Effects Of Enzyme Replacement Therapy Research Articles

Effects of imiglucerase treatment on traumatic fracture and bone and blood abnormalities in a patient with previously untreated type 1 gaucher disease

Objective: This letter reports on the effect of enzyme replacement therapy with imiglucerase on bone healing and bone and blood abnormalities in a woman with previously untreated type 1 Gaucher disease (GD). Methods: The 49-year-old patient had been diagnosed with GD at the age of 28 years and had previously undergone splenectomy. She presented with pseudarthrosis 14 months after sustaining a traumatic fracture of the tibia and fibula. Therapy was begun with imiglucerase 60 U/kg q2wk. The effects of treatment on bone healing were monitored radiographically, and effects on blood and bone marrow biology were monitored by hemograms, myelograms, and hematopoietic and mesenchymal clonogenic assays. Results: Objective bone healing was observed starting in the third month of imiglucerase treatment. Blood abnormalities normalized and bone marrow parameters improved over the first 9 months, including a decrease in Gaucher cells, an increase in bone marrow CD34+ cell cloning efficiency, and the appearance of mesenchymal progenitors. Conclusion: This research letter reports the results of hematologic and bone evaluations during enzyme replacement therapy with imiglucerase in a woman with previously untreated type 1 GD who presented with a traumatic fracture.

P322 Pompe Disease: a spectrum of phenotypes. Effect of enzyme replacement therapy (ERT)

P322 Pompe Disease: a spectrum of phenotypes. Effect of enzyme replacement therapy (ERT)

A detailed pathologic examination of heart tissue from three older patients with Anderson–Fabry disease on enzyme replacement therapy

Cardiac disease causes considerable morbidity and mortality in men and women with Anderson-Fabry disease (AFD), an X-linked inborn metabolic defect caused by deficiency of the lysosomal enzyme α-galactosidase A. Treatment with recombinant enzyme preparations aims to attenuate and reverse accumulation of the major enzyme substrate, globotriaosylceramide (Gb3). Pathologic data examining the effect of enzyme replacement therapy (ERT) in vivo are scant. A detailed examination of three whole hearts from patients (all male, aged 55, 59, 73 years) with AFD that had received ERT prior to death (for between 18 months and 4 years) was performed. In spite of ERT, Gb3 accumulation was present in myocytes, within both atria and ventricles, endothelial cells, smooth muscle cells, coronary arteries, aorta, and valve tissue. Nearly all myocytes within the right and left ventricles were hypertrophied with marked vacuolization of the cytoplasm. In all three cases, there was focal myocyte apoptosis and myocyte necrosis associated with macrophage accumulation and a small T-lymphocytic infiltrate. Extensive areas of replacement fibrosis (mean, 15%) associated with areas of myocyte disarray were present in all three hearts. This study highlights the pancardiac nature of AFD; demonstrates the extent of fibrotic changes; and reports, for the first time, myocyte disarray, necrosis, and apoptosis in hearts from patients affected by AFD and receiving ERT. These findings have major implications for the timing and efficacy of ERT in AFD.

Mortality and cause of death in mucopolysaccharidosis type II—a historical review based on data from the Hunter Outcome Survey (HOS)

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease caused by a deficiency of iduronate-2-sulfatase. Patients with the severe form of the disease have cognitive impairment and typically die in the second decade of life. Patients with the less severe form do not experience significant cognitive involvement and may survive until the fifth or sixth decade of life. We studied the relationship of both severity of MPS II and the time period in which patients died with age at death in 129 patients for whom data were entered retrospectively into HOS (Hunter Outcome Survey), the only large-scale, multinational observational study of patients with MPS II. Median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years; p = 0.024). These data indicate that cognitive involvement is indicative of more severe disease and lower life expectancy in patients with MPS II. Median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 versus 14.1 years; p alpha 0.001). The difference in age at death between patients dying in or before, relative to after, the selected cut-off date of 1985 may reflect improvements in patient identification, care and management over the past two decades. Data from patients who died after 1985 could serve as a control in analyses of the effects of enzyme replacement therapy with idursulfase on mortality in patients with MPS II.

Reversal of Cardiac Dysfunction after Enzyme Replacement in Patients with Infantile-Onset Pompe Disease

To compare the effects of enzyme replacement therapy (ERT) on cardiac performance in symptomatic and symptom-free infants with Pompe disease. Patients diagnosed between 1983 and 2008 were identified. Before the initiation of ERT, systolic dysfunction appeared only in patients > or = 5 months; thus we used this cut-point in age to divide clinically symptomatic patients into early and late treatment groups (Clin-E and Clin-L). Newborn screening (NBS) identified symptom-free patients. Among a total of 40 patients, 14 received ERT: 5 in the Clin-L, 4 in the Clin-E, and 5 in the NBS groups. All patients showed cardiomegaly, hypertrophic myocardium, and elevated B-type natriuretic peptide (measured in the Clin-E and NBS groups). ERT improved the survival and outcomes. Regressed myocardial hypertrophy and lowered B-type natriuretic peptide level occurred after 1 to 6 months of ERT. Nonetheless, there were 2 deaths and 2 survivors requiring ventilator support in the Clin-L group. Despite the regressed QRS voltage and shortened QT dispersion, life-threatening arrhythmias were still observed in 3, but none in the NBS group. ERT may restore the cardiac function in both symptomatic and symptom-free patients, but the beneficial effect may be unpredictable if given after the age of 5 months.

Effects of enzyme-replacement therapy in patients with Anderson–Fabry disease: a prospective long-term cardiac magnetic resonance imaging study

Background:Anderson–Fabry disease is a multisystem X linked disorder of lipid metabolism frequently associated with cardiac symptoms, including left ventricular (LV) hypertrophy gradually impairing cardiac function. Evidence showing that enzyme-replacement therapy...

Agalsidase alfa and kidney dysfunction in Fabry disease.

In male patients with Fabry disease, an X-linked disorder of glycosphingolipid metabolism caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, kidney dysfunction becomes apparent by the third decade of life and invariably progresses to ESRD without treatment. Here, we summarize the effects of agalsidase alfa on kidney function from three prospective, randomized, placebo-controlled trials and their open-label extension studies involving 108 adult male patients. The mean baseline GFR among 54 nonhyperfiltrating patients (measured GFR <135 ml/min per 1.73 m(2)) treated with placebo was 85.4 +/- 29.6 ml/min per 1.73 m(2); during 6 mo of placebo, the mean annualized rate of change in GFR was -7.0 +/- 32.9 ml/min per 1.73 m(2). Among 85 nonhyperfiltrating patients treated with agalsidase alfa, the annualized rate of change was -2.9 +/- 8.7 ml/min per 1.73 m(2). Treatment with agalsidase alfa did not affect proteinuria. Multivariate analysis revealed that GFR and proteinuria category (< 1 or > or = 1 g/d) at baseline significantly predicted the rate of decline of GFR during treatment. This summary represents the largest group of male patients who had Fabry disease and for whom the effects of enzyme replacement therapy on kidney function have been studied. These data suggest that agalsidase alfa may stabilize kidney function in these patients.

The natural course and the impact of therapies of cardiac involvement in the mucopolysaccharidoses

To analyze cardiac involvement and its progression in mucopolysaccharidoses, and to assess the short term impact of new therapeutic strategies. We studied echocardiographically 57 patients with various types of mucopolysaccharidoses, specifically types I, II, III, IV and VI, with a median age at the diagnosis of cardiac involvement of 5 years, following them for a median of 4.6 years, with a range from 0.9 to 21.2 years. We used a scoring system, along with the so-called delta score, to quantify the severity of involvement at baseline and at last examination, and to chart their progression over time. Cases with cardiac involvement increased from 59.6% to 87.3% at the last examination. The scores increased with age, and were significantly different according to the specific type of mucopolysaccharidosis. Involvement of the mitral valve was most common, often associated with an aortic valvar anomaly and/or left ventricular hypertrophy. Patients with the first and second types had more severe involvement than those with the third or fourth types. Patients undergoing transplantation of haematopoietic stem cells seem to stabilize after an initial worsening while, in contrast, we were unable to demonstrate an effect of enzyme replacement therapy on the progression of the cardiac disease, possibly because those receiving such treatment had a higher median age, more severe cardiac disease and shorter follow-up. Cardiac involvement was present early in more than a half of the patients identified as having mucopolysaccharidosis, and generally progressed, being more frequent and severe in the first and second types of the disease. Longer follow-up is needed to demonstrate any significant improvement induced by new therapies.

Kidney transplantation in patients with Fabry disease

Little is known about the effects of enzyme replacement therapy (ERT) in kidney transplant recipients with Fabry disease. Clinical characteristics of transplant recipients in the Fabry Outcome Survey (FOS) were therefore examined in patients with Fabry disease with or without ERT. Of the 837 European patients in FOS (March 2006), 34 male patients and two female patients had received kidney transplants. Mean age at transplantation was 37.6 +/- 10.9 years, mean time since transplantation was 7.7 +/- 6.4 years, median estimated glomerular filtration rate (eGFR) was 44.4 ml/min/1.73 m(2), and median proteinuria was 296 mg/24 h. Of 27 patients with baseline data, 59% had hypertension, 74% had left ventricular hypertrophy, 22% had cardiac valve disease, 30% had arrhythmia, and 22% had transient ischaemic attacks and 15% stroke. Twenty patients (74%; two female patients, 18 male patients) were receiving ERT with agalsidase alfa. At enrollment or at the start of ERT, median eGFRs were 59 and 35 ml/min/1.73 m(2) (P = 0.05) and median proteinuria levels were 240 and 420 mg/24 h (not significant) in treated and untreated patients respectively. Renal function remained stable in patients receiving ERT. In conclusion, agalsidase alfa is well tolerated in patients with Fabry disease who have undergone renal transplantation.

50. Pulmonary arterial hypertension in Gaucher disease: Predictors of progression and effect of enzyme replacement therapy

50. Pulmonary arterial hypertension in Gaucher disease: Predictors of progression and effect of enzyme replacement therapy

Agalsidase Alfa Slows the Decline in Renal Function in Patients with Fabry Disease

The aim of this study was to determine the effects of enzyme replacement therapy with agalsidase α on renal function in patients with Fabry nephropathy. Serum creatinine data were collected from 165 adult patients during 3 years of treatment. Serum creatinine increased in all men whereas it was stable in women, except in stage II renal disease (Kidney Disease Outcomes Quality Initiative). The estimated glomerular filtration rate (eGFR) declined in males with stage I and II (from 115.0 ± 22.2 to 98.3 ± 27.3 and from 76.5 ± 8.1 to 66.3 ±21.6 ml/min/1.73 m², respectively; both p < 0.01), whereas eGFR was stable in stage III. In females, eGFR was stable in stages I and III, and decreased in stage II (from 72.5 ± 8.3 to 67.3 ± 13.6 ml/min/1.73 m²; p = 0.01). The 24-hour proteinuria was <1 g in all patients, and most patients (96%) were treated with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors. Agalsidase α in combination with ACE inhibitors/ARB may be effective in slowing the deterioration in renal function in Fabry nephropathy.

Coronary Microvascular Dysfunction in Patients with Cardiomyopathies

Anginal symptoms and electrocardiographic changes suggestive of myocardial ischemia, despite angiographically normal coronary arteries, are common in patients with cardiomyopathies and those with left ventricular hypertrophy secondary to pressure overload. Studies using positron-emission tomography (PET) to measure regional myocardial blood flow have demonstrated that maximum myocardial blood flow and coronary flow reserve are severely blunted in patients with hypertrophic as well as dilated cardiomyopathy.1,2 In the absence of epicardial stenoses, blunted maximum myocardial blood flow and coronary flow reserve are suggestive of coronary microvascular dysfunction.3,4 Furthermore, it has been demonstrated that in both hypertrophic and dilated cardiomyopathy, the severity of coronary microvascular dysfunction, assessed by measuring myocardial blood flow with PET, is an independent predictor of prognosis.2,5 In patients with cardiomyopathies, coronary microvascular dysfunction can be sustained by a number of different pathogenetic mechanisms. These include structural and functional abnormalities of the intramural arterioles as well as extravascular mechanisms (eg, increased extramural compression).4 Article 161 Anderson-Fabry disease (AFD) is an X-linked deficiency of lysosomal α-galactosidase A.6 This deficiency results in multiorgan damage from glycosphingolipid deposition, leading to renal, cardiac, and cerebrovascular disease and premature death. Patients with AFD complain of angina despite angiographically normal coronary arteries. Recent studies have also shown that there is progressive deterioration in left ventricular systolic function and myocardial scarring in patients with AFD cardiomyopathy. A number of mechanisms may contribute to microvascular dysfunction in these patients. AFD cardiomyopathy is characterized by globotriaosyl-ceramide (Gb3) and related glycosphingolipid deposition in myocytes, conduction tissue, vascular endothelium, and valvular tissue. This is accompanied by secondary changes, such as myocyte hypertrophy and fibrosis, often mimicking hypertrophic cardiomyopathy.7 In the vasculature, Gb3 accumulates in endothelial and smooth muscle cells, possibly causing structural abnormalities that may be responsible for vascular dysfunction. In addition, it …

Initial report from the Hunter Outcome Survey

PurposeHunter syndrome (Mucopolysaccharidosis II) is a rare, X-linked disorder of glycosaminoglycan metabolism. It is caused by a deficiency in the lysosomal enzyme iduronate-2-sulfatase, and in affected patients glycosaminoglycan accumulates in lysosomes of various tissues and organs and contributes to the pathophysiology of Hunter syndrome. The Hunter Outcome Survey (HOS) was established to better describe the natural history of this disorder and to evaluate the long-term effect of enzyme replacement therapy. MethodsHOS is an international, multicenter, long-term observational survey that will collect data on participating patients with a confirmed diagnosis of Hunter syndrome. Data will be collected during regular physician examinations and entered into an electronic database. Examples of observations include vital signs, laboratory values, signs and symptoms of organ involvement, and the results of selected functional tests (e.g., audiometry, echocardiogram, joint mobility, etc.). ResultsAs of May 15, 2007, 263 patients from 16 countries have enrolled in HOS; 24% of these patients were currently being treated with enzyme replacement therapy. The median age at enrollment was 12.2 years. The median age of onset of symptoms and diagnosis of Hunter syndrome were 1.5 and 3.5 years, respectively. Otitis media and abdominal hernia were the earliest presenting symptoms. Facial dysmorphism and hepatosplenomegaly were demonstrated by 95% and 89% of patients, respectively. ConclusionsHOS will be a valuable resource for enhancing the understanding of Hunter syndrome and will provide important information about the natural history of the disease and the role of enzyme replacement therapy in its treatment. Patients and their physicians should be encouraged to participate.

Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48‐month longitudinal cohort study

Sims KB, Pastores GM, Weinreb NJ, Barranger J, Rosenbloom BE, Packman S, Kaplan P, Mankin H, Xavier R, Angell J, Fitzpatrick MA, Rosenthal D. Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study. Clin Genet 2008: 73: 430–440. © Blackwell Munksgaard, 2008Progressive skeletal disease accounts for some of the most debilitating complications of type 1 Gaucher disease. In this 48-month, prospective, non-randomized, open-label study of the effect of enzyme replacement therapy on bone response, 33 imiglucerase-naïve patients (median age 43 years with one or more skeletal manifestations such as osteopenia, history of bone crisis, or other documented bone pathology) received imiglucerase 60 U/kg/2 weeks. Substantial improvements were observed in bone pain (BP), bone crises (BC), and bone mineral density (BMD). Improvements in BP were observed at 3 months (p < 0.001 vs baseline) and continued progressively throughout the study, with 39% of patients reporting pain at 48 months vs 73% at baseline. Eleven of the 13 patients with a pre-treatment history of BC had no recurrences. Biochemical markers for bone formation increased; markers for bone resorption decreased. Steady improvement of spine and femoral neck BMD, measured using dual-energy X-ray absorptiometry was noted. Mean Z score for spine increased from −0.72 ± 1.302 at baseline to near-normal levels (−0.09 ± 1.503) by month 48 (p = 0.042) and for femoral neck from −0.59 ± 1.352 to −0.17 ± 1.206 (p = 0.035) at month 36. This increase was sustained at 48 months. With imiglucerase treatment, patients should anticipate resolution of BC, rapid improvement in BP, increases in BMD, and decreased skeletal complications.

WHAT'S IN OTHER JOURNALS

This study examined the effect of enzyme replacement therapy on differential gene expression in peripheral blood mononuclear cells of children with Fabry disease who had not previously been exposed to enzyme replacement therapy.

Évaluation d’une atteinte cornéenne dans le cadre d’une maladie de Fabry par microscopie confocale

Description of corneal findings in Fabry disease-related keratopathy using in vivo confocal microscopy. A 65-year-old man presenting with a cerebral ischemic lesion was referred to our clinic for ophthalmologic evaluation with a suspicion of inaugural Fabry disease. Slit lamp biomicroscopy showed whorl-like lines in the inferior cornea of both eyes. In vivo confocal microscopy revealed the presence of numerous hyperreflective intracellular inclusions in the corneal epithelium and stroma. The whorl-like lines are related to deposition and accumulation of glycosphingolipids in the epithelial and stromal layers of the cornea. This case is also interesting for the late manifestation of Fabry disease, showing the variability in the expression of this condition. In vivo confocal microscopy may be an important tool in the follow-up of Fabry disease-related keratopathy, enabling us to monitor the effect of enzyme replacement therapy.

Apoptotic abnormalities in differential gene expression in peripheral blood mononuclear cells from children with Fabry disease

This study was designed to examine the effect of enzyme replacement therapy (ERT) on differential gene expression in peripheral blood mononuclear cells (PBMCs) of children with Fabry disease who had not previously been exposed to ERT. Thirteen children with Fabry disease (age range, 6.5-17.0 years) were studied as part of a 6-month, open-label study of ERT with agalsidase alfa. Paired blood samples were taken at the start of the study and after 6 months of ERT. Further blood samples were also taken from 16 age-matched control subjects. PBMCs were isolated and, following RNA extraction, differential gene expression analysis was performed using the Human Genome U133 Plus 2.0 microarray. Twenty-one genes were determined to be differentially expressed in PBMCs of ERT-naïve children with Fabry disease compared with healthy controls; neuronal apoptosis inhibitory protein ranked as the most significantly differentially expressed gene. Comparison of gene expression in children with Fabry disease prior to and after ERT showed that two genes were significantly differentially expressed (p < or = 0.05) following treatment; the expressed sequence tag (probe set ID, 243259_at) was downregulated, while expression of apoptosis-inducing factor was increased, possibly as an antioxidant counter-regulatory response. This study identifies a number of genes that are differentially expressed in a small cohort of children with Fabry disease relative to healthy controls. These genes may relate to the underlying biological abnormalities in Fabry disease.

The mild form of mucopolysaccharidosis type I (Scheie syndrome) is associated with increased ascending aortic stiffness

Mucopolysaccharidosis type I (MPS IS) is a rare autosomal recessive disease caused by a deficiency of the lysosomal enzyme alpha-L-iduronidase, which is involved in the degradation of sulfated glycosaminoglycans (GAGs). The deficiency results in the intra-and pericellular accumulation of the GAGs heparan sulfate and dermatan sulfate. Eight adult patients with typical features of MPS IS aged 31.5 +/- 6.8 years (five men) were included and compared to age-and gender-matched controls. With transthoracic echocardiography, cyclic ascending aortic diameter changes were measured and ascending aortic elastic properties were calculated to characterize aortic elasticity. In MPS IS patients, aortic stiffness index was significantly increased (23.1 +/- 10.4 vs 3.9 +/- 1.5, P < 0.001), while aortic distensibility was significantly decreased (1.6 +/- 0.8 vs 4.6 [corrected] +/- 1.9 cm(2)/dynes [corrected] 10(-6), P < 0.001) compared to age-and sex-matched controls. The results of the present study demonstrate that in addition to the known cardiac complications, MPS IS patients have an impairment of ascending aortic elasticity. Further follow-up studies are needed to examine arterial elasticity using other methods in this patient population, and to detect possible effects of enzyme replacement therapy.

105. Effect of enzyme replacement therapy with imiglucerase (Cerezyme.) every 4 weeks in patients with type I Gaucher disease

105. Effect of enzyme replacement therapy with imiglucerase (Cerezyme.) every 4 weeks in patients with type I Gaucher disease

Lysosomal storage diseases as differential diagnoses to rheumatic disorders

To describe the latest findings on lysosomal storage diseases relevant to rheumatologists, including literature findings on the natural history, clinical features, diagnostic measures, and treatment. Many relevant investigations are based on large lysosomal storage disease registries. The steadily growing number of patients has resulted in an increasingly accurate description of the natural history of the diseases and permits the investigation of special problems, including monitoring the long-term safety and effectiveness of treatment. For Gaucher disease, several semi-quantitative and quantitative techniques have been proposed to measure bone marrow involvement and thus to monitor the effectiveness of enzyme replacement therapy. Given the unspecific symptoms of Fabry disease during childhood, several studies highlight the importance of a thoroughly recorded family history in making the correct diagnosis. Two investigations describe the specific features of Fabry disease in women. Given the rheumatologist's awareness of lysosomal storage diseases, the latest findings on the natural history of lysosomal storage diseases allow earlier diagnosis and treatment. The results of enzyme replacement therapy are promising, but large studies with control groups carried out over a longer period of time are lacking.