Enzyme Replacement Research Articles

Fabry Cardiomyopathy: Myocardial Fibrosis, Inflammation, and Down-Regulation of Mannose-6-Phosphate Receptors Cause Low Accessibility to Enzyme Replacement Therapy.

The clinical impact of enzyme replacement therapy on advanced Fabry disease cardiomyopathy appears to be limited. The pathologic mechanisms involved are still unclear. Ten male patients with advanced Fabry disease cardiomyopathy on enzyme replacement therapy, whose disease progressed from maximal wall thickness of 15.4±2.2 to 19.3±2.1 mm in 8.6±1.4 years of follow-up, underwent left ventricular endomyocardial biopsy before and 4 hours after β-agalsidase infusion (1 mg/kg). Comparative studies between pre- and postinfusion samples included the following: histology, electron microscopy and assessment of myocardial α-galactosidase A activity; immunohistochemistry for α-galactosidase A and semiquantitative evaluation (from 0 to 3) of its cardiomyocyte content; and ultrastructural immunogold analysis with anti-α-galactosidase A ab; and Western blot quantification of mannose-6-phosphate receptors. Controls were surgical biopsies from patients with mitral stenosis. Histologic and ultrastructural evaluation showed myocarditis in 7 of 10 patients, There was no removal of storage material while myocardial fibrosis was 9.8%±6.8% versus 3.8%±2.0% of controls. At ultrastructural immunogold analysis, myocardial α-galactosidase A activity increased in postinfusion samples by overall 1.89-fold. Alpha-galactosidase A immunostaining in cardiomyocytes was absent at baseline in all patients and did not significantly improve in postinfusion samples. Immunogold particles increased by 1.33-fold (17.6±3.6 preinfusion versus 21.5±5.9 postinfusion), remaining far from normal controls (86.9±6.6). Protein analysis showed mannose-6-phosphate receptors to be 81% lower than in a normal heart. In spite of enzyme delivery to cardiac tissue, our study shows a low accessibility to enzyme replacement therapy of cardiomyocytes affected by advanced Fabry disease cardiomyopathy. It is sustained by myocardial fibrosis, inflammation, and severe down-regulation of mannose-6-phosphate receptors.

Radiological and morphological characteristics of the femoral head osteonecrosis in type I Gaucher disease.

BACKGROUND: Osteonecrosis of the femoral head in Gaucher disease typeI is an irreversible bone manifestation of the disease. The cause and mechanisms of osteonecrosis in Gaucher disease are still unknown, and their clinical and radiological characteristics must be taken into account when choosing treatment strategy. AIM: To analyze the radial and morphological changes in the proximal femur after osteonecrosis of the femoral head in typeI Gaucher disease. MATERIALS AND METHODS: The study included 251adult patients with typeI Gaucher disease from the Russian National Registry; histological examination of 22removed femoral bone fragments obtained during total hip replacement in 20patients with Gaucher disease and 9 in patients of the control group was performed. RESULTS: Osteonecrosis of the femoral head is detected in 30% of adult patients with Gaucher disease, and in 20% of patients it lead to femoral head collapse. Spongy bone osteosclerosis of the metaphysis, expansion/swelling of the bone marrow cavity with secondary osteopenia and osteoporosis of the proximal femur were often accompanied by osteonecrosis of the femoral head, creating technical difficulties during surgery. The histological picture revealed a picture of chronic bone ischemia of the proximal femoral metaepiphysis, which was confirmed by the identification of common areas of osteosclerosis during X-ray and MRI examination. Bone marrow infiltration by Gaucher cells in histological preparations persisted regardless of the duration of enzyme replacement therapy against the background of preserved regenerative potential of bone tissue. CONCLUSIONS: Тhe revealed features of the X-ray, MRI and histological picture should be taken into account when planning and conducting orthopedic operations for osteonecrosis of the femoral head in patients with type I Gaucher disease.

Long-Term Outcomes of Early Enzyme Replacement Therapy With Asfotase Alfa in Perinatal Benign Hypophosphatasia: Amelioration of Bone Deformities in a Young Child

Long-Term Outcomes of Early Enzyme Replacement Therapy With Asfotase Alfa in Perinatal Benign Hypophosphatasia: Amelioration of Bone Deformities in a Young Child

Management of presymptomatic juvenile patients with late-onset Pompe disease (LOPD).

Late-onset Pompe disease (LOPD) includes patients from 1 year of age to adulthood. The vast heterogeneity in clinical manifestations and disease progression is not fully explained; however, a short disease duration and a young age seem to be good predictors of a better response to treatment. For this purpose, we investigated and followed up a cohort of 13 juvenile patients with LOPD from the clinical and therapeutic point of view, mainly pointing out the transition from presymptomatic to symptomatic status. We retrospectively collected clinical, morphological, biochemical and molecular data from 13 juvenile LOPD patients. Motor and respiratory functional data, obtained during annual follow-up visits, were analyzed. The data included serial evaluations of the Medical Research Council (MRC) scale, the 6-Minute Walking Test (6MWT), the Gait, Stairs, Gower, and Chair (GSGC) score, and seated and supine Forced Vital Capacity (FVC). Muscle Magnetic Resonance Imaging (MRI) was also included, although it was not performed in all cases. Currently, patients mean age is 18 years. All patients but one were diagnosed because of an isolated hyperCKemia: the mean age at diagnosis was 6.8 years (range 1-18). The onset of symptoms occurred from 6 months to 12 years after the diagnosis. The mean clinical follow-up duration was 9 years (range 2-18). From the genetic point of view, the most shared mutation was c.32-13T>G, found in twelve patients as compound heterozygosis. Seven patients underwent muscle biopsy, which showed vacuolar myopathy with glycogen accumulation in four of them with unspecific changes in the other three cases. Five patients developed proximal muscle weakness during the follow-up with a mild waddling gait and a positive Gowers manoeuver. Muscle MRI revealed mild hypotrophy of the thighs at the development of symptoms in four out of five cases. Four patients started alglucosidase alfa, and one avalglucosidase alfa. These five patients on Enzyme Replacement Therapy (ERT) showed motor and respiratory stability in the following years. Timely identification of emerging clinical manifestations in presymptomatic LOPD patients, as a result of careful follow-up, is essential to start prompt treatment to modify the disease natural course.

Retrospective cohort study evaluating the economic burden of patients with Pompe disease treated with enzyme replacement therapy in the United States

Retrospective cohort study evaluating the economic burden of patients with Pompe disease treated with enzyme replacement therapy in the United States

Long term follow up of bone mineral density in Egyptian Gaucher disease type 3 patients on enzyme replacement therapy

Long term follow up of bone mineral density in Egyptian Gaucher disease type 3 patients on enzyme replacement therapy

Predicting liver fibrosis in Gaucher disease: Investigation of contributors and development of a clinically applicable Gaucher liver fibrosis score.

Gaucher disease (GD) is a rare genetic disorder with multi-system involvement. Liver fibrosis is a long-term complication of GD, potentially leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. There are currently no validated clinical tools for the monitoring of liver fibrosis in patients with GD. In this study, we aim at assessing the validity of common fibrosis-predicting scores, developed for other diseases, for the use in GD, using transient elastography as a gold-standard, as well as developing the first GD-specific liver fibrosis predicting score. We enrolled 19 adult patients with GD who had been on treatment for a minimum of 1year on enzyme replacement therapy or substrate reduction therapy and who had no evidence of any other liver disease except GD or metabolic-associated steatotic liver disease (MASLD), which is a common comorbidity of GD. We analyzed the correlation between liver stiffness and genotype, treatment modality (imiglucerase or other therapies), clinical severity, and clinical laboratory tests. We found that the common liver fibrosis scores APRI, FIB-4, and NFS did not accurately predict liver fibrosis in people with GD. We also found that male sex, the DS3 score, AST, and GGT levels significantly correlated with liver stiffness, and used these to create a simple but accurate fibrosis-predicting score specifically for GD (the "Gaucher liver fibrosis score", or GLFS), with high accuracy (AUC=0.8571, p=0.0206). We believe that our new GLFS may be used in clinical practice to help prioritize GD patients for closer monitoring of liver fibrosis.

Single centre experience of starting/ switching to one of two new enzyme replacement therapies in LOPD

Single centre experience of starting/ switching to one of two new enzyme replacement therapies in LOPD

Retrospective cohort study evaluating the disease burden of patients with Pompe disease treated with enzyme replacement therapy in the United States

Retrospective cohort study evaluating the disease burden of patients with Pompe disease treated with enzyme replacement therapy in the United States

Prospective longitudinal analysis of cardiac function in patients with CLN2 disease under enzyme replacement therapy (ICV-ERT) with cerliponase alfa

Prospective longitudinal analysis of cardiac function in patients with CLN2 disease under enzyme replacement therapy (ICV-ERT) with cerliponase alfa

Enzyme replacement therapy (ERT) combined with transient low-dose methotrexate (TLD-MTX) results in age- and disease-dependent immune profile changes in infantile- vs. late-onset Pompe disease patients

Enzyme replacement therapy (ERT) combined with transient low-dose methotrexate (TLD-MTX) results in age- and disease-dependent immune profile changes in infantile- vs. late-onset Pompe disease patients

Kinetic evolution of plasma biomarkers in acid sphingomyelinase deficiency patients under enzyme replacement therapy: A French experience

Kinetic evolution of plasma biomarkers in acid sphingomyelinase deficiency patients under enzyme replacement therapy: A French experience

Enzyme replacement therapy with renin-angiotensin system inhibition prevents kidney function decrease in most Finnish Fabry disease patients treated for 5 or 10 years

Enzyme replacement therapy with renin-angiotensin system inhibition prevents kidney function decrease in most Finnish Fabry disease patients treated for 5 or 10 years

A single centre review of pre-medications used in patients receiving enzyme replacement (ERT) infusions with evaluation of risk of adrenal insufficiency

A single centre review of pre-medications used in patients receiving enzyme replacement (ERT) infusions with evaluation of risk of adrenal insufficiency

Standardization of home enzyme replacement therapy for lysosomal disease in Japan

Standardization of home enzyme replacement therapy for lysosomal disease in Japan

Cardiomyopathy and reduced volume enzyme replacement therapy in patients with MPS I

Cardiomyopathy and reduced volume enzyme replacement therapy in patients with MPS I

Home infusion experience with enzyme replacement therapy for lysosomal diseases

Home infusion experience with enzyme replacement therapy for lysosomal diseases

Differences in initiation of enzyme replacement therapy across the United Kingdom

Differences in initiation of enzyme replacement therapy across the United Kingdom

Will rapid administration of enzyme replacement therapy impact patients' satisfaction?

Will rapid administration of enzyme replacement therapy impact patients' satisfaction?

Long term enzyme replacement therapy after hematopoietic stem cell transplant results in immune tolerance and improved biochemical outcomes

Long term enzyme replacement therapy after hematopoietic stem cell transplant results in immune tolerance and improved biochemical outcomes