scholarly journals Pharmacological Chaperone Therapy for Pompe Disease

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7223
Author(s):  
Marc Borie-Guichot ◽  
My Lan Tran ◽  
Yves Génisson ◽  
Stéphanie Ballereau ◽  
Cécile Dehoux
Keyword(s):  
Motor Neurons ◽  
Pompe Disease ◽  
Storage Disease ◽  
Protein Stabilization ◽  
Lysosomal Storage ◽  
Pharmacological Chaperone ◽  
Pharmacological Chaperones ◽  
Enzyme Replacement ◽  
Alpha Glucosidase ◽  
Gaa Gene

Pompe disease (PD), a lysosomal storage disease, is caused by mutations of the GAA gene, inducing deficiency in the acid alpha-glucosidase (GAA). This enzymatic impairment causes glycogen burden in lysosomes and triggers cell malfunctions, especially in cardiac, smooth and skeletal muscle cells and motor neurons. To date, the only approved treatment available for PD is enzyme replacement therapy (ERT) consisting of intravenous administration of rhGAA. The limitations of ERT have motivated the investigation of new therapies. Pharmacological chaperone (PC) therapy aims at restoring enzymatic activity through protein stabilization by ligand binding. PCs are divided into two classes: active site-specific chaperones (ASSCs) and the non-inhibitory PCs. In this review, we summarize the different pharmacological chaperones reported against PD by specifying their PC class and activity. An emphasis is placed on the recent use of these chaperones in combination with ERT.

scholarly journals Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1339
Author(s):  
Naresh K. Meena ◽  
Nina Raben
Keyword(s):  
Pompe Disease ◽  
Specific Treatment ◽  
Lysosomal Storage Diseases ◽  
Glycogen Storage Disease Type ◽  
Glycogen Storage ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Monogenic Diseases ◽  
Progressive Accumulation ◽  
Alpha Glucosidase

Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase resides in the lysosome gave rise to the concept of lysosomal storage diseases, and Pompe disease became the first among many monogenic diseases caused by loss of lysosomal enzyme activities. The only disease-specific treatment available for Pompe disease patients is enzyme replacement therapy (ERT) which aims to halt the natural course of the illness. Both the success and limitations of ERT provided novel insights in the pathophysiology of the disease and motivated the scientific community to develop the next generation of therapies that have already progressed to the clinic.

scholarly journals Delivery and postpartum management of a patient with Pompe disease: Case report and review of the literature

2017 ◽  
Vol 10 (3) ◽  
pp. 150-151 ◽  
Author(s):  
Kazibe Koyuncu ◽  
Batuhan Turgay ◽  
Rusen Aytac ◽  
Feride Soylemez
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Pompe Disease ◽  
Autosomal Recessive ◽  
Late Onset ◽  
Autosomal Recessive Disorder ◽  
Enzyme Replacement ◽  
Disease Case ◽  
Alpha Glucosidase ◽  
Gaa Gene

Pompe disease is an autosomal-recessive disorder caused by acid alpha-glucosidase deficiency due to mutations in the GAA gene. There are two forms of the disease: infantile-onset Pompe disease and late-onset Pompe disease. The worldwide incidence of both forms of the disease is commonly reported to be 1 in 40,000. Adult patients are affected by limb-girdle muscular weakness and respiratory insufficiency. Enzyme replacement therapy with alglucosidase-alpha is available since 2006. There is little knowledge about pregnant woman with Pompe disease. These women should be considered as high-risk pregnant women. Here, we aim to present Cesarean delivery and postpartum management of a case with an interrupted enzyme replacement therapy during pregnancy.

scholarly journals M Mode Ultrasound and Tissue Doppler Imaging to Assess Diaphragm Function in Late Onset Pompe Disease

2020 ◽  
Author(s):  
Paris Meng ◽  
Adam Ogna ◽  
Abdallah Fayssoil
Keyword(s):  
Tissue Doppler Imaging ◽  
Pompe Disease ◽  
Skeletal Muscles ◽  
Storage Disease ◽  
Late Onset ◽  
Tissue Doppler ◽  
Doppler Imaging ◽  
Lysosomal Storage ◽  
Diaphragm Function

Late onset Pompe disease is a recessive lysosomal storage disease. Clinical features include skeletal muscles deficiency and diaphragm weakness. Clinical management relies on supportive treatment and mechanical ventilation in patents with chronic respiratory failure. M mode ultrasound and tissue Doppler imaging can be used to assess and to follow up diaphragm function.

scholarly journals Cardiac Murmur in a Boy with Normal Paternal Prenatal Carrier Screening for Pompe Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-3
Author(s):  
Allison M. Jay ◽  
Premchand Anne ◽  
David Stockton
Keyword(s):  
Newborn Screening ◽  
Pompe Disease ◽  
Autosomal Recessive ◽  
Genetic Test ◽  
Carrier Screening ◽  
Lysosomal Storage ◽  
Cardiac Murmur ◽  
Enzyme Replacement ◽  
Prenatal Test ◽  
Infantile Type

Introduction. Pompe disease is an autosomal recessive lysosomal storage disorder with marked morbidity and mortality, if untreated. With the advent of enzyme replacement therapy, it is essential to identify the infantile-type as early as possible to mitigate the effects of the enzyme deficiency. Identification is possible prenatally with testing of both parents. More recently, many states have instituted newborn screening for this condition. Case. We report a patient with infantile-onset Pompe disease with a normal paternal carrier genetic test, born prior to newborn screening for Pompe disease in the state of Michigan. The infant’s father was retested once the infant was diagnosed with Pompe disease postnatally and noted to have a mutation conducive to Pompe disease. Conclusion. Providers should have a strong clinical suspicion for disorders even if prenatal parental carrier screening is normal. A normal parental prenatal test does not exclude the possibility that the fetus may be diagnosed with a disorder postnatally, and pediatricians may be faced with limitations in accuracy of parents’ recollection of parental testing results.

scholarly journals Orthopedic Management of Patients with Pompe Disease: A Retrospective Case Series of 8 Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Gerrit Haaker ◽  
Jürgen Forst ◽  
Raimund Forst ◽  
Albert Fujak
Keyword(s):  
Surgical Treatment ◽  
Pompe Disease ◽  
Neuromuscular Disorders ◽  
Young Patients ◽  
Case Series ◽  
Deformity Correction ◽  
Lysosomal Storage ◽  
Retrospective Case ◽  
Enzyme Replacement ◽  
Spine Stabilization

Introduction.Pompe disease (PD), a lysosomal storage disease as well as a neuromuscular disorder, is a rare disease marked by progressive muscle weakness. Enzyme replacement therapy (ERT) in recent years allowed longer survival but brought new problems to the treatment of PD with increasing affection of the musculoskeletal system, particularly with a significantly higher prevalence of scoliosis. The present paper deals with the orthopedic problems in patients with PD and is the first to describe surgical treatment of scoliosis in PD patients.Patients and Methods.The orthopedic problems and treatment of eight patients with PD from orthopedic consultation for neuromuscular disorders are retrospectively presented. We analyzed the problems of scoliosis, hip dysplasia, feet deformities, and contractures and presented the orthopedic treatment options.Results.Six of our eight PD patients had scoliosis and two young patients were treated by operative spine stabilization with benefits for posture and sitting ability. Hip joint surgery, operative contracture release, and feet deformity correction were performed with benefits for independent activity.Conclusion.Orthopedic management gains importance due to extended survival and musculoskeletal involvement under ERT. Surgical treatment is indicated in distinct cases. Further investigation is required to evidence the effect of surgical spine stabilization in PD.

Cholesteryl ester storage disease: a rare and possibly treatable cause of premature vascular disease and cirrhosis

2013 ◽  
Vol 66 (11) ◽  
pp. 918-923 ◽  
Author(s):  
Tim Reynolds
Keyword(s):  
Enzyme Activity ◽  
Cholesteryl Ester ◽  
Storage Disease ◽  
Treatment Options ◽  
Failure To Thrive ◽  
Early Death ◽  
Dried Blood Spots ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Reduced Activity

Cholesteryl ester storage disease (CESD) is an autosomal recessive lysosomal storage disorder caused by a variety of mutations of the LIPA gene. These cause reduced activity of lysosomal acid lipase, which results in accumulation of cholesteryl esters in lysosomes. If enzyme activity is very low/absent, presentation is in infancy with failure to thrive, malabsorption, hepatosplenomegaly and rapid early death (Wolman disease). With higher but still low enzyme activity, presentation is later in life with hepatic fibrosis, dyslipidaemia and early atherosclerosis.Identification of this rare disorder is difficult as it is essential to assay leucocyte acid phosphatase activity. An assay using specific inhibitors has now been developed that facilitates measurement in dried blood spots. Treatment of CESD has until now been limited to management of the dyslipidaemia, but this does not influence the liver effects. A new enzyme replacement therapy (Sebelipase) has now been developed that could change treatment options for the future.

scholarly journals Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Helena Costa-Verdera ◽  
Fanny Collaud ◽  
Christopher R. Riling ◽  
Pauline Sellier ◽  
Jayme M. L. Nordin ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Scale Up ◽  
Neuromuscular Disorder ◽  
Adeno Associated Virus ◽  
Peripheral Tissues ◽  
Pharmacological Chaperones ◽  
Enzyme Replacement ◽  
Hepatic Expression ◽  
Alpha Glucosidase

AbstractPompe disease (PD) is a severe neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). PD is currently treated with enzyme replacement therapy (ERT) with intravenous infusions of recombinant human GAA (rhGAA). Although the introduction of ERT represents a breakthrough in the management of PD, the approach suffers from several shortcomings. Here, we developed a mouse model of PD to compare the efficacy of hepatic gene transfer with adeno-associated virus (AAV) vectors expressing secretable GAA with long-term ERT. Liver expression of GAA results in enhanced pharmacokinetics and uptake of the enzyme in peripheral tissues compared to ERT. Combination of gene transfer with pharmacological chaperones boosts GAA bioavailability, resulting in improved rescue of the PD phenotype. Scale-up of hepatic gene transfer to non-human primates also successfully results in enzyme secretion in blood and uptake in key target tissues, supporting the ongoing clinical translation of the approach.

scholarly journals Fabry Disease

2021 ◽  
Author(s):  
Ida Kåks ◽  
Peter Magnusson
Keyword(s):  
Fabry Disease ◽  
Severe Disease ◽  
Gastrointestinal Symptoms ◽  
Specific Treatment ◽  
Skin Lesions ◽  
Lysosomal Storage ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Related Quality ◽  
Health Related

Fabry disease (FD) is a lysosomal storage disorder where deficient or completely absent activity of the enzyme α-galactosidas A leads to accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in lysosomes. The condition is rare, approximately 1:50,000, although underdiagnosis seems frequent. The condition can affect multiple organ systems, including the skin, nervous system, kidneys, and heart. Early manifestations include skin lesions (angiokeratoma), neuropathic pain, and gastrointestinal symptoms. Later on, FD can result in cardiomyopathy, kidney failure, and stroke. Both lifespan and health-related quality of life are affected negatively by FD. Patients are divided into a classical or a non-classical phenotype based on presentation, where the diagnosis of classical FD requires that a set of specific criteria are met. Patients with non-classical FD often have a less severe disease course, sometimes limited to one organ. The hereditary pattern is X-linked. Thus, men are in general more severely affected than women, although there is an overlap in symptomatic burden. Two types of specific treatment options are available: enzyme replacement therapy and pharmacological chaperone therapy. In addition to this, management of each organ manifestation with usual treatment is indicated.

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