplan-Meier curves analysis and Cox-regression models. Results Among 435 patients (aged 25 years; interquartile range [IQR]: 21–32) with a median T1D duration of 13 years (IQR: 9–18), only 5% were categorized into the high ST1RE group. Within a median follow-up of 9.2 years (IQR 6.0-10.7), 5.5% of patients experienced a CV event (1.6%, 14.9%, and 50% from the low, moderate, and high-risk groups, respectively). The hazard ratios (HRs) for CV events were greater in the high-risk group (HR 52.02; 95% CI 18.60–145.51, p

Introduction: Spontaneous tumor regression is the volumetric reduction or complete disappearance of a primary tumor or metastatic sites (single or multiple) without the administration of treatments. This rare phenomenon occurs most commonly in certain types of neoplasms. Case Presentation: In this manuscript, we describe a spontaneous tumor regression in an adult patient followed at the Modena Cancer Center and affected by retroperitoneal inflammatory myofibroblastic tumor, an ultra-rare subtype of sarcoma. Finally, we will provide a concise review of the literature and try to explain the mechanisms underlying the tumor regression described in the clinical case. Conclusion: The etiopathogenetic mechanisms for spontaneous tumor regression are not yet fully understood and likely involve a complex interplay among immunological mechanisms, growth factors, cytokines, and hormonal factors.

One of the most recognized decorations of the pick-up technique is the millefiori glass, which has been commonly attributed to Venetian production. However, Portugal is the country where the largest known assemblage of this type of glass artefact has been studied and published. In this work, two important archeological contexts were selected: (1) Santa Clara-a-Velha monastery (SCV) and (2) São João de Tarouca monastery (SJT). The fragments selection was made based on the diversity of decorative motifs, colors, and original forms that has been associated with Portuguese production. The compositional characterization was conducted by performing micro-particle-induced X-ray emission (µ-PIXE) mapping, which facilitated the visualization of the distribution of different oxides across the different glass layers and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to obtain the major, minor, and trace elements composition, including rare earth elements (REEs) to determine which kind of raw materials were used. Additionally, µ-Raman spectroscopy was employed to investigate the opacifiers, while UV–Visible spectroscopy was used to study which chromophores are presented in the glass samples. All the analyzed glass layers can be considered to be of a soda–lime–silica type, and four different geological patterns (from GP1 to GP4) were detected and reported. This result can indicate that these objects were made by using silica sources taken from four different geological settings. Interestingly, the GP3 represents about 41% of the analyzed glass fragments and is compatible with the pattern detected in some production wastes found in two different archeological contexts located in Lisbon, which reinforces the veracity of the theory that this GP can be attributed to a Portuguese production. On the other hand, GP1 was probably attributed Granada provenance.

Abstract Background Trauma systems are crucial for enhancing survival and quality of life for trauma patients. Understanding trauma triage and patient outcomes is essential for optimizing resource allocation and trauma care. Aims The aim was to explore prehospital trauma triage in Region Zealand, Denmark. Specifically, characteristics for patients who were either primarily admitted or secondarily transferred to major trauma centers were described. Methods A retrospective descriptive study of severely injured trauma patients was conducted from January 2017 to December 2021. Results The study comprised 744 patients including 55.6% primary and 44.4% secondary patients. Overall, men accounted for 70.2% of patients, and 66.1% were aged 18–65 years. The secondary patients included more women—34.2% versus 26.3% and a higher proportion of Injury Severity Score of ≥ 15—59.6% versus 47.8%, compared to primary patients. 30-day survival was higher for secondary patients—92.7% versus 87%. Medical dispatchers assessed urgency as Emergency level A for 98.1% of primary patients and 86.3% for secondary patients. Physician-staffed prehospital units attended primary patients first more frequently—17.1% versus 3.5%. Response times were similar, but time at scene was longer for primary patients whereas time from injury to arrival at a major trauma center was longer for secondary patients. Conclusions Secondary trauma patients had higher Injury Severity Scores and better survival rates. They were considered less urgent by medical dispatchers and less frequently assessed by physician-staffed units. Prospective quality data are needed for further investigation of optimal triage and continuous quality improvement in trauma care.

BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION: There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING: None.

Abstract: Groundwater contains high levels of dissolved ions, which pose health risks when consumed. This study proposes biochar production for fluoride (F‒) removal from aqueous solutions using sustainable materials and functionalization processes.Biochar derived from coffee grounds carbonization at 500 °C was functionalized with hydrogen peroxide (H2O2). Structural morphology analysis utilized SEM+EDS, BET, and BJH techniques, while XRD and FTIR analyses assessed surface chemistry. Effects of pH, dosage, and initial F‒ concentration on adsorption were evaluated, along with kinetics and thermodynamics.H2O2 increased acid functional groups on the surface without significantly altering surface area or pore volume. The highest adsorption capacity (0.179 mg g-1) and removal efficiency (25.5%) were at pH = 4. Kinetic studies highlighted the influence of initial F‒ concentration on adsorption equilibrium time and capacity. Experimental data fitting to pseudo-second-order and Elovich models suggested chemical mechanisms predominance, with intraparticle diffusion as the rate-limiting step. Adsorption isotherm fitting to Langmuir and Freundlich models indicated physical and chemical processes combination. The highest adsorption capacity was recorded at 1.46 mg g‒1 at 55 °C. Thermodynamic analysis revealed endothermic and non-spontaneous nature, potentially affecting F‒ affinity towards the adsorbent.

Abstract Spaceborne-based monitoring for environmental purposes has become a well-established practice. The recent progress of synthetic aperture radar (SAR) sensors, including through the European Space Agency’s (ESA) Sentinel-1 constellation, has enabled the scientific community to identify and monitor several geohazards, including subsidence ground deformations. A case study in the Tuscany Region, Italy, highlights the effectiveness of interferometric synthetic aperture radar (InSAR) in detecting abrupt increases in ground deformation rates in an industrial area of Montemurlo municipality. In this case, InSAR data enabled prompt identification of the phenomenon, supporting the authorities in charge of environmental management to thoroughly investigate the situation. First, an on-site validation was performed via field surveys confirming the presence of cracks and fissures on some edifices. Further analysis, including water pumping rates, settlement gauge and topographic levelling, corroborated the InSAR data's findings regarding vertical deformation. Integration of collected data allowed for spatial identification and assessment of the subsidence bowl and its source depth recognized by the remote sensing data. The Montemurlo case offers a procedural guideline for managing abrupt accelerations, identified by InSAR data in subsidence-prone areas due to fluid overexploitation. In fact, these data proved useful in helping local authorities responsible for hydrogeomorphological risk management. With the exacerbation of deformation issues in subsidence-prone regions due to climate change, early detection and monitoring of such phenomena are increasingly crucial, with InSAR data playing a central role in achieving this goal.

Abstract Background Low adherence to the number of insulin injections and glycemic variability are among the challenges of insulin therapy in type 1 diabetes (T1D). The TOP1 study investigated the effect of switching from twice-daily (BID) basal insulin to once daily (OD) insulin glargine 300 U/mL (Gla-300) on glycemic control and quality of life. Methods In this 28-week, phase 4 trial, people with T1D aged ≥ 18 years, who were treated with BID basal insulin in combination with prandial rapid-acting insulin for at least 1 year, and had HbA1c between 7.5% and 10.0%, were switched to Gla-300 OD as basal insulin. The present study aimed to evaluate the impact of this change on HbA1c, glycemic profile, treatment satisfaction and safety. The change in HbA1c from baseline to Week 24 was the primary endpoint. Results One hundred and twenty-three people with T1D (mean age 37 ± 11 years; 54.5% female) were studied. The disease duration was 20.0 ± 9.8 years, baseline HbA1c and fasting plasma glucose (FPG) were 8.6 ± 0.7% and 201 ± 80.3 mg/dL, respectively. After switching from BID to OD insulin regimen, no significant change in HbA1c was observed from baseline to Week 24 (p = 0.873). There were significant reductions in fasting self-monitoring blood glucose (SMBG) from baseline to Week 24 (175 ± 42 vs. 156 ± 38 mg/dL; p

Introduction: Thyroid hormones have systemic effects on the human body and play a key role in the development and function of virtually all tissues. They are regulated via the hypothalamic–pituitary–thyroid (HPT) axis and have a heritable component. Using genetic information, we applied tissue-specific transcriptome-wide association studies (TWAS) and plasma proteome-wide association studies (PWAS) to elucidate gene products related to thyrotropin (TSH) and free thyroxine (FT4) levels. Results: TWAS identified 297 and 113 transcripts associated with TSH and FT4 levels, respectively (25 shared), including transcripts not identified by genome-wide association studies (GWAS) of these traits, demonstrating the increased power of this approach. Testing for genetic colocalization revealed a shared genetic basis of 158 transcripts with TSH and 45 transcripts with FT4, including independent, FT4-associated genetic signals within the CAPZB locus that were differentially associated with CAPZB expression in different tissues. PWAS identified 18 and ten proteins associated with TSH and FT4, respectively (HEXIM1 and QSOX2 with both). Among these, the cognate genes of five TSH- and 7 FT4-associated proteins mapped outside significant GWAS loci. Colocalization was observed for five plasma proteins each with TSH and FT4. There were ten TSH and one FT4-related gene(s) significant in both TWAS and PWAS. Of these, ANXA5 expression and plasma annexin A5 levels were inversely associated with TSH (PWAS: P = 1.18 × 10−13, TWAS: P = 7.61 × 10−12 (whole blood), P = 6.40 × 10−13 (hypothalamus), P = 1.57 × 10−15 (pituitary), P = 4.27 × 10−15 (thyroid)), supported by colocalizations. Conclusion: Our analyses revealed new thyroid function-associated genes and prioritized candidates in known GWAS loci, contributing to a better understanding of transcriptional regulation and protein levels relevant to thyroid function.

In the last few years, data fusion has been an active research topic for the expected advantages of exploiting and combining different but complementary techniques for 3D documentation. The data fusion process consists of merging data coming from different sensors and platforms, intrinsically different, to produce complete, coherent, and precise 3D reconstructions. Although extensive research has been dedicated to this task, we still have many gaps in the integration process, and the quality of the results is hardly sufficient in several cases. This is especially evident when the integration occurs in a later stage, e.g., merging the results of separate data processing. New opportunities are emerging, with the possibility offered by some proprietary tools to jointly process heterogeneous data, particularly image and range-based data. The article investigates the benefits of data integration at different processing levels: raw, middle, and high levels. The experiments are targeted to explore, in particular, the results of the integration on large and complex architectures.

Various types of pollutants are present in wastewaters, which can combine and form even more toxic components or interfere with the treatments used for purification. Among emerging contaminants are microplastics and surfactants, which coexist in different types of wastewaters. This study aimed to assess the effects of the anionic surfactant linear alkylbenzene sulfonate (LAS) and the nonionic surfactant polyoxyethylene sorbitan monolaurate (Tween 20) on the removal of microplastics from pristine and aged glitter PVC surfaces using electrocoagulation with aluminum electrodes. To avoid interference from other substances, a benchtop reactor operating in batch mode with particles suspended in ultrapure water was developed for the experiments. The analysis methods employed included counting with the aid of a magnifying glass, gravimetry, zeta potential measurements, and scanning electron microscopy. The results revealed that the addition of surfactants led to a reduction in the removal efficiency of plastic microparticles. The lowest removal percentages were observed at a concentration of 100 ppm, and the inclusion of Tween 20 resulted in a decrease of 23% for pristine microplastics and 45% for aged microplastics. In contrast, the addition of LAS led to a decrease of 6% for pristine microplastics and 24% for aged microplastics. Therefore, the decrease in removal efficiency was more pronounced for degraded microplastics in both the Tween 20 and LAS experiments. Comparing the reduction in removal efficiency between the two types of surfactants, it can be observed that the nonionic surfactant (Tween 20) had a greater impact on the removal of microplastics by electrocoagulation.

Abstract Background The decision to administer palliative radiotherapy (RT) to patients with bone metastases (BMs), as well as the selection of treatment protocols (dose, fractionation), requires an accurate assessment of survival expectancy. In this study, we aimed to develop three predictive models (PMs) to estimate short‐, intermediate‐, and long‐term overall survival (OS) for patients in this clinical setting. Materials and Methods This study constitutes a sub‐analysis of the PRAIS trial, a longitudinal observational study collecting data from patients referred to participating centers to receive palliative RT for cancer‐induced bone pain. Our analysis encompassed 567 patients from the PRAIS trial database. The primary objectives were to ascertain the correlation between clinical and laboratory parameters with the OS rates at three distinct time points (short: 3 weeks; intermediate: 24 weeks; prolonged: 52 weeks) and to construct PMs for prognosis. We employed machine learning techniques, comprising the following steps: (i) identification of reliable prognostic variables and training; (ii) validation and testing of the model using the selected variables. The selection of variables was accomplished using the LASSO method (Least Absolute Shrinkage and Selection Operator). The model performance was assessed using receiver operator characteristic curves (ROC) and the area under the curve (AUC). Results Our analysis demonstrated a significant impact of clinical parameters (primary tumor site, presence of non‐bone metastases, steroids and opioid intake, food intake, and body mass index) and laboratory parameters (interleukin 8 [IL‐8], chloride levels, C‐reactive protein, white blood cell count, and lymphocyte count) on OS. Notably, different factors were associated with the different times for OS with only IL‐8 included both in the PMs for short‐ and long‐term OS. The AUC values for ROC curves for 3‐week, 24‐week, and 52‐week OS were 0.901, 0.767, and 0.806, respectively. Conclusions We successfully developed three PMs for OS based on easily accessible clinical and laboratory parameters for patients referred to palliative RT for painful BMs. While our findings are promising, it is important to recognize that this was an exploratory trial. The implementation of these tools into clinical practice warrants further investigation and confirmation through subsequent studies with separate databases.

Objectives To evaluate a postpartum telephone-based lifestyle intervention to prevent diabetes in high-risk women with recent gestational diabetes mellitus (GDM).Design Multicentre parallel randomised clinical trial.Setting Specialised antenatal clinics in the Brazilian National System.Methods Lifestyle Intervention for Diabetes Prevention After Pregnancy compared (1:1) postpartum telephone support for lifestyle changes with conventional care in women with recent GDM at substantial risk for diabetes. Randomisation started on 28 March 2015 and ended on 13 March 2020, with the onset of the COVID-19 pandemic. We used Cox regression to estimate HRs for diabetes and analysis of covariance adjusted for follow-up time to assess weight change.Outcomes The primary outcome was incident diabetes ascertained with blinded measurements of oral glucose tolerance tests. The secondary outcome was a change in measured weight.Results We enrolled 5323 women with GDM, 2735 (51%) being at high risk. After invitations, baseline assessment and exclusions, we assigned 466 women to intervention (231) or control (235) groups. Attendance was satisfactory (≥7/20 phone sessions) in 75%. Over an average follow-up of 29.7 (15.6) months, 142 (30.5%) women progressed to diabetes, 75 (32%) in the control and 67 (29%) in the intervention group. There was no reduction in the incidence of diabetes (HR=0.84; 0.60–1.19) and only a non-significant 0.97 kg less weight gain (p=0.09). Among the 305 women randomised more than 1 year before the COVID-19 pandemic, the intervention did not reduce the incidence of diabetes (HR=0.71; 0.48–1.04) despite a 2.09 kg (p=0.002) lesser weight gain.Conclusion The strategy to identify women with GDM at high risk proved valid, as women often gained weight and frequently developed diabetes. Over a 30-month follow-up, telephone support for lifestyle changes at postpartum did not reduce weight gain or diabetes incidence, although only 75% attended the minimum number of telephone sessions. The COVID-19 pandemic negatively impacted trial conduction.Trial registration number NCT02327286.

Summary: Nuclear pore complexes (NPCs) regulate nucleocytoplasmic transport and are anchored in the nuclear envelope by the transmembrane nucleoporin NDC1. NDC1 is essential for post-mitotic NPC assembly and the recruitment of ALADIN to the nuclear envelope. While no human disorder has been associated to one of the three transmembrane nucleoporins, biallelic variants in AAAS, encoding ALADIN, cause triple A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia, and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints. In this report, diagnostic exome and/or RNA sequencing was performed in seven individuals from four unrelated consanguineous families with AAAS-negative triple A syndrome. Molecular and clinical studies followed to elucidate the pathogenic mechanism. The affected individuals presented with intellectual disability, motor impairment, severe demyelinating with secondary axonal polyneuropathy, alacrima, and achalasia. None of the affected individuals has adrenal insufficiency. All individuals presented with biallelic NDC1 in-frame deletions or missense variants that affect amino acids and protein domains required for ALADIN binding. No other significant variants associated with the phenotypic features were reported. Skin fibroblasts derived from affected individuals show decreased recruitment of ALADIN to the NE and decreased post-mitotic NPC insertion, confirming pathogenicity of the variants. Taken together, our results implicate biallelic NDC1 variants in the pathogenesis of polyneuropathy and a triple A-like disorder without adrenal insufficiency, by interfering with physiological NDC1 functions, including the recruitment of ALADIN to the NPC.