ALG13-Congenital Disorder of Glycosylation (ALG13-CDG): Updated clinical and molecular review and clinical management guidelines.

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.

Complex metabolic disharmony in PMM2-CDG paves the way to new therapeutic approaches.

PMM2-CDG is the most common defect among the congenital disorders of glycosylation. In order to investigate the effect of hypoglycosylation on important cellular pathways, we performed extensive biochemical studies on skin fibroblasts of PMM2-CDG patients. Among others, acylcarnitines, amino acids, lysosomal proteins, organic acids and lipids were measured, which all revealed significant abnormalities. There was an increased expression of acylcarnitines and amino acids associated with increased amounts of calnexin, calreticulin and protein-disulfid-isomerase in combination with intensified amounts of ubiquitinylated proteins. Lysosomal enzyme activities were widely decreased as well as citrate and pyruvate levels indicating mitochondrial dysfunction. Main lipid classes such as phosphatidylethanolamine, cholesterol or alkyl-phosphatidylcholine, as well as minor lipid species like hexosylceramide, lysophosphatidylcholines or phosphatidylglycerol, were abnormal. Biotinidase and catalase activities were severely reduced. In this study we discuss the impact of metabolite abnormalities on the phenotype of PMM2-CDG. In addition, based on our data we propose new and easy-to-implement therapeutic approaches for PMM2-CDG patients.

[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.

ALG8-CDG: Molecular and phenotypic expansion suggests clinical management guidelines.

Congenital disorders of glycosylation are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid glycan biosynthesis. These disorders mostly manifest with multisystem involvement. Individuals with ALG8-CDG commonly present with hypotonia, protein-losing enteropathy, and hepatic involvement. Here, we describe seven unreported individuals diagnosed with ALG8-CDG based on biochemical and molecular testing and we identify nine novel variants in ALG8, bringing the total to 26 individuals with ALG8-CDG in the medical literature. In addition to the typical multisystem involvement documented in ALG8-CDG, our cohort includes the two oldest patients reported and further expands the phenotype of ALG8-CDG to include stable intellectual disability, autism spectrum disorder and other neuropsychiatric symptoms. We further expand the clinical features in a variety of organ systems including ocular, musculoskeletal, dermatologic, endocrine, and cardiac abnormalities and suggest a comprehensive evaluation and monitoring strategy to improve clinical management.

Therapeutic approaches in Congenital Disorders of Glycosylation (CDG) involving N-linked glycosylation: an update.

Congenital disorders of glycosylation (CDG) are a group of clinically and genetically heterogeneous metabolic disorders. Over 150 CDG types have been described. Most CDG types are ultrarare disorders. CDG types affecting N-glycosylation are the most common type of CDG with emerging therapeutic possibilities. This review is an update on the available therapies for disorders affecting the N-linked glycosylation pathway. In the first part of the review, we highlight the clinical presentation, general principles of management, and disease-specific therapies for N-linked glycosylation CDG types, organized by organ system. The second part of the review focuses on the therapeutic strategies currently available and under development. We summarize the successful (pre-) clinical application of nutritional therapies, transplantation, activated sugars, gene therapy, and pharmacological chaperones and outline the anticipated expansion of the therapeutic possibilities in CDG. We aim to provide a comprehensive update on the treatable aspects of CDG types involving N-linked glycosylation, with particular emphasis on disease-specific treatment options for the involved organ systems; call for natural history studies; and present current and future therapeutic strategies for CDG.

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation.

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.

An emerging role for endothelial barrier support therapy for congenital disorders of glycosylation.

Congenital disorders of glycosylation (CDGs) are clinically heterogeneous disorders defined by a decreased ability to modify biomolecules with oligosaccharides. Critical disruptions in protein recognition, interaction, binding, and anchoring lead to broad physiological effects. Patients present with endocrinopathy, immunodeficiency, hepatopathy, coagulopathy, and neurodevelopmental impairment. Patients may experience mortality/morbidity associated with shock physiology that is frequently culture negative and poorly responsive to standard care. Oedema, pleural and pericardial effusions, ascites, proteinuria, and protein-losing enteropathy are observed with an exaggerated inflammatory response. The negative serum protein steady state results from several mechanisms including reduced hepatic synthesis and secretion, increased consumption, and extravasation. Disruption of the glycocalyx, a layer of glycosylated proteins that lines the endothelium preventing thrombosis and extravasation, is a suspected cause of endothelial dysfunction in CDG patients. We performed a retrospective review of CDG patients admitted to our institution with acute illness over the past 2 years. Longitudinal clinical and laboratory data collected during the sick and well states were assessed for biomarkers of inflammation and efficacy of interventions. Six patients representing 4 CDG subtypes and 14 hospitalisations were identified. Acute D-dimer elevation, proteinuria, decreased serum total protein levels, coagulation proteins, and albumin were observed with acute illness. Infusion of fresh frozen plasma, and in some cases protein C concentrate, was associated with clinical and biomarker improvement. This was notable with intra-patient comparison of treated vs untreated courses. Use of endothelial barrier support therapy may reduce endothelial permeability by restoring both regulatory serum protein homeostasis and supporting the glycocalyx and is likely a critical component of care for this population.

Rare blood donor needed.

BACKGROUND: Here, we describe a 14-year-old male with leukocyte adhesion deficiency type 2 who was transferred to a university hospital with anemia (hemoglobin 6 g/dL) and multiple singular abscesses refractory to antimicrobials. CASE REPORT: As leukocyte adhesion deficiency type 2 is associated with Bombay phenotype, the patient's red blood cells (RBCs) were tested with commercial anti-H lectin Ulex europaeus. An allogeneic adsorption with phenotype-matched cells was performed. RBCs negative for H antigen (Oh ) were tested with patient's plasma. The American Rare Donor Program was contacted to find granulocyte donors. The patient was Bombay phenotype (Oh ). All major clinically significant alloantibodies were excluded testing Oh cells and allogeneic adsorbed plasma. Two Bombay RBC units and five doses of granulocytes were requested from the blood center. Two frozen Bombay RBC units were obtained through another blood center. The American Rare Donor Program found one eligible granulocyte donor who lived 4 hours by car from the collection center. Because of this concern and other major logistic challenges, the blood center considered other options. These methods included gravity sedimentation and a cell separation system to isolate the RBCs from granulocytes. Unfortunately, neither one could be implemented. Auspiciously, the patient's condition improved and granulocytes were no longer needed. CONCLUSION: To avoid the challenge of finding compatible granulocyte donors for patients with rare blood types and clinically significant antibodies, our blood center considered validating and implementing gravity separation to remove the incompatible RBCs from granulocyte collections.

CDG Therapies: From Bench to Bedside.

Congenital disorders of glycosylation (CDG) are a group of genetic disorders that affect protein and lipid glycosylation and glycosylphosphatidylinositol synthesis. More than 100 different disorders have been reported and the number is rapidly increasing. Since glycosylation is an essential post-translational process, patients present a large range of symptoms and variable phenotypes, from very mild to extremely severe. Only for few CDG, potentially curative therapies are being used, including dietary supplementation (e.g., galactose for PGM1-CDG, fucose for SLC35C1-CDG, Mn2+ for TMEM165-CDG or mannose for MPI-CDG) and organ transplantation (e.g., liver for MPI-CDG and heart for DOLK-CDG). However, for the majority of patients, only symptomatic and preventive treatments are in use. This constitutes a burden for patients, care-givers and ultimately the healthcare system. Innovative diagnostic approaches, in vitro and in vivo models and novel biomarkers have been developed that can lead to novel therapeutic avenues aiming to ameliorate the patients’ symptoms and lives. This review summarizes the advances in therapeutic approaches for CDG.

Solving glycosylation disorders: fundamental approaches reveal complicated pathways.

Over 100 human genetic disorders result from mutations in glycosylation-related genes. In 2013, a new glycosylation disorder was reported every 17 days. This trend will probably continue given that at least 2% of the human genome encodes glycan-biosynthesis and -recognition proteins. Established biosynthetic pathways provide many candidate genes, but finding unanticipated mutated genes will offer new insights into glycosylation. Simple glycobiomarkers can be used in narrowing the candidates identified by exome and genome sequencing, and those can be validated by glycosylation analysis of serum or cells from affected individuals. Model organisms will expand the understanding of these mutations' impact on glycosylation and pathology. Here, we highlight some recently discovered glycosylation disorders and the barriers, breakthroughs, and surprises they presented. We predict that some glycosylation disorders might occur with greater frequency than current estimates of their prevalence. Moreover, the prevalence of some disorders differs substantially between European and African Americans.

What is new in CDG?

Congenital disorders of glycosylation (CDG) are one group among the disorders of glycosylation. The latter comprise defects associated with hypoglycosylation but also defects with hyperglycosylation. Genetic diseases with hypoglycosylation can be divided in primary congenital disorders of glycosylation (CDG) and in genetic diseases causing secondary hypoglycosylation. This review covers the human CDG highlights from the last 3 years (2014-2016) following a summary of the actual status of CDG. It expands on 23 novel CDG namely defects in SLC39A8, CAD, NANS, PGM3, SSR4, POGLUT1, NUS1, GANAB, PIGY, PIGW, PIGC, PIGG, PGAP1, PGAP3, VPS13B, CCDC115, TMEM199, ATP6AP1, ATP6V1A, ATP6V1E1, TRAPPC11, XYLT1 and XYLT2. Besides, it discusses novel phenotypes of known CDG (DHDDS-CDG, ALG9-CDG, EXT2-CDG, PIGA-CDG, PIGN-CDG), the elucidation of putative glycosyltransferase disorders as O-mannosylglycan synthesis disorders (TMEM5-CDG, ISPD-CDG, FKTN-CDG, FKRP-CDG), a novel CDG mechanism, advances in diagnosis, pathogenesis, treatment and finally an updated list of the 104 known CDG.

Public and patient involvement in needs assessment and social innovation: a people-centred approach to care and research for congenital disorders of glycosylation.

BACKGROUND: Public and patient involvement in the design of people-centred care and research is vital for communities whose needs are underserved, as are people with rare diseases. Innovations devised collectively by patients, caregivers, professionals and other members of the public can foster transformative change toward more responsive services and research. However, attempts to involve lay and professional stakeholders in devising community-framed strategies to address the unmet needs of rare diseases are lacking. In this study, we engaged with the community of Congenital Disorders of Glycosylation (CDG) to assess its needs and elicit social innovations to promote people-centred care and research. METHODS: Drawing on a qualitative study, we conducted three think tanks in France with a total of 48 participants, including patients/family members (n = 18), health care professionals (n = 7), researchers (n = 7) and people combining several of these roles (n = 16). Participants came from 20 countries across five continents. They were selected from the registry of the Second World Conference on CDG through heterogeneity and simple random sampling. Inductive and deductive approaches were employed to conduct interpretational analysis using open, axial and selective coding, and the constant-comparison method to facilitate the emergence of categories and core themes. RESULTS: The CDG community has unmet needs for information, quality health care, psychosocial support and representation in decision-making concerned with care and research. According to participants, these needs can be addressed through a range of social innovations, including peer-support communities, web-based information resources and a CDG expertise platform. CONCLUSION: This is one of the few studies to engage lay and professional experts in needs assessment and innovation for CDG at a global level. Implementing the innovations proposed by the CDG community is likely to have ethical, legal and social implications associated with the potential donation of patients' clinical and biological material that need to be assessed and regulated with involvement from all stakeholders. To promote people-centred care for the CDG community, and increase its participation in the governance of care and research, it is necessary to create participatory spaces in which the views of people affected by CDG can be fully expressed.

Clinical diagnostics and therapy monitoring in the congenital disorders of glycosylation.

Abnormal protein glycosylation is observed in many common disorders like cancer, inflammation, Alzheimer's disease and diabetes. However, the actual use of this information in clinical diagnostics is still very limited. Information is usually derived from analysis of total serum N-glycan profiling methods, whereas the current use of glycoprotein biomarkers in the clinical setting is commonly based on protein levels. It can be envisioned that combining protein levels and their glycan isoforms would increase specificity for early diagnosis and therapy monitoring. To establish diagnostic assays, based on the mass spectrometric analysis of protein-specific glycosylation abnormalities, still many technical improvements have to be made. In addition, clinical validation is equally important as well as an understanding of the genetic and environmental factors that determine the protein-specific glycosylation abnormalities. Important lessons can be learned from the group of monogenic disorders in the glycosylation pathway, the Congenital Disorders of Glycosylation (CDG). Now that more and more genetic defects are being unraveled, we start to learn how genetic factors influence glycomics profiles of individual and total serum proteins. Although only in its initial stages, such studies suggest the importance to establish diagnostic assays for protein-specific glycosylation profiling, and the need to look beyond the single glycoprotein diagnostic test. Here, we review progress in and lessons from genetic disease, and review the increasing opportunities of mass spectrometry to analyze protein glycosylation in the clinical diagnostic setting. Furthermore, we will discuss the possibilities to expand current CDG diagnostics and how this can be used to approach glycoprotein biomarkers for more common diseases.

[Congenital disorder of glycosylation type Ia (CDG Ia) - underdiagnosed entity?]. / Synnynnäinen tyypin Ia glykosylaation häiriö.

Congenital disorders of glycosylation (CDG) are a relatively recently identified group of multisystem disorders caused by defective glycosylation of N-glycosylated proteins. They mainly involve the central and peripheral nervous system, but other organ systems are involved as well. Type CDG Ia accounts for over 80% of cases, characterized by decreased activity of the enzyme phosphomannomutase caused by mutations in chromosome 16 PMM2 gene. Treatment of CDG Ia remains symptomatic.

Antisense-mediated therapeutic pseudoexon skipping in TMEM165-CDG.

Deficiencies in glycosyltransferases, glycosidases or nucleotide-sugar transporters involved in protein glycosylation lead to congenital disorders of glycosylation (CDG), a group of genetic diseases mostly showing multisystem phenotype. Despite recent advances in the biochemical and molecular knowledge of these diseases, no effective therapy exists for most. Efforts are now being directed toward therapies based on identifying new targets, which would allow to treat specific patients in a personalized way. This work presents proof-of concept for the antisense RNA rescue of the Golgi-resident protein TMEM165, a gene involved in a new type of CDG with a characteristic skeletal phenotype. Using a functional in vitro splicing assay based on minigenes, it was found that the deep intronic change c.792+182G>A is responsible for the insertion of an aberrant exon, corresponding to an intronic sequence. Antisense morpholino oligonucleotide therapy targeted toward TMEM165 mRNA recovered normal protein levels in the Golgi apparatus of patient-derived fibroblasts. This work expands the application of antisense oligonucleotide-mediated pseudoexon skipping to the treatment of a Golgi-resident protein, and opens up a promising treatment option for this specific TMEM165-CDG.

A new case of UDP-galactose transporter deficiency (SLC35A2-CDG): molecular basis, clinical phenotype, and therapeutic approach.

Congenital disorders of glycosylation (CDG) are a group of hereditary metabolic diseases characterized by abnormal glycosylation of proteins and lipids. Often, multisystem disorders with central nervous system involvement and a large variety of clinical symptoms occur. The main characteristics are developmental delay, seizures, and ataxia. In this paper we report the clinical and biochemical characteristics of a 5-year-old girl with a defective galactosylation of N-glycans, resulting in developmental delay, muscular hypotonia, epileptic seizures, inverted nipples, and visual impairment. Next generation sequencing revealed a de novo mutation (c.797G > T, p.G266V) in the X-chromosomal gene SLC35A2 (solute carrier family 35, UDP-galactose transporter, member A2; MIM 300896). While this mutation was found heterozygous, random X-inactivation of the normal allele will lead to loss of normal SLC35A2 activity in respective cells. The functional relevance of the mutation was demonstrated by complementation of UGT-deficient MDCK-RCA(r) and CHO-Lec8 cells by normal UGT-expression construct but not by the mutant version. The effect of dietary galactose supplementation on glycosylation was investigated, showing a nearly complete normalization of transferrin glycosylation.

Congenital disorders of glycosylation: new defects and still counting.

Almost 50 inborn errors of metabolism have been described due to congenital defects in N-linked glycosylation. These phenotypically diverse disorders typically present as clinical syndromes, affecting multiple systems including the central nervous system, muscle function, transport, regulation, immunity, endocrine system, and coagulation. An increasing number of disorders have been discovered using novel techniques that combine glycobiology with next-generation sequencing or use tandem mass spectrometry in combination with molecular gene-hunting techniques. The number of "classic" congenital disorders of glycosylation (CDGs) due to N-linked glycosylation defects is still rising. Eight novel CDGs affecting N-linked glycans were discovered in 2013 alone. Newly discovered genes teach us about the significance of glycosylation in cell-cell interaction, signaling, organ development, cell survival, and mosaicism, in addition to the consequences of abnormal glycosylation for muscle function. We have learned how important glycosylation is in posttranslational modification and how glycosylation defects can imitate recognizable, previously described phenotypes. In many CDG subtypes, patients unexpectedly presented with long-term survival, whereas some others presented with nonsyndromic intellectual disability. In this review, recently discovered N-linked CDGs are described, with a focus on clinical presentations and therapeutic ideas. A diagnostic approach in unsolved N-linked CDG cases with abnormal transferrin screening results is also suggested.

Therapies and therapeutic approaches in Congenital Disorders of Glycosylation.

Inborn errors in glycoconjugate biosynthesis termed 'Congenital Disorders of Glycosylation' (CDG) comprise a rapidly expanding group of metabolic diseases in man. Up till now more than 60 different inherited disorders in N- and O-glycosylation pathways have been identified. They affect the biosynthesis of glycan moieties linked to proteins as well as lipids. Due to failures in protein glycosylation, CDG patients suffer from multi systemic disorders, which mostly present with severe psychomotor and mental retardations, muscular impairment, ataxia, failure to thrive and developmental delay. Although improved biochemical and genetic investigations led to identification of a variety of new molecular defects in glycoconjugate biosynthesis, effective therapies for most types of the CDG are so far not available. Therefore, intensive investigations on treatment options for this group of diseases have been carried out in recent years.

Thyroid function in PMM2-CDG: diagnostic approach and proposed management.

Glycoproteins are essential in the production, transport, storage and regulation of thyroid hormones. Altered glycosylation has a potential impact on thyroid function. Abnormal thyroid function tests have been described in patients with congenital disorders of glycosylation. We evaluated the reliability of biochemical markers and investigated thyroid function in 18 PMM2-CDG patients. We propose an expectative therapeutic approach for neonates with thyroid abnormalities in CDG.