Congenital disorder of glycosylation type Ia in a Chinese family: Function analysis of a novel PMM2 complex heterozygosis mutation.

Congenital disorder of glycosylation type Ia (CDG-Ia) is an autosomal recessive genetic disease caused by a mutation in the phosphomannomutase 2 (PMM2) gene. We have identified a 13-month-old boy who has been diagnosed with CDG-Ia. He displays several characteristic symptoms, including cerebellar hypoplasia, severe developmental retardation, hypothyroidism, impaired liver function, and abnormal serum ferritin levels. Through whole-exome sequencing, we discovered novel complex heterozygous mutations in the PMM2 gene, specifically the c.663C > G (p.F221L) mutation and loss of exon 2. Further analysis revealed that the enzymatic activity of the mutant PMM2 protein was significantly reduced by 44.97% (p < 0.05) compared to the wild-type protein.

PIGN c.776T>C (p.Phe259Ser) variant present in trans with a pathogenic variant for PIGN-congenital disorder of glycosylation: Bella-Noah syndrome.

Glycosylation is the most common protein and lipid post-translational modification in humans. Congenital disorders of glycosylation (CDG) are characterized by both genetic and clinical heterogeneity, presenting multisystemic manifestations, and in most cases are autosomal recessive in inheritance. The PIGN gene is responsible for the addition of phosphoethanolamine to the first mannose in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, a highly conserved process that enables proteins to bind to the cell surface membrane. Here, we report a family with two siblings pediatric cases with the exact same compound heterozygous variants in PIGN. The (c.776T > C) variant of uncertain significance (VUS) together with a known pathogenic variant (c.932T > G), resulting in clinical features compatible with PIGN-related conditions, more specific the CDG. This is the first time that PIGN variant c.776T > C is reported in literature in individuals with PIGN-congenital disorder of glycosylation (PIGN-CDG), and the current submission in ClinVar by Invitae® is specifically of our case. Detailed clinical information and molecular analyses are presented. Here, we show for the first time two affected siblings with one pathogenic variant (c.932T > G) and the c.776T > C VUS in trans. In honor of the family, we propose the name Bella-Noah Syndrome for disorder.

Neural and metabolic dysregulation in PMM2-deficient human in vitro neural models.

Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a rare inborn error of metabolism caused by deficiency of the PMM2 enzyme, which leads to impaired protein glycosylation. While the disorder presents with primarily neurological symptoms, there is limited knowledge about the specific brain-related changes caused by PMM2 deficiency. Here, we demonstrate aberrant neural activity in 2D neuronal networks from PMM2-CDG individuals. Utilizing multi-omics datasets from 3D human cortical organoids (hCOs) derived from PMM2-CDG individuals, we identify widespread decreases in protein glycosylation, highlighting impaired glycosylation as a key pathological feature of PMM2-CDG, as well as impaired mitochondrial structure and abnormal glucose metabolism in PMM2-deficient hCOs, indicating disturbances in energy metabolism. Correlation between PMM2 enzymatic activity in hCOs and symptom severity suggests that the level of PMM2 enzyme function directly influences neurological manifestations. These findings enhance our understanding of specific brain-related perturbations associated with PMM2-CDG, offering insights into the underlying mechanisms and potential directions for therapeutic interventions.

PIGO-CDG: A case study with a new genotype, expansion of the phenotype, literature review, and nosological considerations.

The phosphatidylinositol glycan anchor biosynthesis class O protein (PIGO) enzyme is an important step in the biosynthesis of glycosylphosphatidylinositol (GPI), which is essential for the membrane anchoring of several proteins. Bi-allelic pathogenic variants in PIGO lead to a congenital disorder of glycosylation (CDG) characterized by global developmental delay, an increase in serum alkaline phosphatase levels, congenital anomalies including anorectal, genitourinary, and limb malformations in most patients; this phenotype has been alternately called "Mabry syndrome" or "hyperphosphatasia with impaired intellectual development syndrome 2." We report a 22-month-old female with PIGO deficiency caused by novel PIGO variants. In addition to the Mabry syndrome phenotype, our patient's clinical picture was complicated by intermittent hypoglycemia with signs of functional hyperinsulinism, severe secretory diarrhea, and osteopenia with a pathological fracture, thus, potentially expanding the known phenotype of this disorder, although more studies are necessary to confirm these associations. We also provide an updated review of the literature, and propose unifying the nomenclature of PIGO deficiency as "PIGO-CDG," which reflects its pathophysiology and position in the broad scope of metabolic disorders and congenital disorders of glycosylation.

"Hide and seek": Misleading transferrin variants in PMM2-CDG complicate diagnostics.

PURPOSE: Congenital disorders of glycosylation (CDG) are one of the fastest growing groups of inborn errors of metabolism. Despite the availability of next-generation sequencing techniques and advanced methods for evaluation of glycosylation, CDG screening mainly relies on the analysis of serum transferrin (Tf) by isoelectric focusing, HPLC or capillary electrophoresis. The main pitfall of this screening method is the presence of Tf protein variants within the general population. Although reports describe the role of Tf variants leading to falsely abnormal results, their significance in confounding diagnosis in patients with CDG has not been documented so far. Here, we describe two PMM2-CDG cases, in which Tf variants complicated the diagnostic. EXPERIMENTAL DESIGN: Glycosylation investigations included classical screening techniques (capillary electrophoresis, isoelectric focusing and HPLC of Tf) and various confirmation techniques (two-dimensional electrophoresis, western blot, N-glycome, UPLC-FLR/QTOF MS with Rapifluor). Tf variants were highlighted following neuraminidase treatment. Sequencing of PMM2 was performed. RESULTS: In both patients, Tf screening pointed to CDG-II, while second-line analyses pointed to CDG-I. Tf variants were found in both patients, explaining these discrepancies. PMM2 causative variants were identified in both patients. CONCLUSION AND CLINICAL RELEVANCE: We suggest that a neuraminidase treatment should be performed when a typical CDG Tf pattern is found upon initial screening analysis.

Congenital diaphragmatic hernia in siblings with PIGA-related congenital disorder of glycosylation.

There are over 150 proteins involved in glycosylphosphatidylinositol (GPI)-anchored protein biosynthesis, a class within the larger category of congenital disorders of glycosylation (CDG). Pathogenic variants identified in phosphatidylinositol glycan class A protein (PIGA) are associated with X-linked PIGA-CDG, a GPI-anchor defect. The disease has primarily been characterized by hypotonia, epilepsy, and global developmental delay; however, only 89 known cases are reported, so the phenotypic spectrum has likely not yet been fully delineated. Congenital diaphragmatic hernia (CDH) has been reported in patients with various GPI-anchor related defects but has only been described in one prior individual with PIGA-CDG. Here, we describe the second and third reported cases of CDH in two brothers with PIGA-CDG caused by a pathogenic missense variant in PIGA: c.355C > T, p.R119W. Chromosomal microarray and whole exome sequencing did not reveal another plausible explanation for the CDH. We relate our patients' clinical features to the single previously reported individual with CDH and PIGA-CDG. We then compare this case series with the subset of individuals with CDH and other GPI-anchor defects. These findings suggest that CDH should be considered in the phenotypic disease spectrum of PIGA-CDG.

An oligogenic case of severe neonatal thrombocytopenia and a purportedly benign variant in GFI1B requiring reinterpretation.

Although thrombocytopenia in neonatal intensive care patients is rarely due to inherited disorders, the number of genetic variants implicated in platelet defects has grown dramatically with increasing genome-wide sequencing. Here we describe a case of severe, oligogenic neonatal thrombocytopenia and reinterpret a reportedly benign mutation that is likely pathogenic. Despite this patient's synonymous mutation (GFI1B 576 C>T, Phe192=) being annotated as benign, GFI1B is a well-known regulator of megakaryopoiesis, this variant alters splicing and megakaryocyte maturation, and our analysis of existing genome-wide associated studies demonstrates that it likely causes gray platelet syndrome. This variant has not been reported in a case of life-threatening thrombocytopenia. We propose that the severity of this patient's phenotype is due to synergistic epistasis between the intrinsic platelet defect caused by this mutation and her concomitant inherited PMM2 congenital glycosylation disorder neither of which have been associated with such a severe phenotype. This case highlights the importance of whole-exome/genome sequencing for critically ill patients, reexamining variant interpretation when clinically indicated, and the need to study diverse genetic variation in hematopoiesis.

What is the context? Low platelets (thrombocytopenia) in the neonatal population is not frequently inherited. As we perform unbiased DNA sequencing in more patients, the number of inherited platelet disorders and implicated variants is growing.The gene GFI1B encodes for a transcription factor that regulates megakaryocytes, the cell type that produces platelets. A synonymous substitution in GFI1B (576 C>T, Phe192=) is annotated as benign; however, experimental studies have shown that it inhibits megakaryocyte production.There is growing appreciation for oligogenic inheritance, where multiple causal variants contribute to clinical phenotypes.What is new? We present a case of life-threatening neonatal macrothrombocytopenia (large, hypogranulated sparse platelets) that has an oligogenic cause. We reinterpret the synonymous substitution GFI1B 576 C>T as pathogenic.This patient's severe phenotype was likely due to the combined effect of GFI1B 576 C>T and her inherited glycosylation disorder (PMM2-CDG). Neither variant alone causes severe thrombocytopenia, but the combined intrinsic platelet defect (GFI1B mutation) and consumption (PMM2-CDG) likely produced her life-threatening phenotype.What is the impact? GFI1B is a critical regulator of megakaryocyte production. The purportedly benign mutation 576 C>T is likely pathogenic causing thrombocytopenia by impairing megakaryocyte maturation.As more patients have unbiased genome sequencing, oligogenic and polygenic inheritance will become increasingly appreciated as causes of platelet disorders.NICU providers should consider whole genome or exome sequencing of neonates with severe thrombocytopenia after reversible causes are ruled out.

Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review.

We report the case of a 2-year-old girl who was diagnosed with Mannose-6-phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) and provide a review of the relevant literature. The young girl presented with recurrent unexplained diarrhea, vomiting, hypoproteinemia, and elevated liver transaminases. Whole-exome sequencing revealed that the patient had compound heterozygous mutations in the MPI gene (NM_0024). An exon 4 (c.455G > T, p.R152l) mutation was inherited from the mother and an exon 7 (c.884G > A, p.R295H) mutation from the father. One week after the start of mannose treatment, the vomiting and diarrhea symptoms disappeared completely and did not show any side effects. We also provide a brief review of the relevant literature. Including the present case, a total of 52 patients from hospitals across 17 countries were diagnosed with MPI-CDG. Age at disease onset ranged from birth to 15 years, with an onset under 2 years in most patients (43/50). Overall, patients presented with at least one or more of the following symptoms: chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44), hepatic fibrosis (20/37), protein-losing enteropathy (30/36), elevated serum transaminases (24/34), hyperinsulinemic-hypoglycemia (24/34), hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20), failure to thrive (13/36), portal hypertension (4/9), epilepsy (2/17), thrombosis (12/14), and abnormally elevated leukocytes (5). None of the patients was reported to have an intellectual disability (0/28). The majority of patients (26/30) showed clinical symptoms, and laboratory results improved after oral mannose administration. Our findings suggest that MPI-CDG should be considered in children with unexplained recurrent digestive and endocrine systems involvement, and gene examination should be performed immediately to obtain a definite diagnosis in order to begin treatment in a timely manner.

Tracer metabolomics reveals the role of aldose reductase in glycosylation.

Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement.

MAGT1 deficiency in XMEN disease is associated with severe platelet dysfunction and impaired platelet glycoprotein N-glycosylation.

BACKGROUND: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease is a primary immunodeficiency due to loss-of-function mutations in the gene encoding for magnesium transporter 1 (MAGT1). Furthermore, as MAGT1 is involved in the N-glycosylation process, XMEN disease is classified as a congenital disorder of glycosylation. Although XMEN-associated immunodeficiency is well described, the mechanisms underlying platelet dysfunction and those responsible for life-threatening bleeding events have never been investigated. OBJECTIVES: To assess platelet functions in patients with XMEN disease. METHODS: Two unrelated young boys, including one before and after hematopoietic stem cell transplantation, were investigated for their platelet functions, glycoprotein expression, and serum and platelet-derived N-glycans. RESULTS: Platelet analysis highlighted abnormal elongated cells and unusual barbell-shaped proplatelets. Platelet aggregation, integrin αIIbß3 activation, calcium mobilization, and protein kinase C activity were impaired between both patients. Strikingly, platelet responses to protease-activated receptor 1 activating peptide were absent at both low and high concentrations. These defects were also associated with decreased molecular weights of glycoprotein Ibα, glycoprotein VI, and integrin αIIb due to partial impairment of N-glycosylation. All these defects were corrected after hematopoietic stem cell transplantation. CONCLUSION: Our results highlight prominent platelet dysfunction related to MAGT1 deficiency and defective N-glycosylation in several platelet proteins that could explain the hemorrhages reported in patients with XMEN disease.

Novel insights into the phenotype and long-term D-gal treatment in PGM1-CDG: a case series.

Phosphoglucomutase-1-congenital disorder of glycosylation (PGM1-CDG) (OMIM: 614921) is a rare autosomal recessive inherited metabolic disease caused by the deficiency of the PGM1 enzyme. Like other CDGs, PGM1-CDG has a multisystemic presentation. The most common clinical findings include liver involvement, rhabdomyolysis, hypoglycemia, and cardiac involvement. Phenotypic severity can vary, though cardiac presentation is usually part of the most severe phenotype, often resulting in early death. Unlike the majority of CDGs, PGM1-CDG has a treatment: oral D-galactose (D-gal) supplementation, which significantly improves many aspects of the disorder. Here, we describe five PGM1-CDG patients treated with D-gal and report both on novel clinical symptoms in PGM1-CDG as well as the effects of the D-gal treatment. D-gal resulted in notable clinical improvement in four patients, though the efficacy of treatment varied between the patients. Furthermore, there was a significant improvement or normalization in transferrin glycosylation, liver transaminases and coagulation factors in three patients, creatine kinase (CK) levels in two, while hypoglycemia resolved in two patients. One patient discontinued the treatment due to urinary frequency and lack of clinical improvement. Furthermore, one patient experienced recurrent episodes of rhabdomyolysis and tachycardia even on higher doses of therapy. D-gal also failed to improve the cardiac function, which was initially abnormal in three patients, and remains the biggest challenge in treating PGM1-CDG. Together, our findings expand the phenotype of PGM1-CDG and underline the importance of developing novel therapies that would specifically treat the cardiac phenotype in PGM1-CDG.

An update on benefits and challenges of treating PGM1-CDG with galactose PGM1-CDG is a rare genetic disorder that affects glycosylation, an important biochemical process happening in every cell of the body. Because glycosylation is essential for correct functioning of the cells and happens in every tissue and organ, patients with PGM1-CDG can have a variety of symptoms affecting many different organs. Main symptoms include low blood glucose levels, hyperinsulinism, bleeding disorder, liver, muscle, heart problems, and so on. This disorder is usually diagnosed based on the genetic testing, patient's symptoms, and transferrin glycosylation test, which detects abnormalities in glycosylation in blood. So far, more than 60 patients have been reported. Unlike many genetic disorders, PGM1-CDG has a treatment in the form of a sugar called galactose, which naturally occurs in milk, and can treat many symptoms of the disorder. The patients are advised to take it every day by mouth in the form of powder. Here, we describe five more patients with PGM1-CDG, who were treated with galactose. Each of the patients had novel symptoms and they responded to the treatment differently, which helps us to better understand the disorder and the effects of therapy better. We found that many symptoms improved or normalized; however, some patients experienced persistent symptoms and even adverse events that made them stop treatment. Unfortunately, we did not observe any improvement of heart-related issues. Given that heart issues are the most severe aspect of PGM1-CDG and can result in early death, therapies that target heart issues in PGM1-CDG are still necessary. In conclusion, we describe novel aspects of PGM1-CDG, which will help understand and diagnose the disorder better, and highlight the importance of developing new therapies for this disorder that would specifically treat the heart.

In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis.

Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy metabolism from glycogen and glycolysis, as it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. PGM1 deficiency is an autosomal recessive disorder characterized by a highly heterogenous clinical spectrum, including hypoglycemia, cleft palate, liver dysfunction, growth delay, exercise intolerance, and dilated cardiomyopathy. Abnormal protein glycosylation has been observed in this disease. Oral supplementation with D-galactose efficiently restores protein glycosylation by replenishing the lacking pool of UDP-galactose, and rescues some symptoms, such as hypoglycemia, hepatopathy, and growth delay. However, D-galactose effects on skeletal muscle and heart symptoms remain unclear. In this study, we established an in vitro muscle model for PGM1 deficiency to investigate the role of PGM1 and the effect of D-galactose on nucleotide sugars and energy metabolism. Genome-editing of C2C12 myoblasts via CRISPR/Cas9 resulted in Pgm1 (mouse homologue of human PGM1, according to updated nomenclature) knockout clones, which showed impaired maturation to myotubes. No difference was found for steady-state levels of nucleotide sugars, while dynamic flux analysis based on 13C6-galactose suggested a block in the use of galactose for energy production in knockout myoblasts. Subsequent analyses revealed a lower basal respiration and mitochondrial ATP production capacity in the knockout myoblasts and myotubes, which were not restored by D-galactose. In conclusion, an in vitro mouse muscle cell model has been established to study the muscle-specific metabolic mechanisms in PGM1 deficiency, which suggested that galactose was unable to restore the reduced energy production capacity.

A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review.

BACKGROUND: The congenital disorder of glycosylation associated with ALG1 (ALG1-CDG) is a rare autosomal recessive disease. Due to the deficiency of ß1,4 mannosyltransferase caused by pathogenic variants in ALG1 gene, the assembly and processing of glycans in the protein glycosylation pathway are impaired, resulting in a broad clinical spectrum with multi-organ involvement. To raise awareness of clinicians for its manifestations and genotype, we here reported a new patient with a novel variant in ALG1 gene and reviewed the literature to study the genotype-phenotype correlation. METHOD: Clinical characteristics were collected, and clinical exome sequencing was used to identify the causative variants. MutationTaster, PyMol, and FoldX were used to predict the pathogenicity, changes in 3D model molecular structure of protein, and changes of free energy caused by novel variants. RESULTS: The proband was a 13-month-old Chinese Han male characterized by epileptic seizures, psychomotor development delay, muscular hypotonia, liver and cardiac involvement. Clinical exome sequencing revealed the biallelic compound heterozygosity variants, a previously reported variant c.434G>A (p.G145N, paternal) and a novel variant c.314T>A (p.V105N, maternal). The literature review found that in severe phenotypes, the incidences of clinical manifestations were significantly higher than that in mild phenotypes, including congenital nephrotic syndrome, agammaglobulinemia, and severe hydrops. Homozygous c.773C>T was a strongly pathogenic variant associated with a severe phenotype. When heterozygous for c.773C>T, patients with another variant leading to substitution in amino acids within the strongly conserved regions (c.866A>T, c.1025A>C, c.1182C>G) may cause a more severe phenotype than those within less-conserved regions (c.434G>A, c.450C>G, c.765G>A, c.1287T>A). c.1129A>G, c.1076C>T, and c.1287T>A were more likely to be associated with a mild phenotype. The assessment of disease phenotypes requires a combination of genotype and clinical manifestations. CONCLUSIONS: The case reported herein adds to the mutations identified in ALG1-CDG and a review of this literature expands the study of the phenotypic and genotypic spectrum of this disorder.

The epilepsy phenotype of ST3GAL3-related developmental and epileptic encephalopathy.

OBJECTIVE: ST3GAL3-related developmental and epileptic encephalopathy (DEE-15) is an autosomal recessive condition characterized by intellectual disability, language and motor impairments, behavioral difficulties, stereotypies, and epilepsy. Only a few cases have been reported, and the epilepsy phenotype is not fully elucidated. METHODS: A retrospective chart review of two siblings with ST3GAL3-related DEE was completed. In addition, we reviewed all published cases of ST3GAL3-related congenital disorder of glycosylation. RESULTS: Two brothers presented with global developmental delay, motor and language impairment, hypotonia, and childhood-onset seizures. Seizures started between 2.5 and 5 years and had tonic components. Both siblings had prolonged periods of seizure freedom on carbamazepine. Tremor was present in the younger sibling. Whole exome sequencing revealed two novel pathogenic variants in ST3GAL3, (a) c.302del, p.Phe102Serfs*34 and (b) c.781C>T, p.Arg261*, which were inherited in trans. Magnetic resonance imaging showed T2 hyperintensities and restricted diffusion in the brainstem and middle cerebellar peduncle in the older sibling, also described in two reported cases. A review of the literature revealed 24 cases of ST3GAL3-related CDG. Twelve cases had information about seizures, and epilepsy was diagnosed in 8 (67%). The median age of seizure onset was 5.5 months. Epileptic spasms were most common (67%). Four children were diagnosed with Infantile Epileptic Spasms syndrome and Lennox Gastaut syndrome (57%). Most children (n = 6, 75%) had seizures despite anti-seizure medication treatment. SIGNIFICANCE: Seizures related to ST3GAL3-related DEE often occur in infancy and may present as epileptic spasms. However, seizure onset may also occur outside of infancy with mixed seizure types and show good response to treatment with prolonged seizure freedom. Tremor may also be uniquely observed in this condition.

The First Congenital Disorders of Glycosylation Patient (Fetus) with Homozygous COG5 c.95T>G Variant.

Introduction: Congenital disorders of glycosylation (CDG) are autosomal recessive hereditary genetic disorders characterized by abnormal glycosylation of N-linked oligosaccharides. Case Presentation: In this research, prenatal testing (24th week of pregnancy) revealed findings like polyhydramnios, hydrocephaly, abnormal facial features/shape, brain morphology abnormality, spina bifida, vertebral column abnormality, macrocephaly, scoliosis, micrognathia, abnormal kidney morphology, short fetal femur length, and short fetal humerus length in the fetus. Whole-exome sequencing was performed; the COG5 gene has shown a pathogenic variant. Discussion: Homozygous patients have never been seen before in the literature for COG5-CDG. We demonstrate the first CDG patient at fetus stage with homozygous COG5 c.95T>G variant.

[Advances in the diagnosis and treatment of phosphomannomutase 2 deficiency]. / ç£·é ¸ç”˜éœ²ç³–å˜ä½é ¶2缺乏症的诊治进展.

Phosphomannomutase 2 deficiency is the most common form of N-glycosylation disorders and is also known as phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG). It is an autosomal recessive disease with multi-system involvements and is caused by mutations in the PMM2 gene (OMIM: 601785), with varying severities in individuals. At present, there is still no specific therapy for PMM2-CDG, and early identification, early diagnosis, and early treatment can effectively prolong the life span of pediatric patients. This article reviews the advances in the diagnosis and treatment of PMM2-CDG.

Mannose: a potential saccharide candidate in disease management.

There are a plethora of antibiotic resistance cases and humans are marching towards another big survival test of evolution along with drastic climate change and infectious diseases. Ever since the first antibiotic [penicillin], and the myriad of vaccines, we were privileged to escape many infectious disease threats. The survival technique of pathogens seems rapidly changing and sometimes mimicking our own systems in such a perfect manner that we are left unarmed against them. Apart from searching for natural alternatives, repurposing existing drugs more effectively is becoming a familiar approach to new therapeutic opportunities. The ingenious use of revolutionary artificial intelligence-enabled drug discovery techniques is coping with the speed of such alterations. D-Mannose is a great hope as a nutraceutical in drug discovery, against CDG, diabetes, obesity, lung disease, and autoimmune diseases and recent findings of anti-tumor activity make it interesting along with its role in drug delivery enhancing techniques. A very unique work done in the present investigation is the collection of data from the ChEMBL database and presenting the targetable proteins on pathogens as well as on humans. It shows Mannose has 50 targets and the majority of them are on human beings. The structure and conformation of certain monosaccharides have a decisive role in receptor pathogen interactions and here we attempt to review the multifaceted roles of Mannose sugar, its targets associated with different diseases, as a natural molecule having many success stories as a drug and future hope for disease management.

Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring.

N-glycoproteomics reveals distinct glycosylation alterations in NGLY1-deficient patient-derived dermal fibroblasts.

Congenital disorders of glycosylation are genetic disorders that occur due to defects in protein and lipid glycosylation pathways. A deficiency of N-glycanase 1, encoded by the NGLY1 gene, results in a congenital disorder of deglycosylation. The NGLY1 enzyme is mainly involved in cleaving N-glycans from misfolded, retro-translocated glycoproteins in the cytosol from the endoplasmic reticulum before their proteasomal degradation or activation. Despite the essential role of NGLY1 in deglycosylation pathways, the exact consequences of NGLY1 deficiency on global cellular protein glycosylation have not yet been investigated. We undertook a multiplexed tandem mass tags-labeling-based quantitative glycoproteomics and proteomics analysis of fibroblasts from NGLY1-deficient individuals carrying different biallelic pathogenic variants in NGLY1. This quantitative mass spectrometric analysis detected 8041 proteins and defined a proteomic signature of differential expression across affected individuals and controls. Proteins that showed significant differential expression included phospholipid phosphatase 3, stromal cell-derived factor 1, collagen alpha-1 (IV) chain, hyaluronan and proteoglycan link protein 1, and thrombospondin-1. We further detected a total of 3255 N-glycopeptides derived from 550 glycosylation sites of 407 glycoproteins by multiplexed N-glycoproteomics. Several extracellular matrix glycoproteins and adhesion molecules showed altered abundance of N-glycopeptides. Overall, we observed distinct alterations in specific glycoproteins, but our data revealed no global accumulation of glycopeptides in the patient-derived fibroblasts, despite the genetic defect in NGLY1. Our findings highlight new molecular and system-level insights for understanding NGLY1-CDDG.