DeCure for PMM2-congenital disorder of glycosylation
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for PMM2-congenital disorder of glycosylation — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePMM2-congenital disorder of glycosylation maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
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Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for pmm2-congenital disorder of glycosylation is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
phosphomannomutase 2 (PMM2) — PMM2 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet g16drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 7O58 · 1.97 Å · ligand 1,6-di-O-phosphono-alpha-D-glucopyranose (G16). Experimental structure, not a prediction.
What the evidence adds up to
PMM2-CDG is the most common congenital disorder of N-glycosylation, caused by deficient activity of the phosphomannomutase 2 enzyme. Clinical presentation ranges from severe antenatal multisystem involvement to mild adult forms limited to minor neurological problems. There are no approved therapies for this condition. The first systematic review and international clinical guidelines for diagnosis, treatment and follow-up were published in 2019, based on available evidence and expert opinion, and focus on a multidisciplinary approach to managing each organ system involved.
Genetic analysis shows that the PMM2 gene is extremely tolerant to missense and loss-of-function mutations in the general population, meaning a partial deficiency of enzyme activity might be beneficial in some circumstances. The biochemical analysis of mutants does not allow a precise genotype–phenotype correlation. Patient phenotype may be influenced by variants in other genes associated with type I disorders of glycosylation. In a mouse model, homozygous deletion of Pmm2 is lethal by embryonic days 2.5 to 3.5, and transmission of the female null allele is impaired, indicating the gene is essential for early development.
A 2022 study used surveys and interviews with PMM2-CDG families and experts to identify the 24 most impactful signs and symptoms across a patient’s lifetime. A literature search found 239 articles containing tools to measure those symptoms, and 80 quality-of-life scales were identified that could be applied or adapted to create the first PMM2-CDG-specific quality-of-life questionnaire. No validated disease-specific quality-of-life scales existed before this work, which the authors describe as a first step toward filling a gap in clinical development.
What is still missing: no approved therapy exists; there are no validated disease-specific quality-of-life scales yet in routine use; the genotype–phenotype correlation remains poor; and the mouse model cannot be used to test treatments because homozygosity is lethal before implantation. Funding for clinical trials, better patient stratification tools, and a viable animal model for therapeutic testing are all lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Inherited Metabolic Disease · 2019 · 149 citations · open access
International clinical guidelines for the management of phosphomannomutase 2‐congenital disorders of glycosylation: Diagnosis, treatment and follow up
AbstractPhosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.
International Journal of Molecular Sciences · 2018 · 44 citations · open access
The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers
AbstractType I disorders of glycosylation (CDG), the most frequent of which is phosphomannomutase 2 (PMM2-CDG), are a group of diseases causing the incomplete N-glycosylation of proteins. PMM2-CDG is an autosomal recessive disease with a large phenotypic spectrum, and is associated with mutations in the PMM2 gene. The biochemical analysis of mutants does not allow a precise genotype–phenotype correlation for PMM2-CDG. PMM2 is very tolerant to missense and loss of function mutations, suggesting that a partial deficiency of activity might be beneficial under certain circumstances. The patient phenotype might be influenced by variants in other genes associated with the type I disorders of glycosylation in the general population.
Child Neurology: A case of PMM2-CDG (CDG 1a) presenting with unusual eye movements
AbstractCongenital disorders of glycosylation encompass a group of diseases resulting from abnormal protein glycosylation. This group includes more than 20 described diseases. 1 PMM2-CDG, previously referred to as congenital disorder of glycosylation type 1a (CDG 1a), is the most common of the congenital disorders of glycosylation. PMM2-CDG is associated with autosomal recessive inheritance of a mutation in the PMM2 gene. This mutation causes a deficiency of phosphomannomutase, an enzyme coded by PMM2, and results in decreased GDPmannose production, abnormal glycosylation of N-linked oligosaccharides, and clinical manifestations.
Patient reported outcomes for phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG): listening to what matters for the patients and health professionals
AbstractAbstract Background Congenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most common CDG is phosphomannomutase 2 (PMM2)-CDG which often has a severe clinical presentation and life-limiting consequences. There are no approved therapies for this condition. Also, there are no validated disease-specific quality of life (QoL) scales to assess the heterogeneous clinical burden of PMM2-CDG which presents a challenge for the assessment of the disease severity and the impact of a certain treatment on the course of the disease. Aim and methods This study aimed to identify the most impactful clinical signs and symptoms of PMM2-CDG, and specific patient and observer reported outcome measures (PROMs and ObsROMs, respectively) that can adequately measure such impact on patients’ QoL. The most burdensome signs and symptoms were identified through input from the CDG community using a survey targeting PMM2-CDG families and experts, followed by family interviews to understand the real burden of these symptoms in daily life. The list of signs and symptoms was then verified and refined by patient representatives and medical experts in the field. Finally, a literature search for PROMs and ObsROMs used in other rare or common diseases with similar signs and symptoms to those of PMM2-CDG was performed. Results Twenty-four signs/symptoms were identified as the most impactful throughout PMM2-CDG patients’ lifetime. We found 239 articles that included tools to measure those community-selected PMM2-CDG symptoms. Among them, we identified 80 QoL scales that address those signs and symptoms and, subsequently, their psychometric quality was analysed. These scales could be applied directly to the PMM2-CDG population or adapted to create the first PMM2-CDG-specific QoL questionnaire. Conclusion Identifying the impactful clinical manifestations of PMM2-CDG, along with the collection of PROMs/ObsROMs assessing QoL using a creative and community-centric methodology are the first step towards the development of a new, tailored, and specific PMM2-CDG QoL questionnaire. These findings can be used to fill a gap in PMM2-CDG clinical development. Importantly, this methodology is transferable to other CDG and rare diseases with multiple signs and symptoms.
Dialnet (Universidad de la Rioja) · 1977 · 0 citations
Instituciones de derecho penal y procesal: curso de lecciones para estudiantes de ciencias políticas
AbstractMutations in the cytosolic enzyme phosphomannomutase 2 (PMM2), which catalyzes the conversion of mannose-6-phosphate to mannose-1-phosphate, cause the most common form of congenital disorders of glycosylation, termed CDG-Ia. It is an inherited multisystemic disease with severe neurological impairment. To study the pathophysiology of CDG-Ia and to investigate possible therapeutic approaches, we generated a mouse model for CDG-Ia by targeted disruption of the Pmm2 gene. Heterozygous mutant mice appeared normal in development, gross anatomy, and fertility. In contrast, embryos homozygous for the Pmm2-null allele were recovered in embryonic development at days 2.5 to 3.5. These results indicate that Pmm2 is essential for early development of mice. Mating experiments of heterozygous mice with wild-type mice could further show that transmission of the female Pmm2-null allele is impaired.
Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics) · 2019 · 0 citations · open access
Congenital disorder of glycosilation PMM2-CDG
AbstractCongenital glycosylation disorders represent a group of genetically determined diseases which violate the synthesis and addition of glycans to glycoproteins and glycolipids, and also the synthesis of glycosylphosphatidyl inositol. The most common defects are the defects of protein N-glycosylation. Jaken syndrome, a congenital disorder of PMM2-CDG glycosylation, is the most commonly diagnosed type (about 800 cases worldwide). However, there are only a few descriptions of clinical cases in the Russian literature. The article presents a clinical observation of a child with this type of congenital glycosylation disorder due to a defect in phosphomannomtase 2 (PMM2 gene). The diagnose was based on the combination of clinical, laboratory and instrumental data: a characteristic phenotype, hyperinsulinism, delayed physical and psychomotor development, neurological manifestations, coagulopathy, liver damage, exudative enteropathy, abnormal forms of transferrin, PMM2 gene mutations associated with Jaken’s syndrome. For the first time the authors described positive clinical and laboratory dynamics due to the inclusion of D-mannose to the therapy for this type of congenital glycosylation disorder.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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