Treatment Options in Congenital Disorders of Glycosylation

Park, Julien H.; Marquardt, Thorsten

doi:10.3389/fgene.2021.735348

Cited by 20 publications

(10 citation statements)

References 140 publications

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“…Briefly, MPI-CDG can be successfully treated by oral mannose supplementation, as exogenous mannose can bypass the deficiency caused by MPI that contributes to N-glycan synthesis through Man-6-P ( Figure 2 ). International consensus guidelines recommend oral administration of mannose at a concentration of 150–170 mg/kg bodyweight, four to five times per day ( 24 ). A review of the literature revealed that of 30 patients who received mannose therapy, 26 showed improved clinical symptoms and laboratory results.…”

Section: Discussionmentioning

confidence: 99%

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

Liang

et al. 2023

Front. Pediatr.

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

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Section: Discussionmentioning

confidence: 99%

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

Liang

et al. 2023

Front. Pediatr.

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“…Most of CDG families were not aware of CTs for their CDGs, clearly demonstrating different advancement levels among different CDGs. In fact, therapeutic research initiatives favour PMM2-CDG [ 10 , 21 , 22 ]. This discrepancy could be perceived as an isolating tendency towards the different CDG, thus not helping families’ involvement.…”

Section: Discussionmentioning

confidence: 99%

Stakeholders’ views on drug development: the congenital disorders of glycosylation community perspective

Monticelli

Francisco

Brasil

et al. 2022

Orphanet J Rare Dis

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Background Congenital disorders of glycosylation (CDG) are a large family of rare genetic diseases for which therapies are virtually nonexistent. However, CDG therapeutic research has been expanding, thanks to the continuous efforts of the CDG medical/scientific and patient communities. Hence, CDG drug development is a popular research topic. The main aim of this study was to understand current and steer future CDG drug development and approval by collecting and analysing the views and experiences of the CDG community, encompassing professionals and families. An electronic (e-)survey was developed and distributed to achieve this goal. Results A total of 128 respondents (46 CDG professionals and 82 family members), mainly from Europe and the USA, participated in this study. Most professionals (95.0%) were relatively familiar with drug development and approval processes, while CDG families revealed low familiarity levels, with 8.5% admitting to never having heard about drug development. However, both stakeholder groups agreed that patients and families make significant contributions to drug development and approval. Regarding their perceptions of and experiences with specific drug development and approval tools, namely biobanks, disease models, patient registries, natural history studies (NHS) and clinical trials (CT), the CDG community stakeholders described low use and participation, as well as variable familiarity. Additionally, CDG professionals and families shared conflicting views about CT patient engagement and related information sharing. Families reported lower levels of involvement in CT design (25.0% declared ever being involved) and information (60.0% stated having been informed) compared to professionals (60.0% and 85.7%, respectively). These contrasting perceptions were further extended to their insights and experiences with patient-centric research. Finally, the CDG community (67.4% of professionals and 54.0% of families) reported a positive vision of artificial intelligence (AI) as a drug development tool. Nevertheless, despite the high AI awareness among CDG families (76.8%), professionals described limited AI use in their research (23.9%). Conclusions This community-centric study sheds new light on CDG drug development and approval. It identifies educational, communication and research gaps and opportunities for CDG professionals and families that could improve and accelerate CDG therapy development.

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“…Even though AI tools are still sporadically employed for CDG drug development, they have been successfully used for the diagnosis and characterization of these diseases [ 14 ]. Few advances in CDG therapy have been made over recent years [ 36 ]. By reviewing the literature, it is noted that four of the drugs advanced to different trial phases are repositioned drugs.…”

Section: Discussionmentioning

confidence: 99%

“…The last few years have seen significant advancements in CDG therapy development with a few promising treatments currently under pre-clinical or clinical evaluation. The therapies include substrate or co-factor supplementation, proteostasis inhibitors, pharmacological chaperones, and antisense and gene therapy [ 36 ]. CDG drug development could be pushed by drug repositioning alone or AI-assisted approaches, as in the case of other RDs [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG)

Brasil

Allocca

Magrinho

et al. 2022

IJMS

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Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders’ views on AI for therapy discovery in CDG.

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Treatment Options in Congenital Disorders of Glycosylation

Cited by 20 publications

References 140 publications

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

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

Stakeholders’ views on drug development: the congenital disorders of glycosylation community perspective

Systematic Review: Drug Repositioning for Congenital Disorders of Glycosylation (CDG)

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