bims-meglyc 2023-02-05 papers

on Metabolic disorders affecting glycosylation

Issue of 2023‒02‒05
fifteen papers selected by
Silvia Radenkovic
Frontiers in Congenital Disorders of Glycosylation Consortium

Mass Spectrometry of Transferrin and Apolipoprotein CIII from Dried Blood Spots for Congenital Disorders of Glycosylation.
Elevated oxysterol and N-palmitoyl-O-phosphocholineserine levels in congenital disorders of glycosylation.
Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.
O-GlcNAc transferase modulates the cellular endocytosis machinery by controlling the formation of clathrin-coated pits.
Quantification of Dolichyl Phosphates Using Phosphate Methylation and Reverse-Phase Liquid Chromatography-High Resolution Mass Spectrometry.
Therapeutics in paediatric genetic diseases: Current and future landscape.
N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy.
AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase I deficiency (PGM1-CDG).
Nonhuman primate genetic models for the study of rare diseases.
Phosphomannomutase 2 hyperinsulinemia: Recent advances of genetic pathogenesis, diagnosis, and management.
Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets.
Human-specific features and developmental dynamics of the brain N-glycome.
Metformin induces mitochondrial fission and reduces energy metabolism by targeting respiratory chain complex I in hepatic stellate cells to reverse liver fibrosis.
Newly discovered roles of triosephosphate isomerase including functions within the nucleus.
Neurodevelopmental disorders (NDD) without boundaries: research and interventions beyond classifications.

Mass Spectrom (Tokyo). 2022 ;11(1): A0113

Mass Spectrometry of Transferrin and Apolipoprotein CIII from Dried Blood Spots for Congenital Disorders of Glycosylation.

Yoshinao Wada, Machiko Kadoya, Nobuhiko Okamoto.

  Dried blood spot (DBS) is the standard specimen for the newborn screening of inborn errors of metabolism (IEM) by tandem mass spectrometry. Availability of DBS for the mass spectrometric analysis of the diagnostic marker proteins, transferrin (Tf) and apolipoprotein CIII (apoCIII), of congenital disorders of glycosylation (CDG) was examined. Recovery of Tf from DBS was only slightly reduced compared with fresh serum. Although oxidation of the core polypeptides was observed, glycans of Tf and apoCIII were unaffected by storage of DBS in the ambient environment for at least 1 month. The combination of DBS and the triple quadrupole mass spectrometer used for IEM screening was sufficient to characterize the aberrant glycoprofiles of Tf and apoCIII in CDG. DBS or dried serum spot on filter paper can reduce the cost of sample transportation and potentially promote mass spectrometric screening of CDG.

Keywords:  apolipoprotein CIII; congenital disorders of glycosylation; dried blood spot; glycoform; transferrin

DOI:  https://doi.org/10.5702/massspectrometry.A0113
J Inherit Metab Dis. 2023 Jan 31.

Elevated oxysterol and N-palmitoyl-O-phosphocholineserine levels in congenital disorders of glycosylation.

An N Dang Do, Irene J Chang, Xutian Jiang, Lynne A Wolfe, Bobby G Ng, Christina Lam, Rhonda E Schnur, Katrina Allis, Hana Hansikova, Nina Ondruskova, Shawn D O'Connor, Amarilis Sanchez-Valle, Arve Vollo, Raymond Y Wang, Zoe Wolfenson, John Perreault, Daniel S Ory, Hudson H Freeze, J Lawrence Merritt, Forbes D Porter.

  Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.

Keywords:  ATP6AP1; N-palmitoyl-O-phosphocholineserine (PPCS); Niemann-pick type C (NPC); bile acids; congenital disorders of glycosylation (CDG); oxysterols

DOI:  https://doi.org/10.1002/jimd.12595
bioRxiv. 2023 Jan 11. pii: 2023.01.11.523512. [Epub ahead of print]

Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity.

Seungyoon B Yu, Richard G Sanchez, Zachary D Papich, Thomas C Whisenant, Majid Ghassemian, John N Koberstein, Melissa L Stewart, Gulcin Pekkurnaz.

Neuronal activity is an energy-intensive process that is largely sustained by instantaneous fuel utilization and ATP synthesis. However, how neurons couple ATP synthesis rate to fuel availability is largely unknown. Here, we demonstrate that the metabolic sensor enzyme O-GlcNAc transferase regulates neuronal activity-driven mitochondrial bioenergetics. We show that neuronal activity upregulates O-GlcNAcylation mainly in mitochondria. Mitochondrial O-GlcNAcylation is promoted by activity-driven fuel consumption, which allows neurons to compensate for high energy expenditure based on fuel availability. To determine the proteins that are responsible for these adjustments, we mapped the mitochondrial O-GlcNAcome of neurons. Finally, we determine that neurons fail to meet activity-driven metabolic demand when O-GlcNAcylation dynamics are prevented. Our findings suggest that O-GlcNAcylation provides a fuel-dependent feedforward control mechanism in neurons to optimize mitochondrial performance based on neuronal activity. This mechanism thereby couples neuronal metabolism to mitochondrial bioenergetics and plays a key role in sustaining energy homeostasis.

DOI: https://doi.org/10.1101/2023.01.11.523512
J Biol Chem. 2023 Jan 30. pii: S0021-9258(23)00095-9. [Epub ahead of print] 102963

O-GlcNAc transferase modulates the cellular endocytosis machinery by controlling the formation of clathrin-coated pits.

Sadia Rahmani, Hafsa Ahmed, Osemudiamen Ibazebo, Eden Fussner-Dupas, Warren W Wakarchuk, Costin N Antonescu.

Clathrin-mediated endocytosis (CME) controls the internalization and function of a wide range of cell surface proteins. CME occurs by the assembly of clathrin and many other proteins on the inner leaflet of the plasma membrane into clathrin-coated pits (CCPs). These structures recruit specific cargo destined for internalization, generate membrane curvature, and in many cases undergo scission from the plasma membrane to yield intracellular vesicles. The diversity of functions of cell surface proteins controlled via internalization by CME may suggest that regulation of CCP formation could be effective to allow cellular adaptation under different contexts. Of interest is how cues derived from cellular metabolism may regulate CME, given the reciprocal role of CME in controlling cellular metabolism. The modification of proteins with O-linked β-N-acetylglucosamine (O-GlcNAc) is sensitive to nutrient availability and may allow cellular adaptation to different metabolic conditions. Here, we examined how the modification of proteins with O-GlcNAc may control CCP formation and thus CME. We used perturbation of key enzymes responsible for protein O-GlcNAc modification, as well as specific mutants of the endocytic regulator AAK1 predicted to be impaired for O-GlcNAc modification. We identify that CCP initiation and the assembly of clathrin and other proteins within CCPs are controlled by O-GlcNAc protein modification. This reveals a new dimension of regulation of CME and highlights the important reciprocal regulation of cellular metabolism and endocytosis.

DOI: https://doi.org/10.1016/j.jbc.2023.102963
Anal Chem. 2023 Jan 30.

Quantification of Dolichyl Phosphates Using Phosphate Methylation and Reverse-Phase Liquid Chromatography-High Resolution Mass Spectrometry.

Dipali Kale, Frauke Kikul, Prasad Phapale, Lars Beedgen, Christian Thiel, Britta Brügger.

Dolichyl monophosphates (DolPs) are essential lipids in glycosylation pathways that are highly conserved across almost all domains of life. The availability of DolP is critical for all glycosylation processes, as these lipids serve as membrane-anchored building blocks used by various types of glycosyltransferases to generate complex post-translational modifications of proteins and lipids. The analysis of DolP species by reverse-phase liquid chromatography-mass spectrometry (RPLC-MS) remains a challenge due to their very low abundance and wide range of lipophilicities. Until now, a method for the simultaneous qualitative and quantitative assessment of DolP species from biological membranes has been lacking. Here, we describe a novel approach based on simple sample preparation, rapid and efficient trimethylsilyl diazomethane-dependent phosphate methylation, and RPLC-MS analysis for quantification of DolP species with different isoprene chain lengths. We used this workflow to selectively quantify DolP species from lipid extracts derived of Saccharomyces cerevisiae, HeLa, and human skin fibroblasts from steroid 5-α-reductase 3- congenital disorders of glycosylation (SRD5A3-CDG) patients and healthy controls. Integration of this workflow with global lipidomics analyses will be a powerful tool to expand our understanding of the role of DolPs in pathophysiological alterations of metabolic pathways downstream of HMG-CoA reductase, associated with CDGs, hypercholesterolemia, neurodegeneration, and cancer.

DOI: https://doi.org/10.1021/acs.analchem.2c03623
Singapore Med J. 2023 Jan;64(1): 7-16

Therapeutics in paediatric genetic diseases: Current and future landscape.

Ai Ling Koh, Saumya Shekhar Jamuar.

  There are more than 7,000 paediatric genetic diseases (PGDs) but less than 5% have treatment options. Treatment strategies targeting different levels of the biological process of the disease have led to optimal health outcomes in a subset of patients with PGDs, where treatment is available. In the past 3 decades, there has been rapid advancement in the development of novel therapies, including gene therapy, for many PGDs. The therapeutic success of treatment relies heavily on knowledge of the genetic basis and the disease mechanism. Specifically, gene therapy has been shown to be effective in various clinical trials, and indeed, these trials have led to regulatory approvals, paving the way for gene therapies for other types of PGDs. In this review, we provide an overview of the treatment strategies and focus on some of the recent advancements in therapeutics for PGDs.

Keywords:  Antisense oligonucleotide; gene therapy; paediatric genetic diseases; therapeutics

DOI:  https://doi.org/10.4103/singaporemedj.SMJ-2021-376
Elife. 2023 Feb 01. pii: e82811. [Epub ahead of print]12

N-terminal domain on dystroglycan enables LARGE1 to extend matriglycan on α-dystroglycan and prevents muscular dystrophy.

Hidehiko Okuma, Jeffrey M Hord, Ishita Chandel, David Venzke, Mary E Anderson, Ameya S Walimbe, Soumya Joseph, Zeita Gastel, Yuji Hara, Fumiaki Saito, Kiichiro Matsumura, Kevin P Campbell.

  Dystroglycan (DG) requires extensive post-translational processing and O-glycosylation to function as a receptor for extracellular matrix (ECM) proteins containing laminin-G-like (LG) domains. Matriglycan is an elongated polysaccharide of alternating xylose (Xyl) and glucuronic acid (GlcA) that binds with high-affinity to ECM proteins with LG-domains and is uniquely synthesized on α-dystroglycan (α-DG) by like-acetylglucosaminyltransferase-1 (LARGE1). Defects in the post-translational processing or O-glycosylation of α-DG that result in a shorter form of matriglycan reduce the size of α-DG and decrease laminin binding, leading to various forms of muscular dystrophy. Previously, we demonstrated that Protein O-Mannose Kinase (POMK) is required for LARGE1 to generate full-length matriglycan on α-DG (~150-250 kDa) (Walimbe et al., 2020). Here, we show that LARGE1 can only synthesize a short, non-elongated form of matriglycan in mouse skeletal muscle that lacks the DG N-terminus (α-DGN), resulting in a ~100-125 kDa α-DG. This smaller form of α-DG binds laminin and maintains specific force but does not prevent muscle pathophysiology, including reduced force production after eccentric contractions or abnormalities in the neuromuscular junctions. Collectively, our study demonstrates that α-DGN, like POMK, is required for LARGE1 to extend matriglycan to its full mature length on α-DG and thus prevent muscle pathophysiology.

Keywords:  biochemistry; cell biology; chemical biology; mouse

DOI:  https://doi.org/10.7554/eLife.82811
Transl Res. 2023 Jan 26. pii: S1931-5244(23)00004-X. [Epub ahead of print]

AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase I deficiency (PGM1-CDG).

B Balakrishnan, R Altassan, R Budhraja, W Liou, A Lupo, S Bryant, A Mankouski, S Radenkovic, G Preston, A Pandey, S Boudina, T Kozicz, E Morava, K Lai.

PGM1 deficiency is recognized as the third most common N-linked Congenital Disorders of Glycosylation (CDG) in humans. Affected individuals present with liver, musculoskeletal, endocrine, and coagulation symptoms; however, the most life-threatening complication is the early onset of dilated cardiomyopathy (DCM). Recently, we discovered that oral D-galactose supplementation improved liver disease, endocrine and coagulation abnormalities, but does not alleviate the fatal cardiomyopathy and the associated myopathy. Here we report on left ventricular ejection fraction (LVEF) in 6 individuals with PGM1-CDG. LVEF was pathologically low in most of these individuals and varied between 10-65%. To study the pathobiology of the cardiac disease observed in PGM1-CDG, we constructed a novel cardiomyocyte-specific conditional Pgm2 gene (mouse ortholog of human PGM1) knockout (Pgm2 cKO) mouse model. Echocardiography studies corroborated a DCM phenotype with significantly reduced ejection fraction and left ventricular dilation similar to those seen in individuals with PGM1-CDG. Histological studies demonstrated excess glycogen accumulation and fibrosis, while ultrastructural analysis revealed Z-disk disarray and swollen/fragmented mitochondria, which was similar to the ultrastructural pathology in the cardiac explant of an individual with PGM1-CDG. In addition, we found decreased mitochondrial function in the heart of KO mice. Transcriptomic analysis of hearts from mutant mice demonstrated a gene signature of DCM. Although proteomics revealed only mild changes in global protein expression in left ventricular tissue of mutant mice, a glycoproteomic analysis unveiled broad glycosylation changes with significant alterations in sarcolemmal proteins including different subunits of laminin-211, which was confirmed by immunoblot analyses. Finally, augmentation of PGM1 in KO mice via AAV9-PGM1 gene replacement therapy prevented and halted the progression of the DCM phenotype.

DOI: https://doi.org/10.1016/j.trsl.2023.01.004
Orphanet J Rare Dis. 2023 Jan 31. 18(1): 20

Nonhuman primate genetic models for the study of rare diseases.

Eric J Vallender, Charlotte E Hotchkiss, Anne D Lewis, Jeffrey Rogers, Joshua A Stern, Samuel M Peterson, Betsy Ferguson, Ken Sayers.

Pre-clinical research and development relies heavily upon translationally valid models of disease. A major difficulty in understanding the biology of, and developing treatments for, rare disease is the lack of animal models. It is important that these models not only recapitulate the presentation of the disease in humans, but also that they share functionally equivalent underlying genetic causes. Nonhuman primates share physiological, anatomical, and behavioral similarities with humans resulting from close evolutionary relationships and high genetic homology. As the post-genomic era develops and next generation sequencing allows for the resequencing and screening of large populations of research animals, naturally occurring genetic variation in nonhuman primates with clinically relevant phenotypes is regularly emerging. Here we review nonhuman primate models of multiple rare genetic diseases with a focus on the similarities and differences in manifestation and etiologies across species. We discuss how these models are being developed and how they can offer new tools and opportunities for researchers interested in exploring novel therapeutics for these and other genetic diseases. Modeling human genetic diseases in translationally relevant nonhuman primates presents new prospects for development of therapeutics and a better understanding of rare diseases. The post-genomic era offers the opportunity for the discovery and further development of more models like those discussed here.

DOI: https://doi.org/10.1186/s13023-023-02619-3
Front Endocrinol (Lausanne). 2022 ;13 1102307

Phosphomannomutase 2 hyperinsulinemia: Recent advances of genetic pathogenesis, diagnosis, and management.

Congli Chen, Yanmei Sang.

  Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and childhood. There are 16 subtypes of CHI-related genes. Phosphomannomutase 2 hyperinsulinemia (PMM2-HI) is an extremely rare subtype which is first reported in 2017, with only 18 families reported so far. This review provides a structured description of the genetic pathogenesis, and current diagnostic and therapeutic advances of PMM2-HI to increase clinicians' awareness of PMM2-HI.

Keywords:  congenital disorder of glycosylation; congenital hyperinsulinism; diazoxide; hypoglycemia; phosphomannomutase 2

DOI:  https://doi.org/10.3389/fendo.2022.1102307
Circ Res. 2023 Feb 03. 132(3): 379-396

Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets.

Konrad Teodor Sawicki, Adam De Jesus, Hossein Ardehali.

  The cardiovascular system requires iron to maintain its high energy demands and metabolic activity. Iron plays a critical role in oxygen transport and storage, mitochondrial function, and enzyme activity. However, excess iron is also cardiotoxic due to its ability to catalyze the formation of reactive oxygen species and promote oxidative damage. While mammalian cells have several redundant iron import mechanisms, they are equipped with a single iron-exporting protein, which makes the cardiovascular system particularly sensitive to iron overload. As a result, iron levels are tightly regulated at many levels to maintain homeostasis. Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich's ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives.

Keywords:  biology; catalysis; electrons; heart; iron; macrophages; metabolism

DOI:  https://doi.org/10.1161/CIRCRESAHA.122.321667
bioRxiv. 2023 Jan 11. pii: 2023.01.11.523525. [Epub ahead of print]

Human-specific features and developmental dynamics of the brain N-glycome.

Thomas S Klarić, Ivan Gudelj, Gabriel Santpere, André M M Sousa, Mislav Novokmet, Frano Vučković, Shaojie Ma, Ivona Bečeheli, Chet C Sherwood, John J Ely, Patrick R Hof, Djuro Josić, Gordan Lauc, Nenad Sestan.

Comparative "omics" studies have revealed unique aspects of human neurobiology, yet an evolutionary perspective of the brain N-glycome is lacking. Here, we performed multi-regional characterization of rat, macaque, chimpanzee, and human brain N-glycomes using chromatography and mass spectrometry, then integrated these data with complementary glycotranscriptomic data. We found that in primates the brain N-glycome has evolved more rapidly than the underlying transcriptomic framework, providing a mechanism for generating additional diversity. We show that brain N-glycome evolution in hominids has been characterized by an increase in complexity and α(2-6)-linked N-acetylneuraminic acid along with human-specific cell-type expression of key glycogenes. Finally, by comparing the prenatal and adult human brain N-glycome, we identify region-specific neurodevelopmental pathways that lead to distinct spatial N-glycosylation profiles in the mature brain.One-Sentence Summary: Evolution of the human brain N-glycome has been marked by an increase in complexity and a shift in sialic acid linkage.

DOI: https://doi.org/10.1101/2023.01.11.523525
Int J Biochem Cell Biol. 2023 Jan 27. pii: S1357-2725(23)00014-6. [Epub ahead of print] 106375

Metformin induces mitochondrial fission and reduces energy metabolism by targeting respiratory chain complex I in hepatic stellate cells to reverse liver fibrosis.

Ying Su, Chenjian Hou, Meili Wang, Kehan Ren, Danmei Zhou, Xiaoli Liu, Shanyu Zhao, Xiuping Liu.

  The activation and proliferation of hepatic stellate cells (HSCs) are critical processes for the treatment of liver fibrosis. It is necessary to identify effective drugs for the treatment of liver fibrosis and elucidate their mechanisms of action. Metformin can inhibit HSCs; however, no systematic studies demonstrating the effects of metformin on mitochondria in HSCs have been reported. This study demonstrated that metformin induces mitochondrial fission by phosphorylating AMPK/DRP1 (S616) in HSCs to decrease the expression of α-SMA and collagen. Additionally, metformin repressed the total ATP production rate, especially the production rate of ATP produced through mitochondrial oxidative phosphorylation, by inhibiting the enzymatic activity of complex I. Further analysis revealed that metformin strongly constrained the transcription of mitochondrial genes (ND1-ND6 and ND4L) that encode the core subunits of respiratory chain I. Upregulation of the mRNA expression of HK2 and GLUT1 slightly enhanced glycolysis. Additionally, metformin increased mitochondrial DNA (mtDNA) copy number to suppress the proliferation and activation of HSCs, indicating that mtDNA copy number can alter the fate of HSCs. In conclusion, metformin can induce mitochondrial fragmentation and low-level energy metabolism in HSCs, thereby suppressing HSCs activation and proliferation to reverse liver fibrosis.

Keywords:  Hepatic stellate cells (HSCs); Liver fibrosis; Metformin; Mitochondrial dynamics; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.biocel.2023.106375
Mol Med. 2023 01 31. 29(1): 18

Newly discovered roles of triosephosphate isomerase including functions within the nucleus.

Tracey D Myers, Michael J Palladino.

  Triosephosphate isomerase (TPI) is best known as a glycolytic enzyme that interconverts the 3-carbon sugars dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P). TPI is an essential enzyme that is required for the catabolism of DHAP and a net yield of ATP from anaerobic glucose metabolism. Loss of TPI function results in the recessive disease TPI Deficiency (TPI Df). Recently, numerous lines of evidence suggest the TPI protein has other functions beyond glycolysis, a phenomenon known as moonlighting or gene sharing. Here we review the numerous functions ascribed to TPI, including recent findings of a nuclear role of TPI implicated in cancer pathogenesis and chemotherapy resistance.

Keywords:  Gene sharing; Genetics; Glycolysis; Metabolism; Moonlighting; TPI deficiency; Triosephosphate isomerase (TPI)

DOI:  https://doi.org/10.1186/s10020-023-00612-x
J Neural Transm (Vienna). 2023 Jan 31.

Neurodevelopmental disorders (NDD) without boundaries: research and interventions beyond classifications.

Cécile Louveau, Pierre Ellul, Anton Iftimovici, Julien Dubreucq, Charles Laidi, Quentin Leyrolle, Diane Purper-Ouakil, Sebastien Jacquemont, Stanislas Lyonnet, Catherine Barthélémy, Marie-Odile Krebs, Jing Bai, Paul Olivier, Boris Chaumette.

On June 2022, the 2nd Webinar "Neurodevelopmental Disorders (NDD) without boundaries took place at the Imagine Institute in Paris and was broadcasted live and in replay. The aim of this webinar is to address NDD in a dimensional rather than in a categorical approach. Several speakers were invited to present their researches on the subject. Classifications in NDD were discussed: irritability in NDD, involvement of the immune system in neurodevelopment, nutrition and gut microbiota modulate brain inflammation and neurodevelopment, co-occurring conditions in autistic adolescents and adults without intellectual disability. Classifications in psychiatric disorders were asked: mapping the effect of genes on cognition and autism risk, epigenetics and symptomatic trajectory in neurodevelopmental disorders, the autism-schizophrenia continuum in two examples: minor neurological signs and EEG microstates, the cerebellum in schizophrenia and autism: from imaging to intervention perspectives. Both genetic and environmental factors, along with clinical and imaging features, argue toward a continnum between NDD but also with adult psychiatric presentations. This new paradigm could modify the therapeutic strategy, with the development of large-spectrum treatments or new psychotherapies addressing co-occuring symptoms. The complexity and the heterogeneity of NDD apply well to the next scientific and political challenges: developing international convergence to push back the frontiers of our knowledge. This article is a summary of the 2nd webinar "Neurodevelopmental Disorders (NDD) without boundaries: research and interventions beyond classifications" sponsored by the French National Academy of Medicine, the autism and neurodevelopmental disorders scientific interest group (GIS), the International Research Network Dev-O-Psy and the French Institute of Psychiatry (GDR3557). Oral presentations are available as a replay on the following website (in French): https://autisme-neurodev.org/evenements/2022/04/12/tnd-sans-frontieres-la-recherche-et-les-interventions-au-dela-des-classifications/ .

DOI: https://doi.org/10.1007/s00702-023-02586-w