更新于：2024-09-05

Glycogen Storage Disease XIV

XIV型糖原贮积病

更新于：2024-09-05

基本信息

别名

CDG It、CDG syndrome type It、CDG-It

+ [20]

简介

A rare genetic congenital disorder of glycosylation and glycogen storage disease with characteristics of a wide range of clinical manifestations, most commonly presenting with bifid uvula with or without cleft palate at birth, associated with growth delay, hepatopathy with elevated aminotransferase serum levels, myopathy (including exercise-related fatigue, exercise intolerance, muscle weakness), intermittent hypoglycaemia, and dilated cardiomyopathy and/or cardiac arrest, due to decreased phosphoglucomutase 1 enzyme activity. Less common manifestations include malignant hyperthermia, rhabdomyolysis, and hypogonadotropic hypogonadism with delayed puberty. Caused by homozygous or compound heterozygous mutation in the PGM1 gene on chromosome 1p31.

关联

项与 XIV型糖原贮积病相关的药物

Galactose(Avalo Therapeutics, Inc.)

靶点-

作用机制

半乳糖替代物

在研机构

Mayo Clinic [+1]

原研机构

Avalo Therapeutics, Inc.

在研适应症

XIV型糖原贮积病 [+1]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 XIV型糖原贮积病相关的临床试验

NCT05402332 / Not yet recruiting临床2期

A Phase 2b, Multicenter, Randomized, Double-blind, Placebo-Controlled, Crossover, Trial Assessing the Efficacy, Safety, and Tolerability of AVTX-801 in Subjects With Phosphoglucomutase 1 Deficiency Related Congenital Disorders of Glycosylation (PGM1-CDG)

You have been asked to take part in this research study because you have been diagnosed with PGM1-CDG and are currently taking D-galactose.

开始日期2024-02-01

申办/合作机构

Mayo Clinic

NCT05634070 / RecruitingN/A

Clinical Trial Evaluating Medical-grade Polycaprolactone-PCL Pectus Scaffold Implantation With Autologous Fat Grafting for Pectus Excavatum Camouflage (IT)

The clinical study evaluates the use of a custom-made medical-grade polycaprolactone-PCL Pectus scaffold implantation with Autologous Fat Grafting for pectus excavatum camouflage (IT). The study aims to demonstrate the safety and clinical performance of the insertion of an absorbable "medical-grade polycaprolactone-PCL Pectus Scaffold" in the thorax region with Autologous Fat Grafting in the correction of congenital Pectus Excavatum unsuitable for conventional treatment with stable cardio-respiratory function.
The PCL Pectus Scaffold-based design has the potential to induce sustained regeneration to fill large volume pectus excavatum defects, with the added benefit of being light weight and resorbable, thus not affecting the patients function capacity and reducing the risk of implant-related complications.

开始日期2022-12-14

申办/合作机构

BellaSeno GmbH初创企业

NCT05687474 / RecruitingN/AIIT

Universal Genomic Newborn Screening in the Wallonia-Brussels Federation: Baby Detect

Newborn screening (NBS) is a global initiative of systematic testing at birth to identify babies with pre-defined severe but treatable conditions. With a simple blood test, rare genetic conditions can be easily detected, and the early start of transformative treatment will help avoid severe disabilities and increase the quality of life.
Baby Detect Project is an innovative NBS program using a panel of target sequencing that aims to identify 126 treatable severe early onset genetic diseases at birth caused by 361 genes. The list of diseases has been established in close collaboration with the Paediatricians of the University Hospital in Liege. The investigators use dedicated dried blood spots collected between the first day and 28 days of life of babies, after a consent sign by parents.

开始日期2022-09-01

申办/合作机构

Centre Hospitalier Universitaire de Liege

[+5]

100 项与 XIV型糖原贮积病相关的临床结果

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100 项与 XIV型糖原贮积病相关的转化医学

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0 项与 XIV型糖原贮积病相关的专利（医药）

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项与 XIV型糖原贮积病相关的文献（医药）

2023-06-25·Current opinion in immunology

ERBIN and phosphoglucomutase 3 deficiency.

Review

作者: Joshua D Milner

ERBIN and phosphoglucomutase 3 (PGM3) mutations both lead to rare primary atopic disorders characterized by allergic disease and connective tissue abnormalities, though each disorder has its own rather unique pattern of multisystem presentations. Pathway studies show how ERBIN mutations allow for enhanced TGFb signaling, and prevent STAT3 from negative-regulating TGFb signaling. This likely explains many elements of clinical overlap between disorders of STAT3 and TGFb signaling. The excessive TGFb signaling leading to increased IL-4 receptor expression also provides the rationale for precision-based therapy blocking the IL-4 receptor to treat the atopic disease. The mechanism by which PGM3 deficiency leads to atopic phenotypes is not well understood, nor is the broad variability in disease penetrance and expressivity, though preliminary studies suggest an overlap with IL-6 receptor signaling defects.

2023-05-04·International journal of molecular sciences

In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis.

Article

作者: Federica Conte ; Angel Ashikov ; Rachel Mijdam ; Eline G P van de Ven ; Monique van Scherpenzeel ; Raisa Veizaj ; Seyed P Mahalleh-Yousefi ; Merel A Post ; Karin Huijben ; Daan M Panneman ; Richard J T Rodenburg ; Nicol C Voermans ; Alejandro Garanto ; Werner J H Koopman ; Hans J C T Wessels ; Marek J Noga ; Dirk J Lefeber

Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy metabolism from glycogen and glycolysis, as it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. PGM1 deficiency is an autosomal recessive disorder characterized by a highly heterogenous clinical spectrum, including hypoglycemia, cleft palate, liver dysfunction, growth delay, exercise intolerance, and dilated cardiomyopathy. Abnormal protein glycosylation has been observed in this disease. Oral supplementation with D-galactose efficiently restores protein glycosylation by replenishing the lacking pool of UDP-galactose, and rescues some symptoms, such as hypoglycemia, hepatopathy, and growth delay. However, D-galactose effects on skeletal muscle and heart symptoms remain unclear. In this study, we established an in vitro muscle model for PGM1 deficiency to investigate the role of PGM1 and the effect of D-galactose on nucleotide sugars and energy metabolism. Genome-editing of C2C12 myoblasts via CRISPR/Cas9 resulted in Pgm1 (mouse homologue of human PGM1, according to updated nomenclature) knockout clones, which showed impaired maturation to myotubes. No difference was found for steady-state levels of nucleotide sugars, while dynamic flux analysis based on ¹³C6-galactose suggested a block in the use of galactose for energy production in knockout myoblasts. Subsequent analyses revealed a lower basal respiration and mitochondrial ATP production capacity in the knockout myoblasts and myotubes, which were not restored by D-galactose. In conclusion, an in vitro mouse muscle cell model has been established to study the muscle-specific metabolic mechanisms in PGM1 deficiency, which suggested that galactose was unable to restore the reduced energy production capacity.

2023-01-26·Translational research : the journal of laboratory and clinical medicine

AAV-based gene therapy prevents and halts the progression of dilated cardiomyopathy in a mouse model of phosphoglucomutase I deficiency (PGM1-CDG).

Article

作者: B Balakrishnan ; R Altassan ; R Budhraja ; W Liou ; A Lupo ; S Bryant ; A Mankouski ; S Radenkovic ; G Preston ; A Pandey ; S Boudina ; T Kozicz ; E Morava ; K Lai

PGM1 deficiency is recognized as the third most common N-linked Congenital Disorders of Glycosylation (CDG) in humans. Affected individuals present with liver, musculoskeletal, endocrine, and coagulation symptoms; however, the most life-threatening complication is the early onset of dilated cardiomyopathy (DCM). Recently, we discovered that oral D-galactose supplementation improved liver disease, endocrine and coagulation abnormalities, but does not alleviate the fatal cardiomyopathy and the associated myopathy. Here we report on left ventricular ejection fraction (LVEF) in 6 individuals with PGM1-CDG. LVEF was pathologically low in most of these individuals and varied between 10-65%. To study the pathobiology of the cardiac disease observed in PGM1-CDG, we constructed a novel cardiomyocyte-specific conditional Pgm2 gene (mouse ortholog of human PGM1) knockout (Pgm2 cKO) mouse model. Echocardiography studies corroborated a DCM phenotype with significantly reduced ejection fraction and left ventricular dilation similar to those seen in individuals with PGM1-CDG. Histological studies demonstrated excess glycogen accumulation and fibrosis, while ultrastructural analysis revealed Z-disk disarray and swollen/fragmented mitochondria, which was similar to the ultrastructural pathology in the cardiac explant of an individual with PGM1-CDG. In addition, we found decreased mitochondrial function in the heart of KO mice. Transcriptomic analysis of hearts from mutant mice demonstrated a gene signature of DCM. Although proteomics revealed only mild changes in global protein expression in left ventricular tissue of mutant mice, a glycoproteomic analysis unveiled broad glycosylation changes with significant alterations in sarcolemmal proteins including different subunits of laminin-211, which was confirmed by immunoblot analyses. Finally, augmentation of PGM1 in KO mice via AAV9-PGM1 gene replacement therapy prevented and halted the progression of the DCM phenotype.

项与 XIV型糖原贮积病相关的新闻（医药）

2023-09-13

·Pharmaceutical Technology

Avalo drops three rare disease assets amid ongoing challenges

Adam Zamecnik @a_zamecnik Avalo drops three rare disease assets amid ongoing challenges. Credit: Shutterstock / Party people studio. Avalo Therapeutics will divest three compounds in its rare disease AVTX-800 series to AUG Therapeutics, marking a further development in the company’s tumultuous past months that included a negative trial readout and a default. The divestment is expected to be completed in Q4 2023, according to a 12 September press release. Recommended Reports Reports Chronic Heart Failure Drugs in Development by Stages, Target, MoA, RoA, Molecule Type and Key Pla... GlobalData Reports Acute Heart Failure Drugs in Development by Stages, Target, MoA, RoA, Molecule Type and Key Players GlobalData View all Companies Intelligence Avalo Therapeutics Inc Avalo, Inc. AUG Therapeutics LLC View all AUG will make an upfront payment of $150,000 for each of the three compounds bought from Avalo. This includes AVTX-801 (D-galactose), AVTX-802 (D-mannose) and AVTX-803 (L-fucose). In addition to the upfront payment, AUG will make a contingent payment of $15m if the first US Food and Drug Administration (FDA) approval is for an indication that is not a rare paediatric disease. AUG will also assume up to $150,000 of certain liabilities incurred before the agreement, based on the 12 September press release. Avalo’s AVTX-801 is a therapeutic dose of D-galactose that was developed for the treatment of the rare inherited disease phosphoglucomutase 1 (PGM1) deficiency. AVTX-803 is a therapeutic dose of L-fucose for use in leukocyte adhesion deficiency type II (LAD II), which is a different type of carbohydrate-deficient glycoprotein syndrome, based on the company’s website. Avalo first shared its plans for a potential divestment in its Q2 financial results update, shared last month. The US-based company stated that it was considering out-licensing or selling its non-core and even possibly core assets to reduce future expenses. The company already entered a non-binding letter of intent for the sale of the AVTX-800 series in July 2023. In the same month, Avalo entered a forbearance agreement with its debt lenders that followed a default. The default happened due to a material adverse change in the company’s business, per the 3 August company update. In June, Avalo announced that the Phase II PEAK study (NCT05288504) of its compound AVTX-002 (quisovalimab) in non-eosinophilic asthma patients missed its primary endpoint . While the trial did not meet the primary endpoint threshold for a reduction in asthma-related events , positive trends were observed in a patient sub-population with heightened baseline serum LIGHT levels, per a 26 June announcement. The company announced plans to evaluate these results to shape the asset’s further development, based on the 3 August update. Beyond AVTX-002, Avalo is focused on developing its preclinical BTLA agonist fusion protein AVTX-008 in autoimmune diseases.