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Background: Glucose (GBT) and lactulose (LBT) breath tests have been recommended for the diagnosis of small intestinal bacterial overgrowth (SIBO). LBT may yield a higher prevalence of SIBO diagnosis, because of its limited small bowel absorption, and therefore colonic fermentation. The aim of this retrospective study was to confirm this hypothesis, in irritable bowel syndrome patients (IBS)., Methods: Among a cohort of 995 patients who underwent GBT or LBT, 287 with typical IBS according to Rome IV criteria, without past digestive surgery or significant medical comorbidities, were included., Results: 155 IBS patients underwent GBT, and 132 LBT (71% women, mean age 45±15, mean BMI: 22.6±4.3 kg/m 2 ). There were no difference between both groups in terms of demographics, IBS type and severity of symptoms. The prevalence of SIBO according to LBT was 47%, versus 4.5% only with GBT (p<0.001). The prevalence of methane values ≥ 10 ppm were similar in both groups (34%)., Conclusion: LBT is very frequently positive in IBS patients, as compared to GBT. The 2 tests are thus not interchangeable for the diagnosis of SIBO. Furthermore, the positivity of both tests was not correlated with symptoms, which may indicate a poor clinical interest of these tests in IBS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: The ubiquitination process plays a crucial role in neuronal differentiation and function. Numerous studies have focused on the expression and functions of E3 ligases during these different stages, far fewer on E2 conjugating enzymes. In mice, as in humans, these E2s belong to 17 conjugating enzyme families. Objectives: We analyzed by real-time PCR the expression dynamics of all known E2 genes during an in vitro differentiation of mouse hippocampal neuronal cultures, and after, we analyzed their stimulation with N-methyl-D-aspartate (NMDA). Results: We found that 36 of the 38 E2 genes were expressed in hippocampal neurons. Many were up-regulated during neuritogenesis and/or synaptogenesis stages, such as Ube2h , Ube2b , and Aktip . Rapid and delayed responses to NMDA stimulation were associated with the increased expression of several E2 genes, such as Ube2i , the SUMO-conjugating E2 enzyme. We also observed similar expression profiles within the same E2 gene family, consistent with the presence of similar transcription factor binding sites in their respective promoter sequences. Conclusions: Our study indicates that specific expression profiles of E2 genes are correlated with changes in neuronal differentiation and activity. A better understanding of the regulation and function of E2s is needed to better understand the role played by the ubiquitination process in physiological mechanisms and pathophysiological alterations involved in neurodevelopmental or neurodegenerative diseases.

MANAGING MEDULLARY THYROID CARCINOMA IN 2024: Medullary thyroid carcinoma is a rare neuroendocrine thyroid cancer with a heterogeneous prognosis which has the particularity of being associated with a RET gene mutation, germline in 20-25% of cases in the context of multiple endocrine neoplasia type 2 (NEM2), and somatic in 70% of sporadic cases. It is often diagnosed on a thyroid nodule or in the context of genetic screening. Calcitonin is a biological marker, used for diagnosis, monitoring of therapeutic response and prognostic evaluation. The only curative treatment is surgery for localized disease. The extent must be carefully assessed, particularly in terms of calcitonin levels and imaging, and carried out by an expert surgeon. The prognosis of locally advanced or metastatic disease is highly heterogeneous. Histological factors, such as high grade, or biological factors, such as calcitonin doubling time, can help assess prognosis. The development of multi-kinase inhibitors cabonzantinib and vandetanib, and RET-targeted inhibitors selpercatinib, has completely changed the therapeutic arsenal for advanced disease, but their prescription is reserved to progressive disease with high tumor volume or to symptomatic disease inaccessible to local treatment in expert centers from the ENDOCAN-TUTHYREF network. Active surveillance is the alternative of choice for slowly progressing disease., Competing Interests: Liens d’intérêts H. Lasolle, F. Borson-Chazot, T. Gauduchon, M. Haissaguerre, F. Illouz, J.-C. Lifante, C. Lussey-Lepoutre, D. Prunier, C. Sajous et R. Varnier déclarent ne pas avoir de liens d’intérêts. J. Hadoux déclare avoir des liens d’intérêts pour grants/research support de la part du laboratoire Lilly; pour des honoraires versés par les laboratoires Lilly, Ipsen, Bayer, PharmaMAr, Roche, HRA pharma, AAA et Eisai. Cet article fait partie du supplément Prise en charge des cancers thyroïdiens en 2024 : avancées diagnostiques et thérapeutiques réalisé avec le soutien institutionnel de Lilly., (Copyright © 2024 Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.)

TIA1/SQSTM1 myopathy is one of the few digenic myopathies. We describe four new French adult male patients carrying the TIA1 p.Asn357Ser and SQSTM1 p.Pro392Leu variant and review the literature to include 20 additional cases to define the spectrum of the disease. These twenty-four patients (75% males) had late-onset (52,6 ± 10,1 years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and myopathic EMG. Two of the four French patients had sensorimotor axonal polyneuropathy and an additional one had neurogenic changes in muscle biopsy. Muscle biopsy showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates. The TIA1 p.Asn357Ser variant was present in all patients and the SQSTM1 p.Pro392Leu was the most frequent (71%) of the four reported SQSTM1 variants. We reviewed the distal myopathy gene panels of Pitié-Salpêtrière's hospital cohort finding a prevalence of 11/414=2.7% of the TIA1 p.Asn357Ser variant, with two patients having an alternative diagnosis (TTN and MYH7) with atypical phenotypes, resembling some of the features seen in TIA1/SQSTM1 myopathy. Overall, TIA1/SQSTM1 myopathy has a homogenous phenotype reinforcing the pathogenicity of its digenic variants. We confirm an increased burden of the TIA1 p.Asn357Ser variant in distal myopathy patients which could act as a genetic modifier., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Abnormal cytoplasmic aggregates containing the TDP-43 protein and its fragments are present in the central nervous system of the majority of patients with amyotrophic lateral sclerosis (ALS) and in patients with frontotemporal lobar degeneration (FTLD). Many studies have focused on the C-terminal cleavage products of TDP-43 (CTFs), but few have focused on the N-terminal products (NTFs), yet several works and their protein domain composition support the involvement of NTFs in pathophysiology. In the present study, we expressed six NTFs of TDP-43, normally generated in vivo by proteases or following the presence of pathogenic genetic truncating variants, in HEK-293T cells. The N-terminal domain (NTD) alone was not sufficient to produce aggregates. Fragments containing the NTD and all or part of the RRM1 domain produced nuclear aggregates without affecting cell viability. Only large fragments also containing the RRM2 domain, with or without the glycine-rich domain, produced cytoplasmic aggregates. Of these, only NTFs containing even a very short portion of the glycine-rich domain caused a reduction in cell viability. Our results provide insights into the involvement of different TDP-43 domains in the formation of nuclear or cytoplasmic aggregates and support the idea that work on the development of therapeutic molecules targeting TDP-43 must also take into account NTFs and, in particular, those containing even a small part of the glycine-rich domain.

Objectives: Patients with inherited metabolic disorders (IMDs) may require emergency hospital care to prevent life-threatening situations such as metabolic decompensation. To date, over one thousand different rare IMDs have been identified, which means that healthcare professionals (HCPs) initiating emergency treatment may not be familiar with these conditions. The objective of this initiative was to provide HCPs with practical guidance for the acute management of children and adults with IMDs who need emergency care, regardless of the underlying reason., Methods: We outline how a multidisciplinary working group from the French IMDs Healthcare Network for Rare Diseases, known as G2M, has created concise and standardized protocols &#95;each consisting of a single double-sided A4 sheet &#95; focused on a specific disease, a group of diseases, or a particular symptom. Prior to validation, these protocols were reviewed by all French reference and competence centres for IMDs, as well as by medical experts from other specialities when necessary, physicians from emergency and intensive care units, and representatives from patient associations., Results and Conclusion: In total, 51 emergency protocols containing essential information have been developed and provided to affected patients. All the emergency protocols are freely available in both French and English at https://www.filiere-g2m.fr/urgences. These standardized protocols aim to enhance the emergency care of patients without delay, while also assisting HCPs by increasing their confidence and efficiency, minimizing the risk of dosage errors when administering specialized treatments, saving time, and reducing the number of phone calls to metabolic medicine specialists on night duty. The protocols are scheduled for annual review to facilitate further improvements based on feedback from HCPs and patients, as well as to accommodate any changes in management practices as they evolve., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to the content of this manuscript. Within the past 36 months, outside of the submitted work: Juliette Bouchereau reports support for attending a meeting from Ultragenyx; Karine Mention reports a research contract with Sanofi, fees for lectures from Sanofi and Chiesi, and participation in a Board for Chiesi; Jérémy Do Cao reports support for attending a meeting and fees for a presentation at this meeting, both from Sanofi Rare Diseases; Aline Cano reports fees for presentations from Sanofi and Genzyme, honorarium for participation in a Scientific Board from Sanofi, and medical writing fees from Nutricia; Célia Hoebeke reports registration and presentation fees from BioMarin for a meeting, registration fees from Sanofi Aventis France, and a meal offered by Orphalan during another meeting; Anaïs Brassier reports fees for lectures from Sanofi and BioMarin, support for attending meetings from Sanofi, and participation in an Advisory Board for Sanofi; Laurent Gouya reports having participated for free in a Scientific Committee for Alnylam Pharmaceuticals and in the IPNET Executive Board, and having been Chairman of the GenOmics Committee of Foundation For Rare Diseases (FFRD, Fondation Maladies Rares); Jean-Baptiste Arnoux reports fees for lectures from Sanofi and Recordati, consulting fees from Sobi, Immedica pharma and Zealand pharma, and support for attending meetings from Immedica pharma; Cécile Acquaviva-Bourdain reports consulting fees from Alnylam Pharmaceuticals, Ultragenix, and Novodordisk, and fees for lectures from Alnylam Pharmaceuticals; Pierre Broué reports payments to the institution that employs him from Mirium Pharma, and personal fees for Advisory Boards from Mirum Pharma and Albireo AB; Claire Douillard reports grants from Sanofi and Ultragenyx, fees for a presentation from Alnylam Pharmaceuticals, and support for attending a meeting from Sanofi., (Copyright © 2024. Published by Elsevier Inc.)

Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by the death of motoneurons. Several mutations in the KIF5A gene have been identified in patients with ALS. Some mutations affect the splicing sites of exon 27 leading to its deletion (Δ27 mutation). KIF5A Δ27 is aggregation-prone and pathogenic for motoneurons due to a toxic gain of function. Another mutation found to be enriched in ALS patients is a proline/leucine substitution at position 986 (P986L mutation). Bioinformatic analyses strongly suggest that this variant is benign. Our study aims to conduct functional studies in Drosophila to classify the KIF5A P986L variant. When expressed in motoneurons, KIF5A P986L does not modify the morphology of larval NMJ or the synaptic transmission. In addition, KIF5A P986L is uniformly distributed in axons and does not disturb mitochondria distribution. Locomotion at larval and adult stages is not affected by KIF5A P986L. Finally, both KIF5A WT and P986L expression in adult motoneurons extend median lifespan compared to control flies. Altogether, our data show that the KIF5A P986L variant is not pathogenic for motoneurons and may represent a hypomorphic allele, although it is not causative for ALS., (© 2024. The Author(s).)

Objective: In studies of concomitant arterial-venous umbilical cord blood gases (CAV-UBGs), approximately 10% of technically valid samples have very similar pH and/or pCO 2 values and were probably drawn from the same type of blood vessel. Without a way to objectively determine the source in these cases, it has been argued that most of these same-source CAV-UBGs are venous because the vein is larger and more easily sampled than the artery. This study aimed to calculate the probability of an arterial (ProbAS) or venous source (ProbVS) of same-source CAV-UBGs in the clinically and medicolegally important pH range of 6.70 to 7.25 using a statistical predictive model based on the cord blood gas values., Study Design: Starting with a dataset of 56,703 CAV-UBGs, the ProbAS, ProbVS, and respective 95% confidence intervals (CIs) were calculated for the 241 sample pairs with near-identical pH, pCO 2 , and pO 2 values and a pH of 6.70 to 7.25. Using a previously validated generalized additive model, the source was categorized as: Probable Arterial or Highly Probable Arterial if the ProbAS and CIs were >0.5 or >0.8, respectively; Probable Venous or Highly Probable Venous if the ProbVS and CIs were >0.5 or >0.8, respectively; or Indeterminant if the CIs encompassed ProbAS/VS = 0.5., Results: A total of 39% of the same-source CAV-UBGs were Probable Arterial, 56% were Probable Venous, and 5% were Indeterminant. However, considering samples with a pH ≤7.19, 80% were Probable Arterial and 16% were Probable Venous. Considering the Highly Probable categories, the more acidemic specimens were 9 times more likely to be arterial than venous. Similarly, CAV-UBGs with pCO 2  > 8.2 kPa (62 mm Hg) or pO 2 ≤ 1.9 kPa (14 mm Hg) were more likely to be in the arterial rather than the venous categories., Conclusion: Same-source CAV-UBGs in the more acidemic, hypercarbic, or hypoxemic ranges are more likely to be arterial than venous., Key Points: · Umbilical cord arterial/venous gases (CAV-UBGs) with similar values are thought to be mainly venous.. · A validated statistical model was used to predict the probability an arterial or venous source.. · CAV-UBGs with very similar values and pH >  7.19 are likely venous; however, those with pH ≤ 7.19 and/or pCO2 >  8.2 kPa and/or pO2 ≤1.9 kPa are more likely arterial.., Competing Interests: D.M. has no potential conflicts of interest. R.L.S. is the President of Grand Rounds Software, LLC; the company has no financial interest in this study. Dr. Stavis is also a consultant in a medicolegal case that involves, among other issues, the identification of the source of an umbilical cord blood gas. His compensation as a consultant is entirely independent of this study., (Thieme. All rights reserved.)

Background: Cholestasis commonly occurs after orthotopic liver transplantation. It can be extrahepatic because of mechanical obstruction or intrahepatic because of various causes. During cholestasis episodes, blood concentrations of tacrolimus (TAC) metabolites may increase, potentially affecting TAC concentrations measured by immunoassays. This study aimed to simultaneously evaluate the analytical performance of 2 TAC immunoassays, a quantitative microsphere system (QMS) immunoassay, and chemiluminescence microparticle immunoassay, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a reference method in liver transplant recipients., Methods: This single-center study included 265 patients who underwent orthotopic liver transplantation. In total, 942 blood samples were collected. TAC trough concentrations were measured using LC-MS/MS and 2 immunoassays in parallel. The plasma concentrations of conjugated bilirubin were measured in all samples. The results were analyzed using Bland-Altman plots and Passing-Bablok regressions., Results: The Bland-Altman plot analysis showed that the TAC QMS immunoassay has a significant bias (+37%) compared with LC-MS/MS, and this bias was higher in patients with cholestasis with hyperbilirubinemia (≤+70% in patients with conjugated bilirubin >150 µmol/L). In comparison, the chemiluminescence microparticle immunoassay showed acceptable analytical performance in patients with hyperbilirubinemia (bias <10%)., Conclusions: In agreement with previous findings, the TAC QMS immunoassay showed a positive bias compared with LC-MS/MS. This bias is remarkably high in patients with cholestasis and hyperbilirubinemia, suggesting the cross-reactivity of TAC metabolites with the monoclonal antibody used in the QMS immunoassay., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We investigate the etiology of amyotrophic lateral sclerosis (ALS) in a 35-year-old woman presenting with progressive weakness in her left upper limb. Prior to sequencing, a comprehensive neurological work-up was performed, including neurological examination, electrophysiology, biomarker assessment, and brain and spinal cord MRI. Six months before evaluation, the patient experienced weakness and atrophy in her left hand, accompanied by brisk reflexes and Hoffman sign in the same arm. Electroneuromyography revealed lower motor neuron involvement in three body regions. Neurofilament light chains were elevated in her cerebrospinal fluid. Brain imaging showed asymmetrical T2 hyperintensity of the corticospinal tracts and T2 linear hypointensity of the precentral gyri. Trio genome sequencing identified a likely pathogenic de novo variant in the KIF1A gene (NM&#95;001244008.2): c.574A>G, p.(Ile192Val). Pathogenic variants in KIF1A have been associated with a wide range of neurological manifestations called KIF1A-associated neurological diseases (KAND). This report describes a likely pathogenic de novo variant in KIF1A associated with ALS, expanding the phenotypic spectrum of KAND and our understanding of the pathophysiology of ALS.

KRAS gain-of-function mutations are frequently observed in sporadic arteriovenous malformations. The mechanisms underlying the progression of such KRAS -driven malformations are still incompletely understood, and no treatments for the condition are approved. Here, we show the effectiveness of sotorasib, a specific KRAS G12C inhibitor, in reducing the volume of vascular malformations and improving survival in two mouse models carrying a mosaic Kras G12C mutation. We then administered sotorasib to two adult patients with severe KRAS G12C-related arteriovenous malformations. Both patients had rapid reductions in symptoms and arteriovenous malformation size. Targeting KRAS G12C appears to be a promising therapeutic approach for patients with KRAS G12C-related vascular malformations. (Funded by the European Research Council and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Determining the cause of hypoglycemia partly relies on blood insulin and C-peptide assays. Although the pancreatic secretion of these peptides is equimolar, discrepancies in their concentrations may occur., Case Presentation: We report the case of a 73-year-old woman with type 2 diabetes mellitus (T2DM) and a history of gastric bypass. The T2DM was initially treated with insulin analogs, which were interrupted due to transient hypoglycemia episodes three years before hospitalization in our endocrinology department. During this hospitalization, the most common etiologies of hypoglycemia were excluded. Fasting insulin level was high (190 mIU/L, reference values (RV): 5-25) on Architect i2000 (an assay recognizing insulin analogs) despite normal blood C-peptide (4.5 μg/L, RV: 0.8-5.2) and slight hypoglycemia (4.5 mmol/L, RV: 4.6-6.1). Insulin level using the Elecsys assay (an assay with low sensitivity to insulin analogs) was very high (>1000 mIU/L, RV: 2.6-24.9). This pattern was observed on several samples, including some taken during a fasting test. Insulin level was only slightly increased using the Mercodia iso-insulin ELISA kit (an assay recognizing insulin analogs). These results excluded an exogenous insulin intake and were suggestive of an interference on insulin assays. To explore the latter possibility, free anti-insulin antibodies were measured and found strongly positive. The presence of interfering insulin-antibody complexes was further investigated using gel filtration chromatography, polyethylene glycol precipitation, and dilution test. Based on these findings, an insulin autoimmune syndrome (IAS) was suspected to cause the hypoglycemic episodes observed., Conclusion: Although a discrepancy between blood insulin and C-peptide levels points to insulin analog intake, IAS should also be considered, particularly in a patient with transient hypoglycemia. IAS is characterized by the presence of insulin-antibody complexes, which can induce varying degrees of interference on insulin immunoassays and may lead to discordant insulin and C-peptide levels according to the insulin immunoassay used., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Sudden Unexplained Death in Childhood (SUDC) needs to be fully assessed considering its impact on the family, parents and siblings. Inborn Errors of Metabolism (IEM) such as Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) should be taken into consideration when SUDC occurres. Our aim is to present a family with two successive SUDC and to discuss the post-mortem genetics investigations revealing an IEM implication., Cases Report: A complete autopsy with genetic testing was performed when the proband, a 4-year-old girl, died. A few years previously, her older brother had died at the same age and off the same condition. Years later, his exhumation was necessary in order to perform a post-mortem diagnosis.The two siblings were revealed to have had the same pathogenic genotype of the ACADM gene, heterozygous substitutions in ACADM (NM&#95;000016.5): c.985 A>G p.(Lys329Glu) and c.347 G>A p.(Cys116Tyr). In addition, they also both carried a VUS in TECRL, a gene implicated in Catecholaminergic Polymorphic Tachycardia Ventricular (CPVT) and SUDC., Conclusion: We illustrate the importance of exome analyses for investigating unexplained sudden death, especially in children, with the possible impact for genetic counselling in the family. The finding of the implication of ACADM gene in this case, raises likely responsibility of the public health system in countries such as France, who delayed implementation of new born screening for these conditions. Exome analyses in this case detected unexpected complexity in interpretation linked to the identification of a second candidate gene for SUDC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Selenium is an essential trace element in our diet, crucial for the composition of human selenoproteins, which include 25 genes such as glutathione peroxidases and thioredoxin reductases. The regulation of the selenoproteome primarily hinges on the bioavailability of selenium, either from dietary sources or cell culture media. This selenium-dependent control follows a specific hierarchy, with "housekeeping" selenoproteins maintaining constant expression while "stress-regulated" counterparts respond to selenium level fluctuations. This study investigates the variability in fetal bovine serum (FBS) selenium concentrations among commercial batches and its effects on the expression of specific stress-related cellular selenoproteins. Despite the limitations of our study, which exclusively used HEK293 cells and focused on a subset of selenoproteins, our findings highlight the substantial impact of serum selenium levels on selenoprotein expression, particularly for GPX1 and GPX4. The luciferase reporter assay emerged as a sensitive and precise method for evaluating selenium levels in cell culture environments. While not exhaustive, this analysis provides valuable insights into selenium-mediated selenoprotein regulation, emphasizing the importance of serum composition in cellular responses and offering guidance for researchers in the selenoprotein field.

Context: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear., Objective: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients., Design: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment., Patients: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database., Results: From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis., Conclusion: The prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear-encoded genes., Methods: Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear-encoded genes., Results: The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases., Interpretation: We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with "possible" PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology., (© 2024 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of The New York Academy of Sciences.)

Background and Aims: Pathogenic variants in the NARS1 gene, which encodes for the asparaginyl-tRNA synthetase1 (NARS1) enzyme, were associated with complex central and peripheral nervous system phenotypes. Recently, Charcot-Marie-Tooth (CMT) disease has been linked to heterozygous pathogenic variants in NARS1 in nine patients. Here, we report two brothers and their mother from a French family with distal hereditary motor neuropathy (dHMN) carrying a previously unreported NARS1 variant., Methods: The NARS1 variant (c.1555G>C; p.(Gly519Arg)) was identified through whole-genome sequencing (WGS) performed on the family members. Clinical findings, nerve conduction studies (NCS), needle electromyography (EMG), and functional assays in yeast complementation assays are reported here., Results: The family members showed symptoms of dHMN, including distal weakness and osteoarticular deformities. They also exhibited brisk reflexes suggestive of upper motor neuron involvement. All patients were able to walk independently at the last follow-up. NCS and EMG confirmed pure motor neuropathy. Functional assays in yeast confirmed a loss-of-function effect of the variant on NARS1 activity., Interpretation: Our findings expand the clinical spectrum of NARS1-associated neuropathies, highlighting the association of NARS1 mutations with dHMN. The benign disease course observed in our patients suggests a slowly progressive phenotype. Further reports could contribute to a more comprehensive understanding of the spectrum of NARS1-associated neuropathies., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

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&#95;006415.4:c.998A>G and NM&#95;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.

Study Question: Is the 24-h urinary gonadotropin assay an effective diagnostic tool in central precocious puberty (CPP) in girls?, Summary Answer: This study is the first to provide 24-h urinary gonadotropin assay data, using an electrochemiluminescent immunoassay (CMIA), and to report its usefulness as a tool for the diagnosis of CPP., What Is Known Already: Data about the GnRH test in the diagnosis of CPP are variable and there is no consensus regarding its interpretation. The measurement of FSH and LH in urines was previously reported to be an alternative biological tool., Study Design, Size, Duration: This is a retrospective two-cohort study, involving a setting and a validation cohort. A total of 516 girls, included between October 2012 and July 2015, and 632 urinary collections were analyzed in the setting cohort. In the validation cohort, 39 girls were included between January 2021 and May 2023, and 49 urinary collections were analyzed., Participants/materials, Setting, Methods: This study included girls who consulted for an investigation of disturbed growth rate or a clinical suspicion of puberty onset in different medical centres across France (setting cohort). Girls with a suspicion of precocious puberty onset were addressed at the expert centre of paediatric endocrinology of the Groupement Hospitalier Lyon Est (validation cohort). Pelvic ultrasonography was performed and enabled their classification according to clinical and morphologic changes criteria (prepubertal or pubertal groups). The parents collected 24-h urine samples (u24) according to standardized instructions. FSH and LH (urinary or plasmatic) were measured using a current and automated CMIA., Main Results and the Role of Chance: The area under the ROC curves for CPP prediction was 0.709 for u24FSH (P < 0.001), 0.767 for u24LH (P < 0.001), and 0.753 for the u24LH/u24FSH ratio (P < 0.001). We retained all possible combinations of the four thresholds in the validation cohort (u24FSH = 1.1 or 2.0 IU/24 h; u24LH = 0.035 or 0.08 IU/24 h). The combination of u24FSH > 1.1 IU/24 h and u24LH > 0.08 IU/24 h had a positive PV of 85.7% and a negative PV of 94.3%, a sensitivity of 85.7% and a specificity of 94.3%, for classifying prepubertal and pubertal girls in this cohort., Limitations, Reasons for Caution: This is a retrospective study, in which a margin of error remains due to the inherent uncertainty regarding the clinical assessment of pubertal onset. It must be considered that the thresholds can only apply to the used reagents; measurements without extractions using other reagents are likely to show important heterogeneity., Wider Implications of the Findings: The assay performed herein is a simple, non-invasive, and analytically robust technique meeting the criteria for an alternative to the GnRH test which could be used to supplement its lack of sensitivity., Study Funding/competing Interest(s): No specific funding was used. All authors declared no conflict of interest., Trial Registration Number: In-house #23-5214 registered study., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

The major gene underlying monogenic forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) is C9ORF72. The causative mutation in C9ORF72 is an abnormal hexanucleotide (G4C2) repeat expansion (HRE) located in the first intron of the gene. The aim of this review is to propose a comprehensive update on recent developments on clinical, biological and therapeutics aspects related to C9ORF72 in order to highlight the current understanding of genotype-phenotype correlations, and also on biological machinery leading to neuronal death. We will particularly focus on the broad phenotypic presentation of C9ORF72-related diseases, that goes well beyond the classical phenotypes observed in ALS and FTD patients. Last, we will comment the possible therapeutical hopes for patients carrying a C9ORF72 HRE., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: McArdle disease, or glycogen storage disease type V (GSD 5), is a rare metabolic myopathy linked to an autosomal recessive myophosphorylase deficiency., Case Report: We report the case of a 17-year-old male patient who was referred to the emergency department for the management of acute inflammatory low back pain, without traumatic context, associated with an increase of CK at 66,336 UI/L (N<192UI/L) and a CRP at 202mg/L. The immunological assessment was negative and the spinal MRI showed images in favor of necrotizing fasciitis affecting the erector spinae muscles, among others. Faced with the description of difficulties in practicing physical activities since childhood and a non-ischaemic forearm exercise test showing no elevation in lactacidemia, genetic tests were carried out, finding two heterozygous variants in the PYGM gene: c.1963G>A (p.Glu655Lys) class 5 and c.2178-1G>A class 4, confirming the diagnosis of McArdle disease., Discussion: GSD 5 is a disease characterized essentially by muscular fatigability during exercise. The case reported here is original in the clinical circumstances leading to the diagnosis, i.e., inaugural acute low back pain with rhabdomyolysis. This symptomatology had already been described before, but in a patient whose diagnosis was already known. Spinal MRI showed non-specific muscle inflammation and necrosis. Muscle biopsy only found necrosis but no pathological elements typical of the diagnosis. If the symptoms are suggestive, it may be preferable to directly perform a non-ischaemic forearm exercise test, in order to go directly to molecular genetic analysis. There is no specific curative treatment of GSD 5. However, some measures can be implemented to limit the symptoms, such as learning physical exercises, limiting intense efforts and adopting dietary recommendations., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Glioblastoma is a highly heterogeneous and infiltrative form of brain cancer associated with a poor outcome and limited therapeutic effectiveness. The extent of the surgery is related to survival. Reaching an accurate diagnosis and prognosis assessment by the time of the initial surgery is therefore paramount in the management of glioblastoma. To this end, we are studying the performance of SpiderMass, an ambient ionization mass spectrometry technology that can be used in vivo without invasiveness, coupled to our recently established artificial intelligence pipeline. We demonstrate that we can both stratify isocitrate dehydrogenase (IDH)-wild-type glioblastoma patients into molecular sub-groups and achieve an accurate diagnosis with over 90% accuracy after cross-validation. Interestingly, the developed method offers the same accuracy for prognosis. In addition, we are testing the potential of an immunoscoring strategy based on SpiderMass fingerprints, showing the association between prognosis and immune cell infiltration, to predict patient outcome., Competing Interests: Declaration of interests É.L.R. has received grant research from Bristol Meyer Squibb and honoraria for lectures or advisory board from Bayer, Janssen, Leo Pharma, Pierre Fabre, Roche, Seattle Genetics, and Servier. M.S. and I.F. are inventors on a patent (priority number WO2015IB57301 20150922) related to part of the described protocol. D.Y., K.J.R., and M.J.L. are current employees of AmberGen, Inc., 44 Manning Road, Billerica, MA, USA. AmberGen, Inc., has filed patent applications on different aspects of MALDI-IHC., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Primary hyperoxalurias (PH) are extremely rare genetic disorders characterized by clinical heterogeneity. Delay in diagnosing these conditions can have detrimental effects on patient outcomes. The primary objective of this study is to assess the current diagnostic delay for PH., Methods: This nationwide, observational and retrospective study included patients who received a genetic diagnosis of PH types 1, 2 and 3 between 1 January 2015 and 31 December 2019. Diagnostic delay was defined as the duration between the onset of symptoms and the time of genetic diagnosis., Results: A total of 52 patients (34 children and 18 adults) were included in the study, with 40 PH1 (77%), 3 PH2 (6%) and 9 PH3 (17%). At the time of diagnosis, 12 patients (23%) required dialysis. Among the PH1 patients, the predominant symptom at onset in adults was renal colic (79% of cases), whereas symptoms in children were more diverse (renal colic in 17% of cases). The diagnostic delay was significantly shorter in children compared with adults [median (interquartile range)]: 1.2 (0.1-3.0) versus 30 (17-36) years, respectively ( P  < .0001). RNA interference was utilized in 23 patients (58%). Five individuals (13%) underwent double liver-kidney transplantation, and five (13%) received isolated kidney transplantation, with lumasiran therapy in four patients. For PH2 and PH3 patients, the diagnostic delay ranges from 0 to 3 years, with renal colic as first symptom in 33% of cases., Conclusion: This extensive and recent cohort of PH underscores the considerable delay in diagnosing PH, particularly in adults, even in a country with a dedicated organization for enhancing the overall management of rare diseases. These findings reinforce the imperative for increased awareness among relevant specialties regarding the evaluation of urolithiasis., Competing Interests: R.P. received funding from Alnylam Pharmaceuticals to attend a national nephrology congress. C.A. received consulting fees for Alnylam and Novonordisk. N.B. received help for medical writing from Alnylam. S.B. received fees from AstraZeneca, Lilly, CSL Vifor, Bayer and IKI. I.B., K.C., C.D., M.G., F.H. and C.R.-R. declare no conflict of interest. E.L. patented Stiripentol to reduce urine oxalate excretion (WO2017140658A1) and received consulting fees from Biocodex Laboratory. J.B. received travel, consulting and speaker fees from Alnylam Pharmaceuticals, and consulting fees from Dicenra/Novonordisk Pharmaceuticals and Biocodex Pharmaceuticals. B.M. received consulting, travel and speaker fees from Alnylam Pharmaceuticals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: The von Hippel-Lindau (VHL) disease is a hereditary tumour syndrome caused by germline mutations in VHL tumour suppressor gene. The identification of VHL variants requires accurate classification which has an impact on patient management and genetic counselling., Methods: The TENGEN (French oncogenetics network of neuroendocrine tumors) and PREDIR (French National Cancer Institute network for Inherited predispositions to kidney cancer) networks have collected VHL genetic variants and clinical characteristics of all VHL-suspected patients analysed from 2003 to 2021 by one of the nine laboratories performing VHL genetic testing in France. Identified variants were registered in a locus-specific database, the Universal Mutation Database-VHL database (http://www.umd.be/VHL/)., Results: Here we report the expert classification of 164 variants, including all missense variants (n=124), all difficult interpretation variants (n=40) and their associated phenotypes. After initial American College of Medical Genetics classification, first-round classification was performed by the VHL expert group followed by a second round for discordant and ambiguous cases. Overall, the VHL experts modified the classification of 87 variants including 30 variants of uncertain significance that were as (likely)pathogenic variants for 19, and as likely benign for 11., Conclusion: Consequently, this work has allowed the diagnosis and influenced the genetic counselling of 45 VHL-suspected families and can benefit to the worldwide VHL community, through this review., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity., Methods: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC)., Results: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants., Conclusions: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Amyotrophic Lateral Sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. The pathophysiology of ALS is not well understood but TDP-43 proteinopathy (aggregation and mislocalization) is one of the major phenomena described. Several factors can influence TDP-43 behavior such as mild pH alterations that can induce conformational changes in recombinant TDP-43, increasing its propensity to aggregate. However to our knowledge, no studies have been conducted yet in a cellular setting, in the context of ALS. We therefore tested the effect of cellular pH alterations on the localization, aggregation, and phosphorylation of TDP-43. HEK293T cells overexpressing wildtype TDP-43 were incubated for 1 h with solutions of different pH (6.4, 7.2, and 8). Incubation of cells for 1 h in solutions of pH 6.4 and 8 led to an increase in TDP-43-positive puncta. This was accompanied by the mislocalization of TDP-43 from the nucleus to the cytoplasm. Our results suggest that small alterations in cellular pH affect TDP-43 and increase its mislocalization into cytoplasmic TDP-43-positive puncta, which might suggest a role of TDP-43 in the response of cells to pH alterations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objectives: The storage of serum tumor markers (STM) at -18 °C for one year has been a legal requirement in France since 1999, but has been abolished in 2022. This raises the question of the relevance of maintaining these biobanks in terms of conditions of storage. These should only be implemented after validation; in order to maintain the integrity of the biological sample and must be controlled over time according to the laboratory's procedures. The aim of the study was to assess the suitability of storing 10 STMs by evaluating their stability after one year of storage at -18 °C., Methods: A new immuno-enzymatic assay (A+1) was conducted on samples that had been stored at -18 °C for one year after an initial assay (A) of one of the following STMs: carcino-embryonic antigen (CEA), alpha-fetoprotein (AFP), carbohydrate antigen 125 (CA125), carbohydrate antigen 15-3 (CA15-3), carbohydrate antigen 19-9 (CA19-9), total (TPSA), and free (FPSA) prostate-specific antigen, calcitonin (CT), thyroglobulin (TG), and neuro-specific enolase (NSE). The results were confronted to four different permissible error sources., Results: In total, 1148 A+1 assays were performed. A strong correlation between A+1 and A values was found for all analytes, but with a statistically significant reduction in the mean A+1 concentration compared to the mean A concentration in 7/10 STMs. The bias induced by conservation seems to be technically unsustainable if we rely on the repositories closest to the current analytical performances., Conclusions: These results support the discontinuation of mandatory STM biobank storage at -18 °C, which requires considerable technical time and organizational effort., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Aldosterone synthase deficiency (ASD) is a rare autosomal recessive disorder involving isolated aldosterone deficiency without any compromise of other adrenal hormones. This condition manifests mainly in the neonatal period and in infants as a salt wasting syndrome with vomiting and failure to thrive. Due to its potentially life-threatening effects, ASD requires a careful and early diagnosis based on appropriate hormonal investigations in order to initiate adequate management: rehydration as well as salt and fludrocortisone supplementation. Genetic analysis of the CYP11B2 gene will confirm ASD in most cases. We report the case of a newborn with a typical clinical presentation associated with some uncommon phenotypic features (hyperhidrosis, liver injury). Furthermore, our patient carries a new CYP11B2 splicing variant to be added to the approximately 60 pathogenic or likely pathogenic variants already reported., Competing Interests: Declaration of Competing Interest No support has been received from any source, and there are no potential conflicts of interest to disclose in this case report., (Copyright © 2023. Published by Elsevier Masson SAS.)

Sodium dependent multivitamin transporter (SMVT) deficiency is a very rare autosomal recessive disorder characterized by multisystemic clinical manifestations due to combined biotin, panthotenic acid and lipoic acid deficiency. About 10 families have been described so far. Accurate diagnosis is crucial because of the possibility of a supplementation treatment with proven efficacy. Here we describe 4 new patients (3 additional families) originating from the same world region (Algeria, Maghreb). All patients, born form consanguineous parents, were homozygous carriers of the same intronic variation, outside of canonical sites, in the SLC5A6 gene encoding SMVT. RNA study in one family allowed confirming the pathogenic effect of the variation and re-classifying this variant of uncertain significance as pathogenic, opening the possibility of genetic counseling and treatment. The identification of the same variation in three distinct and apparently unrelated families is suggestive of a founder effect. The phenotype of all patients was very similar, with systematic optic atrophy (initially considered as a very rare sign), severe cyclic vomiting, and rapidly progressive mixed axonal and demyelinating sensory motor neuropathy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mansour-Hendili, Gitiaux, Harion, Latouche, Heron, Stojkovic, Rama, Smol, Sophie Jourdain, Mention, Nadjar, Schiff, Lemale, Ghoumid, Gottrand, Talbotec, Rötig, Funalot and Desguerre.)

Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) is a major cause of complications and death. Here, we set out to identify high-performance predictive biomarkers of DCI and its underlying metabolic disruptions using metabolomics and lipidomics approaches. This single-center prospective observational study enrolled 61 consecutive patients with severe aSAH; among them, 22 experienced a DCI. Nine patients without aSAH were included as validation controls. Blood and cerebrospinal fluid (CSF) were sampled within the first 24 h after admission. We identified a panel of 20 metabolites that, together, showed high predictive performance for DCI. This panel of metabolites included lactate, cotinine, salicylate, 6 phosphatidylcholines, and 4 sphingomyelins. The interplay of the metabolome and the lipidome found between CSF and plasma in our patients underscores that aSAH and its associated DCI complications can extend beyond cerebral implications, with a peripheral dimension as well. As an illustration, early biological disruptions that might explain the subsequent DCI found systemic hypoxia driven mainly by higher blood lactate, arginine, and proline metabolism likely associated with vascular NO and disrupted ceramide/sphingolipid metabolism. We conclude that targeting early peripheral hypoxia preceding DCI could provide an interesting strategy for the prevention of vascular dysfunction.

Background: Major depression is associated with changes in plasma L-carnitine and acetyl-L-carnitine. But its association with acylcarnitines remains unclear. The aim of this study was to assess metabolomic profiles of 38 acylcarnitines in patients with major depression before and after treatment compared to healthy controls (HCs)., Methods: Metabolomic profiles of 38 plasma short-, medium-, and long-chain acylcarnitines were performed by liquid chromatography-mass spectrometry in 893 HCs from the VARIETE cohort and 460 depressed patients from the METADAP cohort before and after 6 months of antidepressant treatment., Results: As compared to HCs, depressed patients had lower levels of medium- and long-chain acylcarnitines. After 6 months of treatment, increased levels of medium- and long-chain acyl-carnitines were observed that no longer differed from those of controls. Accordingly, several medium- and long-chain acylcarnitines were negatively correlated with depression severity., Conclusions: These medium- and long-chain acylcarnitine dysregulations argue for mitochondrial dysfunction through fatty acid β -oxidation impairment during major depression.

Aims: Dolutegravir (DTG) and rilpivirine (RPV) dual therapy is now recommended as a switch option in virologically suppressed HIV patients. Literature suggests that virological failure with dual therapy could possibly relate to subtherapeutic drug concentrations. In this study, we aimed at describing the DTG and RPV trough plasma concentrations (Cmin) and plasma HIV-1 RNA viral load (VL) during maintenance dual therapy., Methods: We performed a retrospective analysis of DTG and RPV therapeutic drug monitoring in people living with HIV/AIDS (PLWHA) with dual therapy in 9 French centres. DTG and RPV trough plasma concentrations were estimated using a Bayesian approach to predict Cmin. The relationship between the pharmacokinetics of DTG and RPV and VL > 50 copies (cp)/mL was explored using joint nonlinear mixed models. The frequency of subtherapeutic threshold (DTG Cmin below 640 ng/mL and RPV Cmin below 50 ng/mL) were compared between PLWHA presenting VL > 50 cp/mL or not during the study., Results: At baseline, 209 PLWHA were enrolled in the study. At week 48, 19 people living with HIV/AIDS (9.1%) discontinued their treatment and 15 PLWHA (7.1%) exhibited VL > 50 cp/mL. Six PLWHA out of 15 (40.0%) with VL > 50 cp/mL during the follow-up had at least 1 Cmin below the respective thresholds while only 26/194 patients (13.4%) without virological replication had at least 1 concentration below the threshold (P = .015)., Conclusion: A majority of PLWHA receiving DTG/RPV maintenance dual therapy demonstrated VL < 50 cp/mL but virological replication was more frequent in people living with HIV/AIDS with subtherapeutic Cmin., (© 2023 The British Pharmacological Society.)

Fukutin-related protein (FKRP) mutations cause a broad spectrum of muscular dystrophies, from a relatively mild limb-girdle muscular dystrophy type 9 (LGMDR9) to severe congenital muscular dystrophy (CMD). This study aims to report two siblings belonging to a non-consanguineous Tunisian family harboring a novel compound heterozygous FKRP variant and presenting a mild LGDMR9 phenotype. For mutation screening, massive parallel sequencing was performed, followed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to validate the existence of the discovered variants. The absence of alpha-dystroglycan was determined by immunohistochemistry. Brain and thigh magnetic resonance imaging (MRI) were performed to detect thigh and brain abnormalities. The two siblings had a late age at onset and clinical examination showed that the pelvic girdles had a predominantly proximal and symmetrical distribution of weakness without cardiac or respiratory involvement. They both had a modified Gardner-Medwin Walton Scale mGMWS grade of 4 and a modified Rankin Scale (mRS) score of 1. The DNA sequencing revealed a novel deletion of exons 2 and 3 in one allele and a missense mutation c.1364C > A, which has been reported to be responsible for congenital muscular dystrophy and mental retardation on the second allele. The simultaneous presence of the two variations in the two cases suggests that the variants segregate with the pathophysiology., Competing Interests: The authors declare that they have no conflicts of interest., (©2023 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

Introduction: Patients with short bowel syndrome (SBS) may exhibit enteric hyperoxaluria (EH), and the prevalence of oxalate nephropathy in SBS is likely underestimated. Plasma oxalate (POx) is a surrogate of systemic oxalate deposition and, consequently, may increase the risk of developing chronic kidney disease (CKD). The main objective of this study was to explore the distribution of POx levels in patients with SBS., Methods: Patients followed for SBS were recruited prospectively in the OXAGO study (NCT04119765) to assess POx during their annual renal follow-up including iohexol clearance. The inclusion criteria were age ≥18 years, and SBS type 2 and type 3 for more than 6 months., Results: A total of 47 patients were included but only 45 patients has a measured POx (55% males, 80% SBS type 2, 66% parenteral nutrition, 61% kidney stone history). POx levels were 6.8 ± 4.4 μmol/l, 29% of patients had POx ≥5 μmol/l. In the whole cohort, mean urinary oxalate (UOx) was 648±415 and 54% were >500 μmol/24h. In the group of patients with high POx levels (HPO), 24-hour urine oxalate was significantly higher than in the group with normal POx levels (NPO) (919 ± 566 vs. 526 ± 257 μmol/l; P  = 0.003). Glomerular filtration rate (GFR) was 66 ± 22 ml/min per 1.73 m 2 , and 91% had CKD. GFR was significantly lower in the HPO than in the NPO group (49 ± 23 vs. 73 ± 18 ml/min per 1.73 m 2 ; P  = 0.0005., Conclusion: Patients with SBS can display increased POx levels even with GFR >30 ml/min per 1.73 m 2 . POx may be an interesting biomarker to assess the severity of EH., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Hyperserotonemia is the most replicated biochemical anomaly associated with autism spectrum disorder (ASD) and has been reported in 35-46% of individuals with ASD. Serotonin is synthesised from the essential amino acid tryptophan (TRP). However, the main catabolic route of TRP is the kynurenine pathway (KP), which competes with serotonin synthesis when indoleamine dioxygenase (IDO) is activated. Using the same cohort of individuals with ASD, we used to report extensive studies of the serotonin/melatonin pathway, and found increased kynurenine (KYN), suggesting IDO activation in 58.7% of individuals with ASD (159/271), supported by a strong negative correlation between KYN/TRP ratio and miR-153-3p plasma levels, which negatively regulates IDO. IDO activation was associated with normoserotonemia, suggesting that IDO activation could mask hyperserotonemia which meant that hyperserotonemia, if not masked by IDO activation, could be present in ~94% of individuals with ASD. We also identified several KP alterations, independent of IDO status. We observed a decrease in the activity of 3-hydroxyanthranilate dioxygenase which translated into the accumulation of the aryl hydrocarbon receptor (AhR) selective ligand cinnabarinic acid, itself strongly positively correlated with the AhR target stanniocalcin 2. We also found a deficit in NAD + production, the end-product of the KP, which was strongly correlated with plasma levels of oxytocin used as a stereotypical neuropeptide, indicating that regulated neuropeptide secretion could be limiting. These results strongly suggest that individuals with ASD exhibit low-grade chronic inflammation that is mediated in most cases by chronic AhR activation that could be associated with the highly prevalent gastrointestinal disorders observed in ASD, and explained IDO activation in ~58% of the cases. Taken together, these results extend biochemical anomalies of TRP catabolism to KP and posit TRP catabolism as a possible major component of ASD pathophysiology., (© 2023. The Author(s).)

Sickle cell disease (SCD) is an hereditary disorder characterized by the production of an abnormal hemoglobin called hemoglobin S (HbS). HbS may polymerize in deoxygenated conditions, which leads to red blood cell (RBC) sickling. Sickled RBCs are more rigid and fragile, and prone to lysis. SCD patients exhibit various acute and/or chronic complications, which may affect several organs. The clinical presentation of SCD is highly variable from one patient to another and cannot be only explained by RBC sickling. Increased blood viscosity, caused by the presence of RBCs with abnormal deformability and aggregation, may increase vascular resistance and increase the risk of acute and chronic vascular complications. Chronic hemolysis results in decreased nitric oxide (NO) bioavailability which may compromise vasodilation and participate to the development of chronic vasculopathy. Furthermore, chronic hemolysis is responsible for increased inflammation and oxidative stress, which affect the vascular system and may promote the adhesion of circulating cells to endothelial cells. Extracellular vesicles and especially RBC microparticles (massively released in the context of SCD) are also at the origin of vascular damages and increased white blood cells adhesion to the endothelium, which may trigger vaso-occlusive crisis and other vascular-related complications. This review highlights the fact that SCD should not only be considered as a hematological disorder but also as a vascular disease., Competing Interests: Declaration of Competing Interest The authors have not supplied their declaration of competing interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

NEW DEVELOPMENTS IN NEONATAL SCREENING. The French national newborn screening program (NBS) celebrated its 50th anniversary in 2022. A few drops of blood are drawn between 48 and 72 hours of life for each newborn on a filter paper and entrusted to a Regional Center for Newborn Screening, which analyses it diligently. When the result is beyond a threshold, the baby and its parents are summoned to a specialized paediatric department. If the suspected disease is confirmed, specific care can be started in time to avoid or limit a disability. Each year, nearly 1.000 sick children are diagnosed by NBS in France, and treated in a specialized hospital team. The 2018 National Rare Disease Plan has relaunched the NBS process. Until then, 7 diseases whose hearing loss were detected. Since then, 7 other diseases have been added to the program, and others were recommended or are being assessed, opening a new page in the history of NBS in France., Competing Interests: D. Cheillan déclare des interventions ponctuelles pour Orchard Therapeutics. M. Polak, T. Nguyen-Khoa, S. Lachambre, P de Lonlay, A. Khemiri et S. Courapied déclarent n’avoir aucun lien d’intérêts. J.-B. Arnoux déclare des interventions ponctuelles pour Ultragenyx, Rezolute, Immedica et Biomarin, et avoir été pris en charge, à l’occasion de déplacement pour congrès, par Immedica et Biomarin.

Background: High-dose daptomycin is increasingly used in patients with bone and joint infection (BJI). This raises concerns about a higher risk of adverse events (AEs), including daptomycin-induced eosinophilic pneumonia (DIEP) and myotoxicity. We aimed to examine pharmacokinetic and other potential determinants of DIEP and myotoxicity in patients with BJI receiving daptomycin., Methods: All patients receiving daptomycin for BJI were identified in a prospective cohort study. Cases were matched at a 1:3 ratio, with controls randomly selected from the same cohort. Bayesian estimation of the daptomycin daily area under the concentration-time curve over 24 hours (AUC24h) was performed with the Monolix software based on therapeutic drug monitoring (TDM) data. Demographic and biological data were also collected. Risk factors of AEs were analyzed using Cox proportional hazards model., Results: From 1130 patients followed over 7 years, 9 with DIEP, 26 with myotoxicity, and 106 controls were included in the final analysis. Daptomycin AUC24h, C-reactive protein, and serum protein levels were associated with the risk of AEs. The adjusted hazard ratio of DIEP or myotoxicity was 3.1 (95% confidence interval [CI], 1.48-6.5; P < .001) for daptomycin AUC24h > 939 mg/h/L, 9.8 (95% CI, 3.94-24.5; P < .001) for C-reactive protein > 21.6 mg/L, and 2.4 (95% CI, 1.02-5.65; P = .04) for serum protein <72 g/L., Conclusions: We identified common determinants of DIEP and myotoxicity in patients with BJI. Because the risk of AEs was associated with daptomycin exposure, daptomycin TDM and model-informed precision dosing may help optimize the efficacy and safety of daptomycin treatment in this setting. A target AUC24h range of 666 to 939 mg/h/L is suggested., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Vancomycin dosing remains challenging in patients receiving intermittent hemodialysis, especially in developing countries, where access to therapeutic drug monitoring and model-based dose adjustment services is limited. The objectives of this study were to describe vancomycin population PK in patients receiving hemodialysis in a Malian and French center and examine the optimal loading dose of vancomycin in this setting., Methods: Population pharmacokinetic analysis was conducted using Pmetrics in 31 Malian and 27 French hemodialysis patients, having a total of 309 vancomycin plasma concentrations. Structural and covariate analyses were based on goodness-of-fit criteria. The final model was used to perform simulations of the vancomycin loading dose, targeting a daily area under the concentration-time curve (AUC) of 400-600 mg.h/L or trough concentration of 15-20 mg/L at 48 hours., Results: After 48 hours of therapy, 68% of Malian and 63% of French patients exhibited a daily AUC of <400. The final model was a 2-compartment model, with hemodialysis influencing vancomycin elimination and age influencing the vancomycin volume distribution. Younger Malian patients exhibited a lower distribution volume than French patients. Dosing simulation suggested that loading doses of 1500, 2000, and 2500 mg would be required to minimize underexposure in patients aged 30, 50, and 70 years, respectively., Conclusions: In this study, a low AUC was frequently observed in hemodialysis patients in Mali and France after a standard vancomycin loading dose. A larger dose is necessary to achieve the currently recommended AUC target. However, the proposed dosing algorithm requires further clinical evaluation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)