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Congenital disorders of glycosylation: narration of a story through its patents

Orphanet Journal of Rare Diseases volume 18, Article number: 247 (2023) Cite this article

Abstract

Congenital disorders of glycosylation are a group of more than 160 rare genetic defects in protein and lipid glycosylation. Since the first clinical report in 1980 of PMM2-CDG, the most common CDG worldwide, research made great strides, but nearly all of them are still missing a cure. CDG diagnosis has been at a rapid pace since the introduction of whole-exome/whole-genome sequencing as a diagnostic tool. Here, we retrace the history of CDG by analyzing all the patents associated with the topic. To this end, we explored the Espacenet database, extracted a list of patents, and then divided them into three major groups: (1) Drugs/therapeutic approaches for CDG, (2) Drug delivery tools for CDG, (3) Diagnostic tools for CDG. Despite the enormous scientific progress experienced in the last 30 years, diagnostic tools, drugs, and biomarkers are still urgently needed.

Background

According to the Orphan Drug Act, a rare disease is a disease or condition that impacts fewer than 200,000 people in the US [1, 2]. European Union considers as rare a disease affecting fewer than 5 people in 10,000 [3]. Over 6,000 rare diseases have been identified, affecting 8–10% of the world’s population [4,5,6].

The low prevalence of each disease, the wide diversity of symptoms and signs that vary not only from disease to disease but also from patient to patient suffering from the same condition, the limited knowledge and unclear underlying biology of many rare diseases, the lack of sufficient medical expertise as well as the lack of rare disease awareness and adequate financial resources, still pose significant challenges to patients, clinicians, and scientists [7,8,9].

Congenital disorders of glycosylation (CDG) are a varied group of rare genetic diseases characterized by protein and lipid hypoglycosylation [10, 11]. In 1980, prof. Jaak Jaeken described a new neurological disorder in twin girls [12]. This disorder’s clinical features, stages, progression, and biochemical analyses were depicted in 1991 [13]. The genetic evidence that phosphomannomutase 2 deficiency was the basis for the disease defined as “carbohydrate-deficient glycoprotein syndrome” was obtained in 1997 [14]. The scientific CDG community has come a long way since then, with an ever-growing number of new patients, new CDG, clinicians and researchers committed to this field, and a large body of research papers related to clinical, genetic, biological and biochemical results, diagnosis, and treatments. However, most CDG still do not have a cure, and a correct diagnosis is often challenging to obtain in a reasonable time [7].

This mini-review looks at CDG through Intellectual Property (IP) indicators. Many reviews on CDG have been published (about 40 only from 2021 to today - Pubmed access on 24th April 2023). Most focus on clinical signs and management, others on pathophysiology or treatment options. Here, we narrate the story of CDG through the associated patents.

Results

Research outcomes

For this review, we used a combination of keywords related to CDG to search the Espacenet database [15]. Queries are specified in Table 1, and the original files are available as Supplementary Files 1, 2, 3 and 4.

Table 1 Search strategies for identifying patents for CDG on EspaceNet (https://worldwide.espacenet.com/)
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We manually analyzed the extracted lists. First, we merged the lists based on the title. Then, patents were selected based on the title and the bibliographic data. We only considered English-written patents that included the original documents. In the cases where the original document was not in English, but the patent had another publication number whose original document was in English, we used the last one. We also considered patents written in other languages whose original document contained an abstract written in English. Refinement of the results included eliminating duplicates and defining a final subset containing 43 patents (Supplementary File 5).

A final reading of the complete original documents allowed a classification in the following classes: (1) Drugs/therapeutic approaches for CDG, (2) Drug delivery tools for CDG, (3) Diagnostic tools for CDG, (4) Production/modification/characterization of glycoconjugates. We discharged the last group, which is not strictly specific to CDG.

Figure 1 shows the distribution of the final list of 43 patents − 25 in class 1 (Drugs/Therapeutic Approaches), 2 in class 2 (Drug Delivery Tools), and 17 in class 3 (Diagnostic Tools) - that were further analyzed and commented on. One patent (EP2905621A1) overlaps both classes 1 and 3.

Fig. 1
figure 1

Classification of the patents derived from the research. For each class, the total number and the percentage are shown

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The first clinical description of CDG dates from 1980, and the first patent regarding CDG from 1995. Nevertheless, according to Google Scholar, in the period 1980–1995, 27 papers were published citing the findings by Jaak Jaeken; among these, only three belonged to the 1980–1990 decade [16,17,18]. In 1991, Jaak Jaeken depicted the newly identified syndrome’s clinical and biochemical phenotype, naming it “carbohydrate-deficient glycoprotein syndrome” [13]. Until 1995, this breakthrough was cited by 33 papers, thus representing a pivotal point after an almost silent decade. In this period, the number of identified patients and their symptoms started to multiply [19,20,21,22,23], and the first description of a different carbohydrate-deficient glycoprotein syndrome appeared, defined as “type II” [24]. Since then, the CDG family has rapidly expanded and currently counts more than 160 CDG [25]. All the patents were granted in the last three decades (Fig. 2).

Fig. 2
figure 2

Temporal distribution of patents’ publications

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On the one hand, those concerning the diagnostic tools are homogeneous in the considered period. However, the variable phenotypic spectrum and the absence of a genotype-phenotype correlation still hampers a fast and correct diagnosis. Moreover, the role of genomic variants in the development of the disease is a critical issue that has not yet been extensively investigated [26,27,28,29].

On the other hand, as expected, the patents regarding drugs and drug delivery tools were produced mainly in the last decade due to the increasing knowledge of the basic molecular mechanisms of the diseases, the development of cell models, the identification of biomarkers, and the development or improvement of biotechnologies such as genetic manipulation.

Figure 3 shows the distribution of patents according to the applicant’s country. Most applicants were from the US (31; 60%). According to the data provided by the World Intellectual Property Organization (WIPO), “More than 85% of all patent filings in 2021 occurred in the IP offices of China, the US, Japan, the Republic of Korea and the EPO (European Patent Office). China accounted for 46.6% of the world total.“ However, according to this site, applicants from China filed firstly in ‘Computer technology’, secondarily in ‘Digital communication’, and thirdly in ‘Electrical machinery, apparatus, energy’; US applicants filed mostly in ‘Computer technology’ too, but their second top technology for applications is ‘Medical technology’ [30]. Even if our results represent a total production over three decades, this aligns with WIPO data.

Fig. 3
figure 3

Geographical distribution of patents’ applicants. US: United States of America; AU, Australia; BE: Belgium; DE: Germany; ES: Spain; FR: France, GB: Great Britain; IT, Italy; JP: Japan; NO: Norway; SE, Sweden. For each country, the total number and the percentage are shown

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Drugs/therapeutic approaches and drug delivery tools for CDG

Table 2 lists patents on drugs and therapeutic approaches, while Table 3 lists those related to drug delivery tools.

Table 2 Drugs/therapeutic approaches for CDG.
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Table 3 Drugs delivery tools for CDG
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Protein N-glycosylation (PMM2-CDG, MPI-CDG, ALG11-CDG)

Nutritional intervention with oral supplementation of sugars or their derivatives has been largely practised among CDG and is still today [31].

Oral mannose supplementation therapy was the first therapeutic approach for the PMM2-CDG, as it successfully restored glycosylation in patients’ fibroblasts [32]. However, no clinical improvement was recorded in PMM2-CDG children during the treatment, so this was dismissed for PMM2-CDG [33]. This treatment did not cause adverse effects on patients [34]; thus, in 1998, upon promising results obtained in vitro using MPI-CDG patient fibroblasts, mannose was orally administered to a newly identified MPI-CDG patient. His clinical symptoms disappeared, and his transferrin glycoprofile normalized (DE19758059A1, [35]). This therapeutic approach has proven to be an effective therapy for MPI-CDG patients [36, 37], and it has been approved both in the EU and the US. International consensus guidelines regarding managing MPI-CDG and oral administration of mannose have been recently proposed [38]. However, liver transplantation might be needed since limited results have been recorded as to the liver disease [39, 40].

PMM2-CDG is the most frequent CDG, with more than 1000 patients diagnosed worldwide. Seven out of 25 patents regarding CDG drugs or therapeutic approaches are related to this condition. It is a disorder of N-linked protein glycosylation, due to defective assembly and transfer of oligosaccharides to protein asparagine residues.

Biochemical characterization of wild-type and mutant PMM2 [41,42,43,44,45], and the knowledge of the molecular mechanisms underlying the disease, allowed the identification of (pro)drugs and the exploration of different therapeutic approaches, which have been an object of patents, too [14, 46, 47].

The first two patents pursued the substrate replacement therapy approach (SRT). The enzyme variants decrease GDP-mannose levels due to a reduced conversion of mannose-6P into mannose-1P. GDP-mannose plays an essential role in N-glycan biosynthesis. The approach explored by patents WO03104247A2 and US2009054353A1 featured the supplementation of mannose-1P. However, this monophosphate is highly polar and cannot diffuse through the cell membrane. On the other hand, hydrolytic enzymes (in the stomach, intestine, and plasma) cause the degradation of monosaccharide monophosphates, limiting their absorption and bioavailability. Thus, the attention moved to the production of derivatives of mannose-1P with increased lipophilicity, namely hydrophobically masked mannose-1P (the WO03104247A2, [48]) and mono-(mannopyranosyl-1), di(mannopyranosyl-1) and tri(mannopyranosyl-1) phosphates (the US2009054353A1, [49]). Endogenous nonspecific enzymes (such as esterases or hydrolases) would ensure the release of the free monophosphate sugar. Ultimately, this approach would permit bypassing the deficient PMM2 activity.

A second exciting approach is using MPI inhibitors to treat PMM2-CDG (WO2011116355A2). PMM2 and MPI compete for mannose-6P. The efficacy of the inhibition of MPI would push the flux of mannose-6P towards the production of mannose-1P [50]. The application of the MPI inhibitor successfully led to the diversion of mannose-6P towards PMM2 and improved the defective N-glycosylation, at least in pre-clinical studies.

A galactose supplementation therapy has also been explored for PMM2-CDG, and an open-label pilot trial has been conducted, but the suitability of this approach has not been fully addressed (EP3806866A1, NCT02955264, [51]).

Despite promising results in vitro, substrate replacement therapy and MPI inhibition have not been approved for PMM2-CDG. However, carbohydrate replacement therapy could become feasible thanks to the refinement of the drug delivery systems that were the object of two patents listed in Table 3. Specifically, both the selected patents regarding the tools for drug delivery (EP3954360A2 and US2022184107A1) describe the preparation of liposomes designed to deliver mannose-1-phosphate. A phase 2 clinical trial of GLM101 for treating PMM2-CDG is underway (NCT05549219).

Recently, another therapeutic approach has been attempted in diseases caused by missense variants where a mutation causes a destabilization, i.e., the use of pharmacological chaperones (PCs) [52]. In these cases, an accurate evaluation of the effect of missense variants on the protein functioning or stability is needed, as it would be difficult to distinguish between disease and non-disease variants [53,54,55] clearly.

In CDG research, this PC therapy is still in its early steps of in vitro investigation. For PMM2-CDG, extensive screening of commercial molecules and rational drug design led to the identification of putative PCs (EP3275863A1, [56, 57]).

The most recent patents regarding drugs to treat PMM2-CDG patients relate to the application of aldose reductase inhibitors (patents WO2020040831A1 [58], US2022017535A1, and WO2021071965A1).

A high-throughput screening of commercially available drugs led to identifying and rationalising this class of compounds for therapeutic purposes. The use of patient-derived fibroblasts, as well as worm and yeast models, ensured the success of this study. Among the AOR inhibitors, epalrestat gained much attention. It is commonly used for treating diabetic neuropathy in Japan and is the only antidiabetic aldose reductase inhibitor approved for use in humans. A phase 3 clinical trial is currently in progress (NCT04925960). The rationale for its efficacy is that it may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homo- or hetero-dimerization [27, 57, 59, 60].

Dietary supplementation and organ transplantation currently represent the only curative therapies available for CDG; most patients can only receive symptomatic and preventive treatments. In this frame, the therapeutic application of cannabidiol (CBD) could represent another available tool. In 2018, the FDA approved CBD for treating seizures associated with rare epilepsy syndromes [61, 62]. As an expansion of this application, CBD significantly reduced the number of seizures in an ALG11-CDG patient (GB2597315A).

Disorders of multiple glycosylation pathways (PGM1-CDG and GNE-CDG)

Nucleotide sugars are the building blocks of glycans; several therapeutic approaches rely on treatments that aim to increase the intracellular concentration of these molecules. This approach produced some patents, mainly regarding disorders of multiple glycosylation pathways such as PGM1-CDG, PGM3-CDG and GNE-CDG.

An example of this approach is the combined therapy of uridine prodrug and sugars (WO2016028894A1), an approach tested in three patients with a different CDG (GNE-myopathy, PGM1-CDG, and DPAGT1-CDG); the coadministration of uridine triacetate and the specific sugar caused increased intracellular concentrations of the UDP-sugar. In a second approach, a sugar supplementation therapy combined UDP-glycans and D-galactose (PMM2-CDG and MPI-CDG) (EP3806866A1). This approach looks like an evolution of the dietary intervention through monosaccharide supplementation, primarily explored in CDG, although not all trials have succeeded [63]. Galactose therapy trials significantly improved biochemical abnormalities, but no clinical progression data have been reported. A metabolomic study shed light on the mechanism of PGM1-CDG and suggested that: “The direct administration of nucleotide sugars may be a more effective and less onerous form of treatment for affected individuals than galactose therapy.“ Such an approach could represent a starting point for other CDG related to nucleotide sugar metabolism and transport [64].

Substrate replacement therapies have also been patented for GNE-CDG. Variations in GNE cause a decrease in activity in either the isomerase or kinase protein domains, resulting in less formation of ManNAc-6-P and, ultimately, less Neu5AcA (sialic acid). In one study, N-acetyl mannosamine and derivatives proved helpful in treating myopathies, muscular atrophy or muscular dystrophy and kidney conditions and diseases in mice (EP3175859A1, [65]). On the other hand, in a phase 1 study, sialic acid was administered to patients (WO2013109906A2, [66]). In a third approach, a prodrug - a phosphoramidate derivative of ManNAc 6-phosphate - has been preferred to the monosaccharide monophosphate (WO2019118486A1, [67]).

Gene therapy is also starting to be applied in CDG, as described for PGM1-CDG (WO2022272056A2, [68]).

O-glycosylation (α-dystroglycanopathies)

Dystroglycanopathies are a subset of muscular dystrophies due to reduced O-glycosylation in α-dystroglycan with diminished laminin-binding activity. Specific molecules can enhance this binding, as it happens for a bispecific antibody. It comprises a first binding domain that binds an extracellular portion of α-dystroglycan and a second binding domain that binds laminin-2 [69]. This approach is the object of patent US10221168B1. The unexpected discovery that ribitol can restore or enhance functional glycosylation of mainly α-dystroglycan led to the application of a sugar supplementation therapy that had also been a subject of a patent (US10456367B2, [70]). Also, small molecules enhancing functional O-mannosylation of α-dystroglycan have been identified (US10221168B1, [71]). These compounds proved active in several applications; they could improve the functional O-mannosylation of α-dystroglycan on B421 cells (partially deficient in DPM2 with a point variant) and FKRP defective cells. DPM2-CDG is a disorder of multiple glycosylation pathways, while FKRP-CDG is a disorder of O-mannosylation.

Gene replacement therapy for FKRP-CDG received great attention. Four patents have been produced (US2017368199A1, [72]; WO2019008157A1, [73]; WO2022147490A1; WO2022076556A2). They all describe the application of adeno-associated virus (AAV9) gene therapy using optimized polynucleotides encoding the fukutin-related protein. Specific constructs have also been studied to produce therapeutical and toxically acceptable levels of protein in the heart (WO2021053124A1).

Two clinical trials are in progress regarding gene therapy for FKRP-CDG (NCT05224505 and NCT05230459).

Diagnostic tools for CDG

Table 4 lists patents concerning diagnostic tools for CDG.

Table 4 Diagnostic tools for CDG
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Serum transferrin isoelectrofocusing (Tf IEF) is still the method of choice for screening N-glycosylation disorders associated with sialic acid deficiency. Initially, the test was introduced for the screening of chronic alcoholism. Serum transferrin is only N-glycosylated, and the bulk of it carries four sialic acids and, thus, four negative charges. Capillary zone electrophoresis is a valuable alternative screening method, but abnormal results have to be controlled by Tf IE [74] (US5993626A).

As expected, many other serum glycoproteins besides transferrin show altered isoforms in CDG. Overall a wide range of methodologies has been explored and developed, such as the enzymatic derivatization of carbohydrate-deficient glycoproteins with fluoresceinylated monosaccharides and measurement of the fluorescence of the re-glycosylated glycoproteins (US5432059A), study of the interaction of glycoproteins with lectins or antibodies (WO0033076A1), and the MS or NMR of the specific peptide pattern obtained by enzymatic hydrolysis of the glycoprotein of interest (US2006216766A1). In addition, methods ensuring a higher sensitivity or a lesser sample handling have also been patented (such as WO0192890A1 and US8877454B2).

Another way to assess alterations of glycosylation profiles is the evaluation of the ratio of the amount of mono-sialylated to non-sialylated Thomsen-Friedenreich antigen in a biological sample, as described in US2014271615A1. Also, a specific method for simultaneous detection of α-DG and glycosylated α-DG for dystroglycanopathy patient biopsies has been patented (US2022291236A1).

Serum Tf IEF has some limitations; moreover, it is not a suitable biomarker for in vitro studies on cell models such as fibroblasts. Recently, polyols were identified as robust biomarkers of PMM2-CDG and several other CDG (WO2022103815A1).

However, genetic analysis is the most reliable diagnostic [75].

The discovery of the defect associated with carbohydrate-deficient glycoprotein syndrome type I or Jaeken disease, subsequently renamed PMM2-CDG, was patented in 1998 (WO9849324A2). Several glycoprotein and glycolipid metabolism enzymes were patented in 2002 (WO0236757A2).

PGM3 has long been considered a biomarker for forensic purposes. In 2006 it was described “as an important mediator for the in vitro or in vivo regulation of cellular interactions and development, in particular of stem cells and their subsequent lineages” (WO2006094344A1, [76]). PGM3 deficiency was first described in 2014 in patients with hyper-IgE syndrome phenotype characterized by recurrent infections, atopy, and elevated serum IgE [77, 78]. In 2015, PGM1-CDG was described at the clinical, biochemical and molecular levels, together with a possible therapeutic strategy based on the dietary supplementation of galactose (EP2905621A1, [79]).

Complementation experiments in yeast addressed the function/dysfunction of several genes involved in N-glycosylation, such as ALG8, ALG9, ALG10, ALG11, and ALG12 (WO2004015110A1).

Discussion

Among the most recent patents regarding drugs and therapeutic approaches, some led to clinical trials that are currently in progress, for example, epalrestat (NCT04925960), GLM101 (NCT05549219), and Adeno-Associated Virus vector carrying the human FKRP transgene (GNT0006, NCT05224505). Other patented drugs are still under development, such as the amide and urea derivatives that could act as pharmacological chaperones (EP3275863A1).

Other drugs under clinical trials were not traceable back to any of the selected patents. This happened, for example, for acetazolamide (for PMM2-CDG, NCT04679389), oral GlcNAc Supplementation (for NGLY1 deficiency, NCT05402345), ManNAc (for GNE myopathy, NCT04231266), AVTX-803 (for Leukocyte Adhesion Deficiency type II, NCT05462587O). Moreover, other drugs, prodrugs or lead compounds are under pre-clinical studies: celastrol (a proteostasis regulator, tested for PMM2-CDG), palovarotene (Sohonos™, an orally bioavailable selective retinoic acid receptor (RAR)γ agonist, tested for EXT1/EXT2-CDG), glucose 1,6 bisphosphate (an activator of the PMM2 that also acts as a pharmacological chaperone, tested for PMM2-CDG), clodronate (inhibitor of PMM1 that could have an indirect beneficial effect on PMM2 activity, tested for PMM2-CDG).

The commercialization of patented molecules is an exciting issue. To take a deeper insight, we focused on patents submitted by companies and screened the web to find information about the patent’s follow-up. The number of newly commercialized drugs is meagre. Substrate replacement therapy with mannose-1-phosphate has been produced as GLM101 by Glycomine; it has received Orphan Drug Designation (ODD) in the US and Europe and Rare Pediatric Disease Designation (RPDD) in the US and is in clinical trial phase 2 (NCT05549219) [80]. AT007, an aldose reductase inhibitor, is currently commercialized as the orphan drug Govorestat by Applied Therapeutics; Govorestat has not yet advanced in clinical trial for PMM2-CDG but is currently in clinical trial for different diseases (galactosemia, NCT04902781, and SORD Deficiency, NCT05397665) [81].

Repurposed drugs provide a different topic, being approved and then repositioned for CDG. For example, this is the case for Epalrestat, the first aldose reductase inhibitor patented by Perlara for use in PMM2-CDG (WO2020040831A1) and currently undergoing clinical trial phase 3.

Interestingly, many of these drugs derive from repositioning, a precious strategy in rare diseases [82,83,84]. With this approach, knowing the patterns involved in the drug’s action helps find different applications, either on known targets or off-targets [85,86,87]. Serendipity is typical in drug repurposing, but on the other hand, data provided by ‘omics’ experiments contain information about the differential regulation of genes by specific treatments. For example, while investigating the effect of acetylsalicylic acid on Fabry patient-derived fibroblasts, Monticelli and co-workers recorded a strong down-regulation of the COG5 protein (0.103 ratio ASA/control [88]).

Blood tests for diagnosis are available, but molecular genetic testing represents the final diagnostic tool. Anyway, screening methods are not 100% reliable and even enzyme measurements could be debatable in mild cases, like in PMM2-CDG, but in many cases genetic results are not conclusive for the diagnosis and a biochemical or functional confirmation is essential for establishing the diagnosis. Therefore, the development of biomarkers, diagnostic and screening tools is of utmost importance. Many people with CDG are undoubtedly misdiagnosed [7], particularly those with mild or atypical phenotypes [89].

The CDG illustrate that incorrect glycosylation is associated with a bewildering broad phenotypic spectrum. However, the absence of a genotype-phenotype correlation shows the remarkable role of genomic variants in the development of the disease [26,27,28,29]. In this regard, it is interesting to note that one of the patents concerns B4GALT1 and describes the protective effect of the p.Asn352Ser variant against one or more cardiovascular conditions (Table 3).

Our data clearly show the increasing interest in CDG by the Scientific Community. In the last few decades, many advances have been pursued. Nevertheless, besides the newly acquired knowledge, few drugs moved to clinical trials, and none of these has been approved, apart from the orphan drug designation. Among the reasons behind these data, the lack of funding for rare diseases is undoubtedly a significant issue [7]. In our opinion, cooperation among the different stakeholder groups (i.e. researchers, clinicians, families and companies) would be a unique possibility to boost CDG research and reach the goal of approved therapies as soon as possible.

Conclusion

Our research on CDG patents identified 25 documents regarding drugs or therapeutic approaches, 17 regarding diagnostic tools and two regarding drug delivery tools. These patents (regarding numbers and specificities) can be considered indicators of the attention paid to the CDG and the success gained through clinical and research activities.

Data availability

not applicable.

Abbreviations

α-DG:

α-dystroglycan

ALG6:

Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase

ALG8:

Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase

ALG9:

α-1,2-mannosyltransferase ALG9

ALG10:

Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase

ALG11:

GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase

ALG12:

Dol-P-Man:Man(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase

B4GALT1:

β-1,4-galactosyltransferase 1

CDG:

Congenital Disorders of Glycosylation

COG5:

Conserved oligomeric Golgi complex subunit 5

DPAGT1:

UDP-N-acetylglucosamine–dolichyl-phosphate N-acetylglucosaminephosphotransferase

EXT1:

Exostosin-1

EXT2:

Exostosin-2

FCMD:

Fukuyama congenital muscular dystrophy

FKRP:

Ribitol 5-phosphate transferase

GNE:

Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase

LMGD2I:

Autosomal recessive form of limb girdle muscular dystrophy (LGMD)

MAN1B1:

Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase

MCK-DG:

Muscle creatine kinase/α-dystroglycan

MDC1D:

Congenital muscular dystrophy type 1D

MEB:

Muscle eye brain disease

MOGS:

Mannosyl-oligosaccharide glucosidase

MPI:

Mannose phosphoisomerase

NANS:

Sialic acid synthase

NGLY:

Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase

PGM1:

Phosphoglucomutase-1

PGM3:

Phosphoglucomutase-3

PIGG:

GPI ethanolamine phosphate transferase 2

PIGO:

GPI ethanolamine phosphate transferase 3

PIGS:

GPI transamidase component PIG-S

PIGT:

GPI transamidase component PIG-T

PIGV:

GPI mannosyltransferase 2

PMM2:

Phosphomannomutase-2

SLC35A2:

UDP-galactose translocator

SLC35C1:

GDP-fucose transporter 1

SLC39A8:

Metal cation symporter ZIP8

Tf IEF:

Serum transferrin isoelectrofocusing

WWS:

Walker-Warburg syndrome

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Acknowledgements

GA acknowledges the National Research Council of Italy, Joint Bilateral Agreement CNR/Slovak Academy of Sciences, Biennial program 2023-24.

Funding

EM was supported by grant titled Frontiers in Congenital Disorders of Glycosylation (1U54NS115198-01) from the National Institute of Neurological Diseases and Stroke (NINDS), the National Center for Advancing Translational Sciences (NCATS), and the Rare Disordes Consortium Research Network (RDCRN).

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Authors and Affiliations

  1. Department of Biology, University of Napoli “Federico II”, Complesso Universitario Monte Sant’Angelo, Via Cinthia, Napoli, 80126, Italy

    Maria Monticelli, Tania D’Onofrio & Maria Vittoria Cubellis

  2. Institute of Biomolecular Chemistry ICB, CNR, Via Campi Flegrei 34, Pozzuoli, 80078, Italy

    Maria Monticelli, Tania D’Onofrio, Giuseppina Andreotti & Maria Vittoria Cubellis

  3. Center of Metabolic Diseases, KU Leuven, Leuven, Belgium

    Jaak Jaeken

  4. Department of Clinical Genomics and Laboratory of Medical Pathology, Mayo Clinic, Rochester, MN, USA

    Eva Morava

  5. Stazione Zoologica “Anton Dohrn”, Villa Comunale, Naples, Italy

    Maria Vittoria Cubellis

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Conceptualization: GA and MVC. Methodology: GA. Data curation: GA, TDO. Original draft preparation: GA. Data analysis, figures and writing of the first draft: GA, TDO and MM. Manuscript editing and critical revision: JJ and EM. Supervision: GA and MVC. Project administration: GA. All authors read and approved the final manuscript.

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Correspondence to Giuseppina Andreotti.

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Monticelli, M., D’Onofrio, T., Jaeken, J. et al. Congenital disorders of glycosylation: narration of a story through its patents. Orphanet J Rare Dis 18, 247 (2023). https://0-doi-org.brum.beds.ac.uk/10.1186/s13023-023-02852-w

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Orphanet Journal of Rare Diseases

ISSN: 1750-1172