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Background: Congenital disorders of glycosylation (CDG) represent a heterogeneous group of rare inherited metabolic disorders due to abnormalities in protein or lipid glycosylation pathways, affecting multiple systems, and frequently being accompanied by neurological symptoms. ALG11-CDG, also known as CDG-1p, arises from a deficiency in a specific mannosyltransferase encoded by the ALG11 gene. To date, only 17 cases have been documented, and these patients have prominent clinical phenotypes, including seizures, developmental delay, and microcephaly., Methods: We describe a novel case of a four-month-old boy from a Chinese family exhibiting developmental delay, seizures, and microcephaly. Trio whole-exome sequencing (WES) and subsequent Sanger sequencing were employed to identify the potential genetic cause, and functional study was performed to evaluate the pathogenicity of genetic variant identified., Results: Trio WES unveiled novel compound heterozygous variants: c.1307G>T (p.G436V) and c.1403G>A (p.R468H) within exon 4 of the ALG11 gene, inherited from the father and mother, respectively. Subsequent in vitro functional analysis revealed decreased stability of the mutant protein and concurrent hypoglycosylation of GP130, a hyperglycosylated protein., Conclusions: Our findings not only expand the clinical and variant spectrum of ALG11-CDG, but also emphasize the importance of WES as a first-tier genetic test in determining the molecular diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Congenital disorders of glycosylation type I (CDG-I) are a group of autosomal recessive genetic multisystem disorders that arise from defective glycoprotein biosynthesis. Although ocular abnormalities have been described in patients with CDG-I, few ocular abnormalities have been associated with ALG12-CDG (CDG-Ig), a rare subtype of CDG-I. We report a case of Duane syndrome, a congenital strabismus syndrome, in a 17-year-old young woman with ALG12-CDG., (Published by Elsevier Inc.)

Phosphoglucomutase-1-congenital disorder of glycosylation (PGM1-CDG) is a rare genetic disorder caused by biallelic variants in the PGM1 gene, leading to the deficiency of the PGM1 enzyme. The most common clinical presentations include muscle involvement, failure to thrive, cleft palate, and cardiac involvement. Abnormal serum N-glycosylation, hypoglycemia, and liver function abnormalities including coagulation abnormalities are the most common laboratory abnormalities. While PGM1-CDG has been extensively studied, little is known about the extent of the coagulation abnormalities in individuals with PGM1-CDG. Unlike most CDG, some symptoms of PGM1-CDG are treatable with D-galactose (D-gal) supplementation, though reliable clinical endpoints are necessary to appropriately evaluate the potential improvement with D-gal in PGM1-CDG. Here, we aimed to describe the incidence of coagulation abnormalities in PGM1-CDG and their evolution, their relation to clinical events, and the ability of D-gal treatment to improve them. A retrospective analysis was conducted on 73 reported individuals. All individuals had a molecularly confirmed PGM1-CDG diagnosis. All incidences of antithrombin (AT), aPTT, PT, factor (F) XI, FX, FIX, FVII, protein C and protein S data and major clinical events related to coagulation abnormalities, were collected. Coagulation information was available for only 58.9 % of the reported individuals, out of which 67.4 % of PGM1-CDG individuals were reported to have abnormalities. The most frequently observed abnormality was AT (mean: 30.8% R:80-120 %) deficiency. Four individuals had major thrombotic events. Coagulation status on D-gal treatment, were reported in 19 individuals. Several factors showed improvement including AT (mean: 64.5 %), indicating galactose is beneficial in treating coagulation abnormalities in PGM1-CDG. Due to the scarcity of the reported data on coagulation parameters, we also evaluated data collected in sixteen PGM1-CDG individuals enrolled in the FCDGC Natural History Study. Longitudinal data showed improvements in several coagulant parameters and disease severity improved for almost all patients of whom we had multiple datapoints on D-gal. AT showed significant improvement on D-gal. We conclude that coagulation abnormalities are frequently present in PGM1-CDG and show improvement on D-gal. We recommend coagulation parameters should be routinely checked in individuals with PGM1-CDG or suspected of having PGM1-CDG. Finally, AT may be used as a primary or secondary clinical endpoint for upcoming clinical trials in PGM1-CDG individuals., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

ALG13-Congenital Disorder of Glycosylation (CDG), is a rare X-linked CDG caused by pathogenic variants in ALG13 (OMIM 300776) that affects the N-linked glycosylation pathway. Affected individuals present with a predominantly neurological manifestation during infancy. Epileptic spasms are a common presenting symptom of ALG13-CDG. Other common phenotypes include developmental delay, seizures, intellectual disability, microcephaly, and hypotonia. Current management of ALG13-CDG is targeted to address patients' symptoms. To date, less than 100 individuals have been reported with ALG13-CDG. In this article, an international group of experts in CDG reviewed all reported individuals affected with ALG13-CDG and suggested diagnostic and management guidelines for ALG13-CDG. The guidelines are based on the best available data and expert opinion. Neurological symptoms dominate the phenotype of ALG13-CDG where epileptic spasm is confirmed to be the most common presenting symptom of ALG13-CDG in association with hypotonia and developmental delay. We propose that ACTH/prednisolone treatment should be trialed first, followed by vigabatrin, however ketogenic diet has been shown to have promising results in ALG13-CDG. In order to optimize medical management, we also suggest early cardiac, gastrointestinal, skeletal, and behavioral assessments in affected patients., Competing Interests: Declaration of competing interest All authors report no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

NGLY1 deficiency is a genetic disease caused by biallelic mutations of the Ngly1 gene. Although epileptic seizure is one of the most severe symptoms in patients with NGLY1 deficiency, preclinical studies have not been conducted due to the lack of animal models for epileptic seizures in NGLY1 deficiency. Here, we observed the behaviors of male and female Ngly1 -/- mice by video monitoring and found that these mice exhibit spontaneous seizure-like behaviors. Gene expression analyses and enzyme immunoassay revealed significant decreases in oxytocin, a well-known neuropeptide, in the hypothalamus of Ngly1 -/- mice. Seizure-like behaviors in Ngly1 -/- mice were transiently suppressed by a single intranasal administration of oxytocin. These findings suggest the therapeutic potential of oxytocin for epileptic seizure in patients with NGLY1 deficiency and contribute to the clarification of the disease mechanism., (© 2024. The Author(s).)

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., (© 2023 Wiley-VCH GmbH.)

Background: Given the lack of reliable data on the prevalence of bleeding abnormalities and thrombotic episodes in PMM2-CDG patients, and whether coagulation abnormalities change over time, we prospectively collected and reviewed natural history data. Patients with PMM2-CDG often have abnormal coagulation studies due to glycosylation abnormalities but the frequency of complications resulting from these has not been prospectively studied., Methods: We studied fifty individuals enrolled in the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study with molecularly confirmed diagnosis of PMM2-CDG. We collected data on prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), platelets, factor IX activity (FIX), factor XI activity (FXI), protein C activity (PC), protein S activity (PS) and antithrombin activity (AT)., Results: Prothrombotic and antithrombotic factor activities were frequently abnormal in PMM2-CDG patients, including AT, PC, PT, INR, and FXI. AT deficiency was the most common abnormality in 83.3% of patients. AT activity was below 50% in 62.5% of all patients (normal range 80-130%). Interestingly, 16% of the cohort experienced symptoms of spontaneous bleeding and 10% had thrombosis. Stroke-like episodes (SLE) were reported in 18% of patients in our cohort. Based on the linear growth models, on average, patients did not show significant change in AT (n = 48; t(23.8) = 1.75, p = 0.09), FIX (n = 36; t(61) = 1.60, p = 0.12), FXI (n = 39; t(22.8) = 1.88, p = 0.07), PS (n = 25; t(28.8) = 1.08, p = 0.29), PC (n = 38; t(68) = 1.61, p = 0.11), INR (n = 44; t(184) = -1.06, p = 0.29), or PT (n = 43; t(192) = -0.69, p = 0.49) over time. AT activity positively correlated with FIX activity. PS activity was significantly lower in males., Conclusion: Based on our natural history data and previous literature, we conclude that caution should be exercised when the AT levels are lower than 65%, as most thrombotic events occur in patients with AT below this level. All five, male PMM2-CDG patients in our cohort who developed thrombosis had abnormal AT levels, ranging between 19% and 63%. Thrombosis was associated with infection in all cases. We did not find significant change in AT levels over time. Several PMM2-CDG patients had an increased bleeding tendency. More long-term follow-up is necessary on coagulation abnormalities and the associated clinical symptoms to provide guidelines for therapy, patient management, and appropriate counseling., Synopsis: Most PMM2-CDG patients display chronic coagulation abnormalities without significant improvement, associated with a frequency of 16% clinical bleeding abnormalities, and 10% thrombotic episodes in patients with severe antithrombin deficiency., Competing Interests: Declaration of Competing Interest Diederik De Graef, Anna N. Ligezka, Joseph Rezents, Gina L. Mazza, Graeme Preston, Kaitlin Schwartz, Wirginia Krzysciak, Christina Lam, Andrew C. Edmondson, Christin Johnsen, Tamas Kozicz, and Eva Morava report no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Congenital disorders of glycosylation (CDG) are a group of rare inherited metabolic disorders caused by defects in various defects of protein or lipid glycosylation pathways. The symptoms and signs of CDG usually develop in infancy. Epilepsy is commonly observed in CDG individuals and is often a presenting symptom. These epilepsies can present across the lifespan, share features of refractoriness to antiseizure medications, and are often associated with comorbid developmental delay, psychomotor regression, intellectual disability, and behavioral problems. In this review, we discuss CDG and infantile epilepsy, focusing on an overview of clinical manifestations and electroencephalographic features. Finally, we propose a tiered approach that will permit a clinician to systematically investigate and identify CDG earlier, and furthermore, to provide genetic counseling for the family., 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 © 2023 Elsevier Inc. All rights reserved.)

Phosphomannomutase-2-congenital disorder of glycosylation (PMM2-CDG) is the most common CDG and presents with highly variable features ranging from isolated neurologic involvement to severe multi-organ dysfunction. Liver abnormalities occur in in almost all patients and frequently include hepatomegaly and elevated aminotransferases, although only a minority of patients develop progressive hepatic fibrosis and liver failure. No curative therapies are currently available for PMM2-CDG, although investigation into several novel therapies is ongoing. We report the first successful liver transplantation in a 4-year-old patient with PMM2-CDG. Over a 3-year follow-up period, she demonstrated improved growth and neurocognitive development and complete normalization of liver enzymes, coagulation parameters, and carbohydrate-deficient transferrin profile, but persistently abnormal IgG glycosylation and recurrent upper airway infections that did not require hospitalization. Liver transplant should be considered as a treatment option for PMM2-CDG patients with end-stage liver disease, however these patients may be at increased risk for recurrent bacterial infections post-transplant., Competing Interests: Declaration of Competing Interest The authors Shawn Tahata, MD, Jody Weckwerth, PA-C, Anna Ligezka, Miao He, PhD, Hee Eun Lee, MD, PhD6 Julie Heimbach, MD, Samar H Ibrahim, M.B.Ch.B, Tamas Kozicz, MD PhD, Katryn Furuya, MD, Eva Morava, MD, PhD have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Congenital disorders of glycosylation are a group of rare related disorders causing multisystem dysfunction, including ovarian failure in females that requires early estrogen replacement. Glycosylation defects also disrupt normal synthesis of several coagulation factors, increasing thrombotic risks and complicating hormone replacement. This series describes four females with different types of CDG who developed venous thromboses while on transdermal estrogen replacement. The authors highlight the knowledge gaps around anticoagulation for this population and propose further investigations., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest related to the development of this manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Deficiency of Conserved Oligomeric Golgi (COG) subunits (COG1-8) is characterized by both N- and O-protein glycosylation defects associated with destabilization and mislocalization of Golgi glycosylation machinery components (COG-CDG). Patients with COG defects present with neurological and multisystem involvement and possible malformation occurrence. Eighteen patients with COG6-CDG (COG6 mutations) were reported to date. We describe a patient with COG6-CDG with novel variants and a novel clinical feature namely a congenital recto-vaginal fistula., Methods: In-depth serum N- and O-glycosylation structural analyses were conducted by MALDI-TOF mass spectrometry. COG6 variants were identified by a gene panel and confirmed by Sanger sequencing., Results: This female newborn presented with facial dysmorphism, distal arthrogryposis and recurrent stool discharges per vaginam. A double-contrast barium-enema X-ray study revealed a dehiscence (approximately 5 mm) at the anterior wall of the rectal ampoule communicating with the vagina consistent with a recto-vaginal fistula. She had developmental delay, corpus callosum dysgenesis, liver and gastrointestinal involvement, hyperthermia episodes and early demise. Serum N- and O-glycosylation analyses pointed to a profound Golgi disarrangement. We identified two novel variants in COG6: a deletion of 1 bp mutation c.823delA creating a shift in the reading frame and a premature stop codon and a 3 bp deletion (c.1141_1143delCTC) producing an in-frame deletion of 1 amino acid., Conclusion: The congenital recto-vaginal fistula is a rare type of anorectal malformation that, to our knowledge, has not been reported in patients with a COG6 defect nor in patients with other COG defects. This study broadens COG6-CDG genetic landscape and spectrum of malformations., (© 2022 The Authors. Birth Defects Research published by Wiley Periodicals LLC.)

Introduction: Congenital disorders of glycosylation (CDG) is a group of rare, hereditary, multisystem disorders, predominantly affecting nervous system. There are N- and O- types of glycosylation. Fucosylation, a form of N-glycosylation, involves many enzymes. Until today, type 1 and type 2 fucosylation defects were identified, having pathogenic variants in genes encoding α-1,6-fucosyltransferase and fucokinase enzymes, respectively. In this article, a patient with type 2 fucosylation defect will be presented, with hypotonia, developmental delay and blindness and a pathogenic variant that was previously described in two patients., Method: Whole exome sequencing (WES) was performed, since the patient had no time to implement diagnostic algorithm for hypotonia etiology., Results: WES revealed a new pathogenic variant of homozygous c.993_1011del (p.Glu335Hisfs*55) frameshift variant of the FUK gene NM_145059 transcript. She had milder clinical manifestation than reported two patients., Conclusion: Congenital Defect of Glycosylation should be considered when the clinical findings cannot be explained by other known diseases, particularly in patients with multisystemic, predominantly neurological involvement., 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 © 2021 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The pathophysiology of congenital defects of glycosylation (CDG) is complex and the diagnosis has been a challenge because of the overlapping clinical signs and symptoms as well as a large number of disorders. Isoelectric focusing of transferrin has been used as a screening method but has limitations. Individual enzyme or molecular genetic tests have been difficult to perform. In this study, we aimed to describe CDG patients who were referred to from different departments either without a preliminary diagnosis or suspected to have a genetic disorder other than CDG. The patients were diagnosed mainly with a 450 gene next-generation DNA sequencing panel for inborn errors of metabolism, which also included 25 genes for CDG. A total of 862 patients were investigated with the panel, whereby homozygous (10) or compound heterozygous (4) mutations were found in a total of 14 (1.6%) patients. A total of 13 different mutations were discovered, 10 of them being novel. Interestingly, none of the patients was suspected to have a CDG before referral. This report expands the clinical/laboratory findings in patients with CDG and stresses on the fact that CDG should be in the differential list for pediatric patients presented with nonspecific dysmorphic features and neurological delays/regression. Also, next-generation DNA sequencing with panel approach was noticed to have a significant diagnostic potential in patients presented with nonspecific neurologic and dysmorphic findings., (© 2021 Wiley Periodicals LLC.)

Pathogenic variants in Steroid 5 alpha reductase type 3 (SRD5A3) cause rare inherited congenital disorder of glycosylation known as SRD5A3-CDG (MIM# 612379). To date, 43 affected individuals have been reported. Despite the development of various dysmorphic features in significant number of patients, facial recognition entity has not yet been established for SRD5A3-CDG. Herein, we reported a novel SRD5A3 missense pathogenic variant c.460 T > C p.(Ser154Pro). The 3D structural modeling of the SRD5A3 protein revealed additional transmembrane α-helices and predicted that the p.(Ser154Pro) variant is located in a potential active site and is capable of reducing its catalytic efficiency. Based on phenotypes of our patients and all published SRD5A3-CDG cases, we identified the most common clinical features as well as some recurrent dysmorphic features such as arched eyebrows, wide eyes, shallow nasal bridge, short nose, and large mouth. Based on facial digital 2D images, we successfully designed and validated a SRD5A3-CDG computer based dysmorphic facial analysis, which achieved 92.5% accuracy. The current work integrates genotypic, 3D structural modeling and phenotypic characteristics of CDG-SRD5A3 cases with the successful development of computer tool for accurate facial recognition of CDG-SRD5A3 complex cases to assist in the diagnosis of this particular disorder globally., (© 2021 Wiley Periodicals LLC.)

Aim: MOGS mutations cause congenital disorders of glycosylation type IIb (CDG-IIb or GCS1-CDG). The specific manifestations caused by the mutations in this gene remain unknown. We aimed to describe the clinical features of CDG- IIb and the effectiveness of urinary oligosaccharide analysis in the diagnosis of CDG- IIb., Methods: Patient 1 was analyzed with whole-exome sequencing (WES) to identify the causative gene of intractable epilepsy and severe developmental delay. After detecting MOGS mutation in patient 1, we analyzed patients 2 and 3 who were siblings and had clinical features similar to those in patient 1. Urinary oligosaccharide analysis was performed to confirm CDG- IIb diagnosis in patient 1. The clinical features of these patients were analyzed and compared with those in eight published cases., Results: Our three patients presented with early infantile epileptic encephalopathy, generalized hypotonia, hepatic dysfunction and dysmorphic features. In two cases, compound heterozygous mutations in MOGS were identified by WES. Isolation and characterization of the urinary oligosaccharide was performed in one of these cases to confirm the diagnosis of CDG-IIb. Although the isoelectric focusing of transferrin (IEF-T) of serum in this patient was normal, urinary excretion of Hex 4 corresponding to Glc 3 Man was observed by mass spectrometry., Conclusion: This report provides clinical manifestations of CDG-IIb with MOGS mutation. CDG-IIb shows a normal IEF profile of serum transferrin and cannot be detected by structural analysis of the patient's glycoproteins. Characterization of urinary oligosaccharides should be considered to detect this disorder., 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 © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

This review discusses a selection of congenital disorders of glycosylation that show peculiar features, such as an unusual presentation, different phenotypes, a novel biochemical/genetic mechanism, a relatively high frequency or a relatively efficient treatment.

Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previous studies suggest that D-galactose administration in juvenile patients leads to more significant and long-lasting effects, stressing the urge of neonatal diagnosis (0-6 months of age). Here, we detail the early clinical presentation of PGM1-CDG in eleven infantile patients, and applied the modified Beutler test for screening of PGM1-CDG in neonatal dried blood spots (DBSs). All eleven infants presented episodic hypoglycemia and elevated transaminases, along with cleft palate and growth delay (10/11), muscle involvement (8/11), neurologic involvement (5/11), cardiac defects (2/11). Standard dietary measures for suspected lactose intolerance in four patients prior to diagnosis led to worsening of hypoglycemia, hepatic failure and recurrent diarrhea, which resolved upon D-galactose supplementation. To investigate possible differences in early vs. late clinical presentation, we performed the first systematic literature review for PGM1-CDG, which highlighted respiratory and gastrointestinal symptoms as significantly more diagnosed in neonatal age. The modified Butler-test successfully identified PGM1-CDG in DBSs from seven patients, including for the first time Guthrie cards from newborn screening, confirming the possibility of future inclusion of PGM1-CDG in neonatal screening programs. In conclusion, severe infantile morbidity of PGM1-CDG due to delayed diagnosis could be prevented by raising awareness on its early presentation and by inclusion in newborn screening programs, enabling early treatments and galactose-based metabolic management., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Variants in SLC35C1 underlie leucocyte adhesion deficiency (LADII) or congenital disorder of glycosylation type 2c (CDGIIc), an autosomal recessive disorder of fucosylation. This immunodeficiency syndrome is generally characterized by severe recurrent infections, Bombay blood group, reduced growth and intellectual disability (ID). Features are all caused by an inability to generate key fucosylated molecules due to a defective transport of GDP-fucose into the Golgi. Here we report the use of exome sequencing to identify biallelic variants in SLC35C1 (c.501_503delCTT, p.(Phe168del) and c.891T > G, p.(Asn297Lys)) in an individual with short stature and ID. Retrospective clinical examination based on the genetic findings revealed increased otitis media as the only immunological feature present in this child. Biochemical analysis of patient serum identified a clear but mild decrease in protein fucosylation. Modelling all described missense mutations on a SLC35C1 protein model showed pathogenic substitutions localise to close to the dimer interface, providing insight into the possible pathophysiology of non-synonymous causative variants identified in patients. Our evidence confirms this is the second family presenting with only a subset of features and broadens the clinical presentation of this syndrome. Of note, both families segregated a common allele (p.Phe168del), suggesting there could be an associated genotype-phenotype relationship for specific variants. Based on two out of 14 reported families not presenting with the characteristic features of SLC35C1-CDG, we suggest there is clinical utility in considering this gene in patients with short stature and ID.

Congenital disorder of N-linked deglycosylation (CDDG, MIM 615273) is a very rare autosomal recessive disorder caused by pathogenic variants in the NGLY1 gene. Transient transaminitis is the typical hepatic dysfunction described in these patients, but also included neonatal jaundice, hepatomegaly, splenomegaly, and steatosis. Microscopically, intrahepatic cytoplasmic inclusions and fibrosis are seen. We report a five-year-old male patient who presented a severe episode of acute liver failure (ALF). Exome sequencing identified compound heterozygous pathogenic/likely pathogenic variants in the NGLY1 gene: NM_018297.3:c.1891del, p.(Gln631Serfs*7) in exon 12 and NM_018297.3:c.531dup, p.(Asn178Glnfs*9) in exon 4. Serology for the most frequent viral hepatitis infections, autoimmune panel, and investigations for metabolic or toxic causes were also normal or negative. Hepatic disease resolved favorably after 46 days. Liver function tests and elastography remains normal after a 2-year follow-up. This is the first report of a reversible ALF among patients with NGLY1-CDDG. Although its definitive cause remains unknown, we suggest a direct relation between liver disease and mitochondrial respiratory chain damage in the context of impaired NGLY1 gene function. Further reports are required in order to know the long-term prognosis of ALF in patients with NGLY1-CDDG., Competing Interests: Declaration of competing interest AMB-A is employee at CENTOGENE, AG, Germany. Rest of the authors have no conflict of interest to declare., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of disorders caused by the defects in the synthesis and processing of glycoproteins. CDG is caused by mannosyl-oligosaccharide glucosidase (MOGS) deficiency, and is an extremely rare type, and only six patients have been reported. Here, we report a patient from China with facial dysmorphism, infantile spams, developmental delay, low vison, and abnormal liver function and low immunoglobulin. Brain MRI showed hypoplasia of the corpus callosum and slightly wide sulci at bilateral frontal parietal lobes. Compound heterozygous mutations of (c.1694G>A: R565Q and c.1619G>A: R540H) in exon 4 of MOGS gene (NM_006302.2) were identified by whole exome sequencing. Further investigation showed that the gene expression of MOGS in patients' peripheral blood was decreased. We observed that two mutations were associated with lower protein expression of MOGS, cell growth, and cell cycle in transiently transfected Hela cells. We also noticed that cell cycle-related proteins, β-catenin, cyclin D1, and C-myc, were decreased in mutant cells. In conclusion, our study suggested whole exome sequencing, and genes associated with CDGs should be analyzed in patients with infantile spams and multiple system involvement, and mutant MOGS-impaired cell cycle progression. Our work broadens the mutation spectrum of MOGS gene.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel therapeutics for reducing low-density lipoprotein cholesterol (LDLc). While serious side-effects have not been observed in short-term clinical trials, there remain concerns that long-term PCSK9 inhibition may cause neurocognitive side-effects., Methods and Results: An adult male with childhood-onset global developmental delay, cerebellar atrophy and severe hypolipidaemia underwent extensive biochemical and genetic investigations. Initial testing revealed low circulating PCSK9 levels and a common loss-of-function PCSK9 polymorphism, but these findings did not fully account for severe hypolipidaemia. Whole-exome sequencing was subsequently performed and identified two pathogenic phosphomannose mutase 2 (PMM2) variants (p.Arg141His and p.Pro69Ser) known to cause PMM2-associated congenital disorder of glycosylation (PMM2-CDG). A diagnosis of PMM2-CDG was consistent with the proband's neurological symptoms and severe hypolipidaemia. Given that PMM2-CDG is characterised by defective protein N-glycosylation and that PCSK9 is a negative regulator of LDLc, we postulated that loss of PCSK9 N-glycosylation mediates hypolipidaemia among patients with PMM2-CDG. First, in an independent cohort of patients with PMM2-CDG (N=8), we verified that circulating PCSK9 levels were significantly lower in patients than controls (p=0.0006). Second, we conducted in vitro experiments in hepatocyte-derived cells to evaluate the effects of PCSK9 N-glycosylation loss on LDL receptor (LDLR) activity. Experimental results suggest that defective PCSK9 N-glycosylation reduces the ability of circulating PCSK9 to degrade LDLR., Conclusion: Life-long exposure to genetically lower PCSK9 per se is unlikely to cause neurocognitive impairment. Both observational and experimental findings suggest that hypolipidaemia in PMM2-CDG may be partially mediated by loss of PCSK9 N-glycosylation and/or its regulators., Competing Interests: Competing interests: GP has received consulting fees from Sanofi, Bristol-Myers Squibb, Lexicomp and Amgen and has received support for research through his institution from Sanofi. MC, GY, DSR, AC, DC and NS declare no competing interests., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

A rare form of congenital disorder of glycosylation (CDG) was recently discovered in individuals with biallelic mutations in fucosyltransferase 8 (FUT8). The clinical characteristics of patients with FUT8-CDG include intrauterine growth retardation, feeding difficulties, hypotonia, microcephaly, seizures, short stature, developmental delay, and respiratory abnormalities. We report the first case of glaucoma in an infant with FUT8-CGD and hypothesize a pathogenesis for glaucoma., (Copyright © 2019 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Background : Congenital disorders of glycosylation (CDG) are a group of hereditary multisystem disorders characterized by hypoglycosylation of glycoproteins. CDG type I results in a defect in the assembly of lipid-linkedoligosaccharides or their transfer onto nascent glycoproteins. Ocular abnormalities are common in CDG, but there is no report of detailed ophthalmologic evaluation in patients with CDG type Ig in the literature. Materials and Methods : Retrospective chart review of a case of CDG type Ig with novel variant in the associated gene: ALG12. Results : In addition to typical systemic findings of CDG, our case was found to have exotropia, bilateralcataracts, and retinitis pigmentosa with extinguished electroretinography in photopic and scotopic conditions. Conclusions : We hope to extend the understanding of ALG12-related CDG type Ig with these ophthalmologic observations.

Patients with phosphoglucomutase (PGM1) deficiency, a congenital disorder of glycosylation (CDG) suffer from multiple disease phenotypes. Midline cleft defects are present at birth. Overtime, additional clinical phenotypes, which include severe hypoglycemia, hepatopathy, growth retardation, hormonal deficiencies, hemostatic anomalies, frequently lethal, early-onset of dilated cardiomyopathy and myopathy emerge, reflecting the central roles of the enzyme in (glycogen) metabolism and glycosylation. To delineate the pathophysiology of the tissue-specific disease phenotypes, we constructed a constitutive Pgm2 (mouse ortholog of human PGM1)-knockout (KO) mouse model using CRISPR-Cas9 technology. After multiple crosses between heterozygous parents, we were unable to identify homozygous life births in 78 newborn pups (P = 1.59897E-06), suggesting an embryonic lethality phenotype in the homozygotes. Ultrasound studies of the course of pregnancy confirmed Pgm2-deficient pups succumb before E9.5. Oral galactose supplementation (9 mg/mL drinking water) did not rescue the lethality. Biochemical studies of tissues and skin fibroblasts harvested from heterozygous animals confirmed reduced Pgm2 enzyme activity and abundance, but no change in glycogen content. However, glycomics analyses in serum revealed an abnormal glycosylation pattern in the Pgm2 +/- animals, similar to that seen in PGM1-CDG., (© 2019 SSIEM.)

Background and Purpose: Congenital disorders of glycosylation (CDG) represent an increasing number of rare inherited metabolic diseases associated with abnormal glycan metabolism and disease onset in infancy or early childhood. Most CDG are multisystemic diseases mainly affecting the central nervous system. The aim of the current study was to investigate hyperkinetic movement disorders in patients affected by CDG and to characterize phenomenology based on CDG subtypes., Methods: Subjects were identified from a cohort of patients with CDG who were referred to the University Hospital of Catania, Italy. Patients were evaluated by neurologists with expertise in movement disorders and videotaped using a standardized protocol., Results: A variety of hyperkinetic movement disorders was detected in eight unrelated CDG patients. Involuntary movements were generally observed early in childhood, maintaining a clinical stability over time. Distribution ranged from a generalized, especially in younger subjects, to a segmental/multifocal involvement. In patients with phosphomannomutase 2 CDG, the principal movement disorders included dystonia and choreo-athetosis. In patients affected by other CDG types, the movement disorders ranged from pure generalized chorea to mixed movement disorders including dystonia and complex stereotypies., Conclusions: Hyperkinetic movement disorder is a key clinical feature in patients with CDG. CDG should be considered in the differential diagnosis of childhood-onset dyskinesia, especially when associated with ataxia, developmental delay, intellectual disability, autism or seizure disorder., (© European Academy of Neurology 2019.)

STT3A-CDG (OMIM# 615596) is an autosomal recessive N-linked glycosylation disorder characterized by seizures, developmental delay, intellectual disability, and a type I carbohydrate deficient transferrin pattern. All previously reported cases (n = 6) have been attributed to a homozygous pathogenic missense variant c.1877C>T (p.Val626Ala) in STT3A. We describe a patient with a novel homozygous likely pathogenic missense variant c.1079A>C (p.Tyr360Ser) who presents with chronically low Factor VIII (FVIII) and von Willebrand Factor (vWF) levels and activities in addition to the previously reported symptoms of developmental delay and seizures. VWF in our patient's plasma is present in a mildly hypoglycosylated form. FVIII antigen levels were too low to quantify in our patient. Functional studies with STT3A -/- HEK293 cells showed severely reduced FVIII antigen and activity levels in conditioned media <10% expected, but normal intracellular levels. We also show decreased glycosylation of STT3A-specific acceptors in fibroblasts from our patient, providing a mechanistic explanation for how STT3A deficiency leads to a severe defect in FVIII secretion. Our results suggest that certain STT3A-dependent N-glycans are required for efficient FVIII secretion, and the decreased FVIII level in our patient is a combined effect of both severely impaired FVIII secretion and lower plasma VWF level. Our report expands both the genotype and phenotype of STT3A-CDG; demonstrating, as in most types of CDG, that there are multiple disease-causing variants in STT3A., (© 2018 SSIEM.)

Phosphomannomutase deficiency (PMM2-CDG) causes a cerebellar syndrome that has been evaluated using the International Cooperative Ataxia Rating Scale (ICARS). However, no particular dysarthria tests have been used. Speech ICARS subscore subjectively assesses fluency and clarity of speech with two items. Repetition of syllables, traditionally used for characterization of ataxic speech, was validated in early-onset ataxia conditions. We assess the validity of the PATA test (SCA Functional Index [SCAFI]) in PMM2-CDG patients.PATA rates from 20 patients were compared with a control population were and correlated with ICARS and neuroimaging.There was a difference between the PATA rate in patients and controls. PATA rate increased with age in controls. In patients, the improvement of PATA rate with age was not significant. In patients, the PATA rate was negatively correlated with the total ICARS score and the Speech ICARS subscore. Regarding neuroimaging, midsaggital vermis relative diameter was positively correlated with PATA results. These last differences were also significant when the results are corrected by age.PATA rate provides an easy measure for a quantitative assessment of dysarthria that may help clinicians to monitor patients' evolution in a regular consultation. It could also be used in PMM2-CDG clinical trials implementing ICARS speech subscore information., Competing Interests: The authors declare that they have no competing interests., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Early-onset retinal dystrophy is usually isolated but can also be the presenting manifestation of an undiagnosed systemic disease. The purpose of this report is to highlight the initial presentation of a girl with early-onset retinal dystrophy and chronic dermatitis who was found to have an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG)., Methods: Retrospective case report., Results: A 13-year-old Baluchi girl was referred for evaluation of low vision since soon after birth. Clinical exam confirmed retinal dystrophy. She also had developmental disability and chronic dermatitis. Brain MRI was normal. Whole exome and confirmatory Sanger sequencing uncovered homozygosity for a SRDA3 deletion (p.Gln96delinsX) that was previously reported in two other Baluchi SRDA3-CDG families with ocular coloboma, optic atrophy, atopic dermatitis, cerebellar hypoplasia, and developmental disability. Early-onset retinal dystrophy was not mentioned in those two families but has since been documented in other SRDA3-CDG families harboring different biallelic variants in the gene., Discussion: Early-onset retinal dystrophy with chronic dermatitis should raise suspicion for biallelic SRDA3 mutations, particularly in the context of developmental disability. Exome sequencing can be a useful analysis in retinal dystrophy patients with multisystem disease. Homozygosity for the SRDA3 deletion p.Gln96delinsX is not always associated with ocular coloboma.

Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals. To identify additional genetic factors, hierarchical clustering of the plasma glycomics data was done, which indicated a subgroup of four patients that shared a unique glycomics signature of hybrid type N-glycans. In two siblings, compound heterozygous mutations were found in SLC10A7, a gene of unknown function in human. These included a missense mutation that disrupted transmembrane domain 4 and a mutation in a splice acceptor site resulting in skipping of exon 9. The two other individuals showed a complete loss of SLC10A7 mRNA. The patients' phenotype consisted of amelogenesis imperfecta, skeletal dysplasia, and decreased bone mineral density compatible with osteoporosis. The patients' phenotype was mirrored in SLC10A7 deficient zebrafish. Furthermore, alizarin red staining of calcium deposits in zebrafish morphants showed a strong reduction in bone mineralization. Cell biology studies in fibroblasts of affected individuals showed intracellular mislocalization of glycoproteins and a defect in post-Golgi transport of glycoproteins to the cell membrane. In contrast to yeast, human SLC10A7 localized to the Golgi. Our combined data indicate an important role for SLC10A7 in bone mineralization and transport of glycoproteins to the extracellular matrix.

Congenital disorders of glycosylation (CDG) linked to defects in Golgi apparatus homeostasis constitute an increasing part of these rare inherited diseases. Among them, COG-CDG, ATP6V0A2-CDG, TMEM199-CDG and CCDC115-CDG have been shown to disturb Golgi vesicular trafficking and/or lumen pH acidification. Here, we report 3 new unrelated cases of CCDC115-CDG with emphasis on diagnosis difficulties related to strong phenotypic similarities with mitochondriopathies, Niemann-Pick disease C and Wilson Disease. Indeed, while two individuals clinically presented with early and severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one "only" showed isolated and late severe liver involvement. Biological results were similar to previously described patients, including hypercholesterolemia, elevated alkaline phosphatases and defects in copper metabolism. CDG screening and glycosylation study finally led to the molecular diagnosis of CCDC115-CDG. Besides pointing to the importance of CDG screening in patients with unexplained and severe liver disease, these reports expand the clinical and molecular phenotypes of CCDC115-CDG. The hepatic involvement is particularly addressed. Furthermore, hypothesis concerning the pathogenesis of the liver disease and of major biological abnormalities are proposed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic disorders that result from abnormal protein or lipid glycosylation. They are often difficult to clinically diagnose because they broadly affect many organs and functions and lack clinical uniformity. However, recent technological advances in next-generation sequencing have revealed a treasure trove of new genetic disorders, expanded the knowledge of known disorders, and showed a critical role in infectious diseases. More comprehensive genetic tools specifically tailored for mammalian cell-based models have revealed a critical role for glycosylation in pathogen-host interactions, while also identifying new CDG susceptibility genes. We highlight recent advancements that have resulted in a better understanding of human glycosylation disorders, perspectives for potential future therapies, and mysteries for which we continue to seek new insights and solutions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Congenital disorders of glycosylation (CDG) are rare inborn diseases of glycan component of N-glycosylated proteins. We report here the case of a 28-year-old patient with CDG syndrome type Ia, who presented with a deep venous thrombosis in the left suro-popliteal vein with no known triggers or antecedents. The patient was treated with rivaroxaban for six months. Blood tests performed after discontinuing anticoagulant treatment showed multiple abnormalities affecting the proteins involved in haemostasis (both coagulation factors and inhibitors), i.e. a combined factor XI, antithrombin and protein C deficiency (35%, 41%, and 42% respectively) associated with a moderate increase of FVIII (179%) and VWFAg (163%) without inflammation. Patient results are here discussed with regard to the limited number of articles addressing haemostasis in this rare disease, as the occurrence of deep venous thrombosis remains uncommon in the literature.

Background: Atrial septal defect often become more severe when encountered in genetic syndromes. Congenital disorder of glycosylation type 1a is an inherited metabolic disorder associated with mutations in PMM2 gene and can affect almost all organs. Cardiac abnormalities vary greatly in congenital disorder of glycosylation type 1a and congenital heart defects have already been reported, but there is little knowledge about the effect of this inherited disorder on an existing congenital heart defect. Herein we report for the first time on a baby with congenital disorder of glycosylation type 1a with atrial septal defect and make a comparison of changes in atrial septal defect by follow-ups to the age of 3., Case Presentation: Our patient was an 8-month-old Han Chinese boy. At the initial visit, he presented with recurrent lower respiratory infection, heart murmur, psychomotor retardation, inverted nipples, and cerebellar atrophy. Echocardiography revealed a 8 mm secundum atrial septal defect with left-to-right shunt (Qp/Qs ratio 1.6). Enzyme testing of phosphomannomutase 2 demonstrated decreased levels of phosphomannomutase 2 activities in fibroblasts. Whole exon sequencing showed he was heterozygous for a frameshift mutation (p.I153X) and a missense mutation (p.I132T) in PMM2 gene. The diagnosis of congenital disorder of glycosylation type 1a with atrial septal defect was issued. Now, he is 3-years old at the time of this writing, with the development of congenital disorder of glycosylation type 1a (cerebellar atrophy become more severe and the symptom of nystagmus emerged), the size of atrial septal defect increased to 10 mm and the Qp/Qs ratio increased to 1.9, which suggested exacerbation of the atrial septal defect. Congenital heart defect-associated gene sequencing is then performed and shows there are no pathogenic mutations, which suggested intrinsic cardiac factors are not the cause of exacerbation of the atrial septal defect in our patient and it is reasonable to assume congenital disorder of glycosylation type 1a can worsen the situation of the existing atrial septal defect., Conclusions: This report highlights the view that congenital disorders of glycosylation type 1a should be excluded when faced with congenital heart defect with cerebellar atrophy or neurodevelopmental delay, especially when the situation of congenital heart defect becomes more and more severe.

BackgroundFetal alcohol syndrome (FAS) is caused by maternal alcohol consumption during pregnancy; although additional factors might be involved, as development and severity are not directly related to alcohol intake. The abnormal glycosylation caused by alcohol might play a role in FAS according to the clinical similarities shared with congenital disorders of glycosylation (CDG). Thus, mutations underlying CDG, affecting genes involved in glycosylation, could also be involved in FAS.MethodsA panel of 74 genes involved in N-glycosylation was sequenced in 25 FAS patients and 20 controls with prenatal alcohol exposure. Transferrin glycoforms were evaluated by HPLC.ResultsRare (minor allele frequency<0.009) missense/splice site variants were more frequent in FAS than controls (84% vs. 50%; P=0.034, odds ratio: 5.25, 95% confidence interval: 1.3-20.9). Remarkably, three patients, but no controls, carried variants with functional effects identified in CDG patients. Moreover, the patient with the most severe clinical phenotype was the only one carrying two variants with functional effects. Family studies support that the combination of a genetic defect and alcohol consumption during pregnancy might have a role in FAS development.ConclusionsOur study supports that the rare variants of genes involved in N-glycosylation could play a role in the development and severity of FAS under prenatal alcohol exposure.

Congenital disorders of glycosylation (CDG) are inborn errors of metabolism due to protein and lipid hypoglycosylation. This rapidly growing family of genetic diseases comprises 103 CDG types, with a broad phenotypic diversity ranging from mild to severe poly-organ -system dysfunction. This literature review summarizes cardiac involvement, reported in 20% of CDG. CDG with cardiac involvement were divided according to the associated type of glycosylation: N-glycosylation, O-glycosylation, dolichol synthesis, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, COG complex, V-ATPase complex, and other glycosylation pathways. The aim of this review was to document and interpret the incidence of heart disease in CDG patients. Heart disorders were grouped into cardiomyopathies, structural defects, and arrhythmogenic disorders. This work may contribute to improved early management of cardiac complications in CDG.