Morquio B Disease. Disease Characteristics and Treatment Options of a Distinct GLB1-Related Dysostosis Multiplex

Morquio B disease (MBD) is an autosomal recessive GLB1-gene-related lysosomal storage disease, presenting with a peculiar type of dysostosis multiplex which is also observed in GALNS-related Morquio A disease. MBD may present as pure skeletal phenotype (pure MBD) or in combination with the neuronopathic manifestations seen in type 2 (juvenile) or type 3 (late onset) GM1 gangliosidosis (MBD plus). The main skeletal features are progressive growth impairment, kyphoscoliosis, coxa/genua valga, joint laxity, platyspondyly and odontoid hypoplasia. The main neuronopathic features are dystonia, ataxia, and intellectual/developmental/speech delay. Spinal cord compression occurs as a complication of spinal dysostosis. Chronic pain is reported, along with mobility issues and challenges with daily living and self-care activities, as the most common health concern. The most commonly reported orthopedic surgeries are hip and knee replacements. Keratan sulphate-derived oligosaccharides are characteristic biomarkers. Residual β-galactosidase activities measured against synthetic substrates do not correlate with the phenotype. W273 L and T500A are the most frequently observed GLB1 variants in MBD, W273L being invariably associated with pure MBD. Cytokines play a role in joint destruction and pain, providing a promising treatment target. In the future, patients may benefit from small molecule therapies, and gene and enzyme replacement therapies, which are currently being developed for GM1 gangliosidosis.

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Pompe disease, a storage cardiomyopathy

Cardiogenetics ◽

10.4081/cardiogenetics.2017.6857 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 1

Author(s):

Tiziana Felice

Keyword(s):

Pompe Disease ◽

Age Of Onset ◽

Late Onset ◽

Treatment Options ◽

Premature Death ◽

Glycogen Storage Disease Type ◽

Lysosomal Storage ◽

Respiratory Compromise ◽

Enzyme Replacement ◽

Geographical Regions

Pompe disease also known as glycogen storage disease type II, is a rare and progressive lysosomal storage disorder caused by the deficiency of the enzyme acid α-glucosidase. This results in the accumulation of glycogen in various tissues particularly involving the heart, skeletal muscle and liver. It is inherited in an autosomal recessive manner due to mutations in the GAA gene. There are several known pathogenic variants, some of which are particularly common in certain geographical regions. Pompe disease is a single disease exhibiting a heterogeneous clinical spectrum depending on the extent of enzyme deficiency, the age of onset, the progression of the disease and the degree of organ involvement. It may lead to muscle weakness, hypotonia, respiratory compromise and premature death. Pompe disease is classically divided into two forms, infantile and late-onset disease. The infantile form is further subdivided into classical and non-classical subtypes. Cardiac involvement is particularly seen in the infantile phenotype of the condition, presenting as severe cardiomyopathy associated with conduction abnormalities. Enzyme replacement therapy with recombinant human acid α-glucosidase is the approved treatment option for patients with this metabolic condition. Further research is currently being done to explore more treatment options. One must keep in mind other metabolic and mitochondrial conditions, which may give a similar cardiac and neurological clinical picture.

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Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy

Nature Communications ◽

10.1038/s41467-021-25697-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Joan Bertolin ◽

Víctor Sánchez ◽

Albert Ribera ◽

Maria Luisa Jaén ◽

Miquel Garcia ◽

...

Keyword(s):

Gene Therapy ◽

Viral Vector ◽

Keratan Sulfate ◽

Whole Body ◽

Mucopolysaccharidosis Type ◽

Lysosomal Storage ◽

Peripheral Tissues ◽

Enzyme Replacement ◽

Morquio A ◽

Mucopolysaccharidosis Type Iva

AbstractMucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.

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The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases

Cells ◽

10.3390/cells9061411 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1411 ◽

Cited By ~ 2

Author(s):

Brianna M. Naumchik ◽

Ashish Gupta ◽

Heather Flanagan-Steet ◽

Richard A. Steet ◽

Sara S. Cathey ◽

...

Keyword(s):

Therapeutic Option ◽

Treatment Options ◽

Lysosomal Storage Diseases ◽

Hematopoietic Cell ◽

Cell Transplant ◽

Lysosomal Storage ◽

Hematopoietic Cell Transplant ◽

Psychomotor Delay ◽

Enzyme Replacement ◽

Enzyme Defects

The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.

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Proteomic Analysis in Morquio A Cells Treated with Immobilized Enzymatic Replacement Therapy on Nanostructured Lipid Systems

International Journal of Molecular Sciences ◽

10.3390/ijms20184610 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4610 ◽

Cited By ~ 4

Author(s):

J. Víctor Álvarez ◽

Susana B. Bravo ◽

María García-Vence ◽

María J. De Castro ◽

Asteria Luzardo ◽

...

Keyword(s):

Replacement Therapy ◽

Delivery System ◽

Skeletal Dysplasia ◽

Cellular Protein ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Morquio A ◽

Mps Iva ◽

Mucopolysaccharidosis Type Iva

Morquio A syndrome, or mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disease due to mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Systemic skeletal dysplasia and the related clinical features of MPS IVA are due to disruption of cartilage and its extracellular matrix, leading to an imbalance of growth. Enzyme replacement therapy (ERT) with recombinant human GALNS, alpha elosulfase, provides a systemic treatment. However, this therapy has a limited impact on skeletal dysplasia because the infused enzyme cannot penetrate cartilage and bone. Therefore, an alternative therapeutic approach to reach the cartilage is an unmet challenge. We have developed a new drug delivery system based on a nanostructure lipid carrier with the capacity to immobilize enzymes used for ERT and to target the lysosomes. This study aimed to assess the effect of the encapsulated enzyme in this new delivery system, using in vitro proteomic technology. We found a greater internalization of the enzyme carried by nanoparticles inside the cells and an improvement of cellular protein routes previously impaired by the disease, compared with conventional ERT. This is the first qualitative and quantitative proteomic assay that demonstrates the advantages of a new delivery system to improve the MPS IVA ERT.

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

Journal of Clinical Pathology ◽

10.1136/jclinpath-2012-201302 ◽

2013 ◽

Vol 66 (11) ◽

pp. 918-923 ◽

Cited By ~ 32

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.

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Liquid Chromatography–Tandem Mass Spectrometry Assay of Leukocyte Acid α-Glucosidase for Post-Newborn Screening Evaluation of Pompe Disease

Clinical Chemistry ◽

10.1373/clinchem.2016.259036 ◽

2017 ◽

Vol 63 (4) ◽

pp. 842-851 ◽

Cited By ~ 10

Author(s):

Na Lin ◽

Jingyu Huang ◽

Sara Violante ◽

Joseph J Orsini ◽

Michele Caggana ◽

...

Keyword(s):

Newborn Screening ◽

Pompe Disease ◽

Late Onset ◽

Treatment Options ◽

Internal Standard ◽

Lysosomal Storage ◽

Blood Samples ◽

Liquid Chromatography Tandem Mass ◽

Progressive Weakness

Abstract BACKGROUND Pompe disease (PD) is the first lysosomal storage disorder to be added to the Recommended Uniform Screening Panel for newborn screening. This condition has a broad phenotypic spectrum, ranging from an infantile form (IOPD), with severe morbidity and mortality in infancy, to a late-onset form (LOPD) with variable onset and progressive weakness and respiratory failure. Because the prognosis and treatment options are different for IOPD and LOPD, it is important to accurately determine an individual's phenotype. To date, no enzyme assay of acid α-glucosidase (GAA) has been described that can differentiate IOPD vs LOPD using blood samples. METHODS We incubated 10 μL leukocyte lysate and 25 μL GAA substrate and internal standard (IS) assay cocktail for 1 h. The reaction was purified by a liquid–liquid extraction. The extracts were evaporated and reconstituted in 200 μL methanol and analyzed by LC-MS/MS for GAA activity. RESULTS A 700-fold higher analytical range was observed with the LC-MS/MS assay compared to the fluorometric method. When GAA-null and GAA-containing fibroblast lysates were mixed, GAA activity could be measured accurately even in the range of 0%–1% of normal. The leukocyte GAA activity in IOPD (n = 4) and LOPD (n = 19) was 0.44–1.75 nmol · h−1 · mg−1 and 2.0–6.5 nmol · h−1 · mg−1, respectively, with no overlap. The GAA activity of pseudodeficiency patients ranged from 3.0–28.1 nmol · h−1 · mg−1, showing substantial but incomplete separation from the LOPD group. CONCLUSIONS This assay allows determination of low residual GAA activity in leukocytes. IOPD, LOPD, and pseudodeficiency patients can be partially differentiated by measuring GAA using blood samples.

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La terapia enzimatica sostitutiva nella malattia di Fabry

Giornale di Clinica Nefrologica e Dialisi ◽

10.33393/gcnd.2019.528 ◽

2019 ◽

Vol 31 (3) ◽

pp. 197-200

Author(s):

Letizia Roggero ◽

Sara Auricchio ◽

Federico Pieruzzi

Keyword(s):

Treatment Options ◽

Clinical Manifestations ◽

Specific Treatment ◽

Left Ventricular ◽

Lysosomal Storage ◽

Igg Antibody ◽

Enzyme Replacement ◽

Gi Symptoms ◽

History Of ◽

Treat All

Anderson-Fabry disease (FD) is a X-linked lysosomal storage disorder, which involves glycosphingolipids metabolism. Specific treatment for FD has been available in the last two decades, after the development and commercialization of recombinant human alfa-galactosidase A. Since then enzyme replacement therapy (ERT) has changed the natural history of the disease. Two different enzymatic formulations are available: agalsidase alfa and agalsidase beta at different dosages. The safety and efficacy profiles are similar. ERT induces Gb3 deposits reduction in renal and cardiac biopsies, improves quality of life, reduces pain and GI symptoms, decreases left ventricular mass and slows down renal function decline. In case of organ involvement, clinical evidence confirms the need to treat all patients with enzyme therapy, both male and female. In all other clinical settings, the decision to start ERT is controversial, because of the extremely variable clinical manifestations of FD. However, data suggest a greater response to ERT if started as early as possible in any patients. Timely treatment appears to be effective in stabilizing and possibly delaying FD progression. ERT infusion reactions due to allergic hypersensitivity or IgG antibody development could occur but can be easily managed. In-hospital and at home infusions are possible. The wide genetic and phenotypic heterogeneity observed in all FD patients requires a tailored approach to treatment options. Patients should be referred to an expert multidisciplinary team for the long term management of this challenging disease.

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Differences in MPS I and MPS II Disease Manifestations

International Journal of Molecular Sciences ◽

10.3390/ijms22157888 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7888

Author(s):

Christiane S. Hampe ◽

Brianna D. Yund ◽

Paul J. Orchard ◽

Troy C. Lund ◽

Jacob Wesley ◽

...

Keyword(s):

Dermatan Sulfate ◽

Treatment Options ◽

Neurological Involvement ◽

Type I ◽

Ionic Balance ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Mps Ii ◽

Corneal Clouding ◽

Mps I

Mucopolysaccharidosis (MPS) type I and II are two closely related lysosomal storage diseases associated with disrupted glycosaminoglycan catabolism. In MPS II, the first step of degradation of heparan sulfate (HS) and dermatan sulfate (DS) is blocked by a deficiency in the lysosomal enzyme iduronate 2-sulfatase (IDS), while, in MPS I, blockage of the second step is caused by a deficiency in iduronidase (IDUA). The subsequent accumulation of HS and DS causes lysosomal hypertrophy and an increase in the number of lysosomes in cells, and impacts cellular functions, like cell adhesion, endocytosis, intracellular trafficking of different molecules, intracellular ionic balance, and inflammation. Characteristic phenotypical manifestations of both MPS I and II include skeletal disease, reflected in short stature, inguinal and umbilical hernias, hydrocephalus, hearing loss, coarse facial features, protruded abdomen with hepatosplenomegaly, and neurological involvement with varying functional concerns. However, a few manifestations are disease-specific, including corneal clouding in MPS I, epidermal manifestations in MPS II, and differences in the severity and nature of behavioral concerns. These phenotypic differences appear to be related to different ratios between DS and HS, and their sulfation levels. MPS I is characterized by higher DS/HS levels and lower sulfation levels, while HS levels dominate over DS levels in MPS II and sulfation levels are higher. The high presence of DS in the cornea and its involvement in the arrangement of collagen fibrils potentially causes corneal clouding to be prevalent in MPS I, but not in MPS II. The differences in neurological involvement may be due to the increased HS levels in MPS II, because of the involvement of HS in neuronal development. Current treatment options for patients with MPS II are often restricted to enzyme replacement therapy (ERT). While ERT has beneficial effects on respiratory and cardiopulmonary function and extends the lifespan of the patients, it does not significantly affect CNS manifestations, probably because the enzyme cannot pass the blood–brain barrier at sufficient levels. Many experimental therapies, therefore, aim at delivery of IDS to the CNS in an attempt to prevent neurocognitive decline in the patients.

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Fabry Cardiomyopathy: Current Treatment and Future Options

Journal of Clinical Medicine ◽

10.3390/jcm10143026 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3026

Author(s):

Irfan Vardarli ◽

Manuel Weber ◽

Christoph Rischpler ◽

Dagmar Führer ◽

Ken Herrmann ◽

...

Keyword(s):

Treatment Options ◽

Current Treatment ◽

Left Ventricular ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Alpha Galactosidase ◽

Nerve System ◽

Future Therapy ◽

Reduced Activity

Fabry disease is a multisystem X-linked lysosomal storage disorder caused by a mutation in the alpha-galactosidase A gene. Deficiency or reduced activity of alpha-galactosidase A (GLA) is leading to progressive intracellular accumulation of globotriaosylceramide (GL3) in various organs, including the heart, kidney and nerve system. Cardiac involvement is frequent and is evident as concentric left ventricular hypertrophy. Currently, the standard treatment is enzyme replacement therapy or chaperone therapy. However, early starting of therapy, before myocardial fibrosis has developed, is essential for long-term improvement of myocardial function. For future treatment options, various therapeutic approaches including gene therapy are under development. This review describes the current and potential future therapy options for Fabry cardiomyopathy.

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Rare Diseases in Neurology — Caring for a Patient with Pompe’s Disease

The Journal of Neurological and Neurosurgical Nursing ◽

10.15225/pnn.2019.8.4.5 ◽

2019 ◽

Vol 8 (4) ◽

pp. 170-176

Author(s):

Anna Roszmann ◽

◽

Mikołaj Hamerski ◽

Marcelina Skrzypek-Czerko ◽

◽

...

Keyword(s):

Clinical Picture ◽

Pompe Disease ◽

Age Of Onset ◽

Late Onset ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Pompe’S Disease ◽

Pompe's Disease ◽

Disease Case ◽

Nurses Role

Introduction. Pompe disease, a severe metabolic myopathy, is caused by mutations in the gene coding for acid alphaglucosidase (GAA), what lead to intralysosomal accumulation of glycogen in all tissues, most notably in skeletal muscles. Pompe disease was the first documented lysosomal storage disease, nowadays we know around 60 similar disorders. Aim. Presentation of the clinical picture of a man with Pompe’s disease. Case Report. A man at the age of 40, diagnosis of the Pompe’s disease was made only at the age of 31. The first symptoms, indicating the patient’s development of the disease, were already present in the early school age. At first, the clinical picture presented by the patient led to the diagnosis of muscular dystrophy. Discussion. Pompe disease presents as a continuum of clinical phenotypes that differ by age of onset, severity, and organ involvement. Pompe disease affects people of all ages with varying degrees of severity. Two main broad types are recognized based on the onset of symptoms and the presence or absence of cardiomyopathy. Infantile onset Pompe disease (IOPD) as one, and the most severe for mod the disease. Other and less destructive is late-onset Pompe disease (LOPD) manifests any time after 12 months of age. The disease can be successfully treated by enzyme replacement therapy with alglucosidase alfa that was approved for human use in 2006. Conclusions. In big importance is nurses role as educators and support for the patients during their hospitalizations for medicine infusions twice a month. It time when the knowledge and significance of proper life style can be discussed and implemented to empower the patients. (JNNN 2019;8(4):170–176) Key Words: Pompe’s disease, treatment, diagnosis, care

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