Effects Of Enzyme Replacement Therapy Research Articles

Fabry disease: renal involvement limited to podocyte pathology and proteinuria in a septuagenarian cardiac variant. Pathologic and therapeutic implications

In men with classical Fabry disease (α-galactosidase A [α-Gal A] deficiency), kidney failure occurs as early as the second decade of life. In contrast, men with the mild “cardiac variant” have late-onset cardiac involvement and proteinuria but usually do not have renal failure. To investigate the nature of renal involvement in the cardiac variant of Fabry disease, the renal function and morphology were assessed in a 75-year-old affected man. He had mild congestive heart failure, a reduced left ventricular ejection fraction, and hypercholesterolemia but lacked the classical Fabry disease manifestations, including angiokeratoma, acroparesthesias, corneal and lenticular opacities, and hypohidrosis. At age 75 years, he had significant proteinuria, and mildly decreased renal function (serum creatinine, 1.8 mg/dL [159 μmol/L]), presumably secondary to hypertensive arteriosclerosis. He had about 4% residual α-Gal A activity in leukocytes, and mutation analysis identified the N215S missense mutation, the common lesion in cardiac variants. Histologic and ultrastructural studies of kidney tissue showed that lysosomal glycosphingolipid deposition was extensive in podocytes, rare in tubular epithelial cells, and absent in mesangial, interstitial, and vascular endothelial and smooth muscle cells. This cardiac variant serves as an “experiment of nature” showing that the residual α-Gal A activity precludes glycosphingolipid deposition in the renal endothelial and other cells that lead to early renal failure in classically affected men, whereas marked podocyte accumulation is associated with proteinuria and possibly late-onset renal dysfunction. These findings have important implications for the renal effectiveness of enzyme replacement therapy in classically affected patients and for the aggressive treatment of proteinuria in Fabry disease.

Effect of enzyme replacement therapy on gammopathies in Gaucher disease

Chronic antigenic stimulation by the abnormal lipid storage has been postulated to be the mechanism underlying anecdotal reports of monoclonal and polyclonal gammopathies as well as an increased incidence of multiple myeloma in patients with Gaucher disease of all ages. With the advent of specific enzyme therapy, it has been possible to ascertain whether signs and symptoms associated with Gaucher disease are true features of the disorder by virtue of their responsiveness to treatment. The purpose of this study was to assess the incidence of polyclonal and monoclonal gammopathies in a large cohort of patients and the effect of enzyme treatment. All adult patients whose records of immunoglobulin levels were available at presentation or at the advent of enzyme replacement therapy (ERT), and who had been followed for 2 years or receiving ERT for at least 2 years, respectively, and for whom there were also immunoglobulin levels at their most recent follow-up, were included in the study. The incidence of polyclonal gammopathies ranged between 14% and 25% among treated and untreated patients. There were statistically significant percentage decreases per year of enzyme therapy in polyclonal but not monoclonal (1% of all patients) gammopathies. Among enzyme-treated patients, there was no statistically significant difference among patients with regard to spleen status or relative to other parameters of disease severity, hepatitis status, age or gender. This study represents the largest database of gammopathies among patients with Gaucher disease from a large referral clinic. Because there was no correlation of abnormal immunoglobulin levels with disease severity, etiology may not be related to lipid accumulation per se but perhaps reflects a secondary, enzyme-sensitive process, whereas monoclonal gammopathies remain unaffected.

Auditory and vestibular findings in Fabry disease: a study of hemizygous males and heterozygous females.

This study aimed to evaluate audiological and vestibular involvement in Fabry disease and the early effects of enzyme replacement therapy with human alpha-galactosidase A. Fourteen patients (10 males, 4 females) aged 14-57 years were studied. Each patient underwent a clinical (history of otological and vestibular aspects, otoscopy) and instrumental (pure tone and speech audiometry, impedance, auditory brainstem response and oto-acoustic emission recordings, vestibular caloric tests, electronystagmography during acceleratory stimulation, dynamic posturography) evaluation before starting enzyme replacement therapy. Fifty per cent of patients complained of hearing symptoms (hearing loss, tinnitus, ear fullness). Subjective hearing loss was present in six cases and in three cases it was the first reported symptom of Fabry disease. In six of the seven cases the onset and/or progression of hearing symptoms were sudden. Vertigo or dizziness was reported by four patients and in two cases was associated with hearing symptoms. Audiological evaluation showed sensorineural hearing loss in eight patients (5 males, 3 females). Hearing loss was unilateral in six cases and bilateral in the remaining two cases. The hearing loss (HL) ranged from 30 to 80 dB HL (mean, 43 dB HL) and the lesion was always cochlear. Vestibular examination showed abnormalities in four patients (bilateral weak/abolished response in three cases, side prevalence in one case), which were not related to either the audiological results or the history of vertigo/dizziness. Involvement of the inner ear is common in men and women with Fabry disease. We found a high incidence of cochlear hearing loss, which was typically unilateral and showed onset and/or progression by sudden episodes. Vascular or hydropic mechanisms could be hypothesized to explain audiological findings. Vestibular involvement had a lower incidence and showed a different pattern, thus suggesting that several pathophysiological mechanisms could play a role in determining inner ear damage in Fabry disease. Our preliminary results show that enzyme replacement therapy may stabilize hearing function; however, further follow-up is required.

Effects of enzyme replacement therapy with agalsidase alfa on glomerular filtration rate in patients with Fabry disease: preliminary data

Effects of enzyme replacement therapy with agalsidase alfa on glomerular filtration rate in patients with Fabry disease: preliminary data

Effects of enzyme replacement therapy with agalsidase alfa on glomerular filtration rate in patients with Fabry disease: preliminary data.

Progressive deposition of globotriaosylceramide results in severe complications involving the kidney, heart and brain in both hemizygous male and heterozygous female patients with Fabry disease. Analysis of renal data from FOS--the Fabry Outcome Survey--suggests that enzyme replacement therapy with agalsidase alfa can significantly improve renal function in patients with Fabry disease, at least in those with a mild decrease in glomerular filtration rate, and may also be able to slow down the natural decline in renal function in patients with a moderate reduction in glomerular filtration rate. Initial results from the large cohort of patients within FOS indicate that treatment with agalsidase alfa has beneficial effects on kidney function in patients with Fabry disease.

Bone Marker Alterations in Patients with Type 1 Gaucher Disease

Bone involvement is one of the most disabling aspects of type I Gaucher disease and its pathophysiology is still not well understood. As an invasive procedure, bone biopsies are not appropriate in a large population study. The development of sensitive bone resorption and formation tests have allowed the authors to study bone metabolism in a noninvasive manner in a group of type 1 Gaucher patients. Ten type I Gaucher adult patients with mild-to-severe bone disease were evaluated. Bone mineral density and markers of bone formation (total alkaline phosphatase and isoenzymes, carboxyterminal propeptide of type I procollagen, osteocalcin) and resorption (carboxyterminal telopeptide of type I collagen, urinary hydroxyproline, free-deoxypyridinoline and calcium) were measured in patients and in a control group, matched for sex and age. In Gaucher patients, carboxyterminal propeptide of type I procollagen (PICP), a bone formation index, was significantly lower compared with normal subjects (mean 101.17 ng/ml vs 140.75 ng/ml, P = 0.038), and analysis of bone resorption indexes showed a significant increase (mean 4.24 ng/ml vs 2.87 ng/ml, P = 0.012) of serum carboxyterminal telopeptide of type I collagen (ICTP). No significant differences were observed in osteocalcin, alkaline phosphatase, and urinary hydroxyproline. Bone mineral density revealed osteopenia in six patients, with a mean Z-score of ?1.04. It was not possible to show a relationship between sex, splenectomy status, age, weight, spleen, and liver volume and bone density, expressed as a Z-score nor a correlation between Z score and severity of skeletal disease. Results have shown a predominance of the resorption phase in the bone metabolism of Gaucher patients. These markers could be useful in monitoring the effect of enzyme replacement therapy on Gaucher disease skeletal involvement.

Enzyme replacement therapy in mucopolysaccharidosis type II (Hunter syndrome): a preliminary report

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked disease caused by a deficiency of the enzyme iduronate-2-sulphatase (IDS), which results in the lysosomal accumulation of glycosaminoglycans (GAG). This paper describes a knockout mouse model of MPS II which has been used to assess the effect of enzyme replacement therapy. Therapy with IDS results in a marked decrease in urinary GAGs, as well as reduced GAG accumulation in several tissues. These studies have been used to support the first clinical trial of recombinant IDS in patients with Hunter syndrome.

Pain assessment: the advantages of using pain scales in lysosomal storage diseases

Routine and standardized assessment of pain should be conducted in patients with conditions, such as Fabry disease, that are associated with chronic pain. Such pain assessments, using validated and reliable pain scales or questionnaires, should cover the severity, location, temporal pattern and quality of the pain and how the pain impacts on quality of life and normal daily activity. The severity or intensity of pain can be assessed on verbal descriptor scales, visual analogue scales and numerical rating scales, which rate pain on a scale from ‘no pain’ through to ‘excruciating pain’ or ‘pain as bad as you can imagine’. Three pain questionnaires that include such rating scales are short enough to be used repeatedly in a clinical or research setting: the Memorial Pain Assessment Card, the McGill Pain Questionnaire and the Brief Pain Inventory (BPI). The BPI also measures the effect of pain on daily activity and quality of life, defines the location of pain and assesses the effectiveness of previous pain relief medication. Conclusions: Reliable instruments are available to assess pain in chronic disease. In Fabry disease, these should be used routinely to aid decisions concerning analgesic/pain control medication and to assess the effect of enzyme replacement therapy.

Enzyme replacement therapy in mucopolysaccharidosis type II (Hunter syndrome): a preliminary report

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X‐linked disease caused by a deficiency of the enzyme iduronate‐2‐sulphatase (IDS), which results in the lysosomal accumulation of glycosaminoglycans (GAG). This paper describes a knockout mouse model of MPS II which has been used to assess the effect of enzyme replacement therapy. Therapy with IDS results in a marked decrease in urinary GAGs, as well as reduced GAG accumulation in several tissues. These studies have been used to support the first clinical trial of recombinant IDS in patients with Hunter syndrome.

Pain assessment: the advantages of using pain scales in lysosomal storage diseases.

Routine and standardized assessment of pain should be conducted in patients with conditions, such as Fabry disease, that are associated with chronic pain. Such pain assessments, using validated and reliable pain scales or questionnaires, should cover the severity, location, temporal pattern and quality of the pain and how the pain impacts on quality of life and normal daily activity. The severity or intensity of pain can be assessed on verbal descriptor scales, visual analogue scales and numerical rating scales, which rate pain on a scale from 'no pain' through to 'excruciating pain' or pain as bad as you can imagine'. Three pain questionnaires that include such rating scales are short enough to be used repeatedly in a clinical or research setting: the Memorial Pain Assessment Card, the McGill Pain Questionnaire and the Brief Pain Inventory (BPI). The BPI also measures the effect of pain on daily activity and quality of life, defines the location of pain and assesses the effectiveness of previous pain relief medication. Reliable instruments are available to assess pain in chronic disease. In Fabry disease, these should be used routinely to aid decisions concerning analgesic/pain control medication and to assess the effect of enzyme replacement therapy.

Effect of enzyme replacement therapy on the ocular manifestations of Fabry disease

Effect of enzyme replacement therapy on the ocular manifestations of Fabry disease

Enzyme replacement therapy: from concept to clinical practice.

In the early 1960s, the first lysosomal storage disease was identified. Since then over 40 such diseases have been reported. The common feature is that enzyme deficiency leads to accumulation of undegraded macromolecules and lysosomal engorgement, resulting in organ dysfunction. Enzyme replacement therapy (ERT) is being developed for many of these disorders. The present paper summarizes the history of the development of ERT, with particular reference to the mucopolysaccharidoses, and specifically, to mucopolysaccharidosis type VII (MPS VII). The rarity of MPS VII has meant that ERT is not yet available for the small number of affected patients, although the study of MPS VII and murine models of the disease have played an important part in the development of treatment for related disorders, including Gaucher disease. Much progress has been made in our understanding of lysosomal storage diseases over the past 40 years. This has led to the development of effective ERT for some of the more common storage diseases, such as Fabry disease and Gaucher disease. Treatment is still awaited, however, for many of the other rare disorders in this area, such as MPS VII.

Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry

PurposeGaucher disease is the first lysosomal storage disorder to be treated with macrophage-targeted enzyme replacement therapy. Previous studies in relatively small numbers of patients demonstrated short-term efficacy of this treatment. This study describes the effects of 2 to 5 years of treatment on specific manifestations of type 1 Gaucher disease. Subjects and methodsPhysicians reported data from 1028 patients to the Gaucher Registry. Assessment of response included serial measurements of hemoglobin concentration, platelet count, liver and spleen volumes, and the occurrence of bone pain and bone crises. ResultsAmong anemic patients, hemoglobin concentration increased to normal or near normal within 6 to 12 months, with a sustained response through 5 years. In thrombocytopenic patients with intact spleens, the most rapid response occurred during the first 2 years, with slower improvement thereafter. The likelihood of achieving a normal platelet count decreased with increasing severity of baseline thrombocytopenia. In patients who had undergone splenectomy, platelet counts returned to normal within 6 to 12 months. Hepatomegaly decreased by 30% to 40% during follow-up; splenomegaly decreased 50% to 60%, but rarely to volumes below five times normal size. In patients with pretreatment bone pain or bone crises, 52% (67/128) were pain free after 2 years and 94% (48/51) reported no additional crises. ConclusionEnzyme replacement therapy prevents progressive manifestations of Gaucher disease, and ameliorates Gaucher disease–associated anemia, thrombocytopenia, organomegaly, bone pain, and bone crises.

Decreased Bone Density in Splenectomized Gaucher Patients Receiving Enzyme Replacement Therapy

ABSTRACTLittle is known about the effect of enzyme replacement therapy (ERT) on the bone abnormalities in Gaucher disease. Splenectomized Gaucher patients tend to suffer the most severe skeletal complications. We hypothesized that vitamin D supplementation would act synergistically with glucocerebrosidase infusions to increase bone density in splenectomized Gaucher patients. In a 24-month study, 29 splenectomized Gaucher patients were randomized to three groups: Group 1, calcitriol (1,25-dihydroxyvitamin D3; 0.25–3.0 μg/day) alone for the first 6 months with the addition of ceredase/cerezyme at 60 IU/kg every 2 weeks during months 7–12; Group 2, calcitriol together with ceredase/cerezyme at 60 IU/kg every 2 weeks during months 1–6; and Group 3, enzyme only at 60 IU/kg body wt every 2 weeks. In all three groups, enzyme dose was halved after the first 6 months of therapy. The primary outcome measure was bone mineral density of the lumbar spine measured by single-energy quantitative CT. Bone density by single-energy CT (P = 0.001) and by dual-energy CT (P = 0.06) declined overall, but there was no significant difference between the groups. Calcitriol had no significant effect on bone density. Fat fraction in lumbar spine increased (P = 0.000) and skeletal MRI scores improved. Bone-specific alkaline phosphatase (P = 0.002) and serum osteocalcin increased (P = 0.008), while blood cyclic AMP and urinary deoxypyridinoline did not change appreciably. Hemoglobin, platelet counts, and liver volume significantly improved. We conclude that ERT alone, or in combination with calcitriol, cannot repair the bone composition in splenectomized adult Gaucher patients. Alternatively, measuring trabecular bone density may be an inadequate marker of clinical efficacy for treating skeletal involvement in Gaucher disease.

Effects of enzyme replacement therapy in thirteen Japanese paediatric patients with Gaucher disease.

To determine treatment effects in the unique and previously internationally unreported Japanese paediatric patient population with Gaucher disease (GD), we analysed six response parameters among 13 patients given enzyme replacement therapy (ERT). Also to obtain insights into optimising maintenance dosing, through subgroup analysis we retrospectively examined effects of three ERT dose reduction schedules from a starting regimen of 60 U/kg of body weight every 2 weeks. Our patients included 11 males and two females, 11 individuals with possible type 1 and two individuals with type 3b GD, six individuals with the L444P/F2131 genotype and five with the L444P/L444P genotype, and five who had been splenectomised. Despite different mutation prevalence, Japanese patients with GD, like their counterparts from other ethnic groups, generally benefitted from ERT. However, early and marked ERT dose reduction (from 60 U/kg to 30 or 15 U/ kg every 2 weeks within < or =6 months) was associated with insufficient improvement of mean haemoglobin level and relative height and with insufficient improvement or worsening of platelet count. Only the subgroup given 60 U/kg of ERT every 2 weeks for 36 months had significant improvement in mean haemoglobin, platelet count, angiotensin-converting enzyme and acid phosphatase levels and relative height at 36 months. These data suggest that long-term high dose enzyme replacement therapy may be required to obtain sufficient improvement to maintain health among paediatric patients with severe Gaucher disease.

Plasma lipoproteins in gaucher disease: Effects of enzyme replacement therapy

Plasma lipoproteins in gaucher disease: Effects of enzyme replacement therapy

Haemostatic abnormalities and lupus anticoagulant activity in patients with Gaucher disease type I.

Gaucher disease (GD) type I (McKusick 230800), the most prevalent lysosomal storage disorder, is due to β-glucocerebrosidase (EC 3.2.1.45) deficiency. It is characterized by the storage of uncleaved β-glucocerebroside in the cells of the reticuloendothelial system, leading to bone marrow infiltration, hepatosplenomegaly and skeletal lesions. Other clinical features include haematological changes with anaemia and thrombocytopenia (Beutler and Grabowski 1995). Enzyme replacement therapy has become available and is effective in reversing hepatosplenomegaly and haematological abnormalities (Charrow et al 1998). Patients with GD type I have a bleeding tendency partially due to thrombocytopenia; a combined deficiency of clotting factors and inhibitors has also been reported (Billet et al 1996; Hollak et al 1997). We undertook this study to gain further insight into the pathophysiology of haemostatic abnormalities associated with Gaucher disease. The effect of enzyme replacement therapy on haemostasis was also monitored in comparison with changes of other laboratory parameters reflecting the status of the disease.

1 Gaucher's disease: past, present and future

A patient with what is now known as Gaucher's disease was first described by P.C.E. Gaucher in 1882. Fifty years later, Aghion reported that patients with this condition accumulated a sphingoglycolipid called glucocerebroside. Considerably more time was required for the demonstration by Brady and co-workers in 1964 that Gaucher's disease was due to reduced activity of a beta-glucosidase called glucocerebrosidase. This information provided the basis for the development of reliable diagnostic tests, detection of most of the carriers of this disorder and the prenatal diagnosis of this condition. Evidence was presented in 1990 and 1991 indicating the highly beneficial effects of enzyme replacement therapy in patients with Gaucher's disease. Gene therapy for Gaucher's disease was initiated in 1995. While little indication of success was obtained in this inaugural attempt, it is expected that improvements in this technology will provide a permanent cure for patients with this disorder.

Effect of enzyme replacement therapy on bone formation in a feline model of mucopolysaccharidosis type VI

A range of skeletal abnormalities are evident in mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) including short stature and dysostosis multiplex, resulting from a deficiency in the lysosomal hydrolase N-acetylgalactosamine-4-sulphatase (4S). In this article, bone pathology was assessed in a feline model of MPS VI to evaluate the efficacy of enzyme replacement therapy (ERT) as a treatment modality for this genetic disorder. Osteopenia is clearly evident in MPS VI animals, with bone mineral volume ( BV TV ) falling well below that of normal animals (4.39% vs. 20.11%, respectively). Trabecular bone architecture was also affected in MPS VI with fewer, thinner, and more widely spaced trabeculae apparent. Bone formation rate ( BFR BS ) was also lower in MPS VI animals than controls (0.0011 mm 3/mm 2 per day vs. 0.008 mm 3/mm 2 per day, respectively). Vertebral and tibial bone length in MPS VI animals progressively fell behind normal values with increasing age, as did cortical bone thickness. Vertebral body shape was also altered. ERT with recombinant human 4S (rh4S) resulted in a vertebral BV TV of 8.23% in animals treated with an intravenous enzyme dose of 1 mg/kg and a BV TV of 14.33% in animals treated with a dose of 5 mg/kg. BFR BS also increased to 0.0034 mm 3/mm 2 per day in animals treated with enzyme doses of either 1.0 or 5.0 mg/kg rh4S. All other affected histomorphometric parameters also improved with ERT to a level intermediate between MPS VI untreated animals and normals. However, individual animals treated with 0.2 mg/kg rh4S intravenously or 1.0 mg/kg rh4S administered subcutaneously did not exhibit an improvement over untreated MPS VI animals. Vertebral and tibial bone lengths, tibial cortical bone thickness, and vertebral body shape also responded to ERT, with a trend away from the untreated group. Thus, ERT had a positive effect on bone development in MPS VI animals that was dependent upon the dose of enzyme administered and the route of administration.

Bone marrow relaxation times in Gaucher disease before and after enzyme replacement therapy

The aim of this work was to monitor the effectiveness of enzyme replacement therapy on the basis of the changes in T1 relaxation times in Gaucher patients. A total of 26 patients underwent MR before enzyme replacement therapy; of them, 18 have been followed-up. A total of 22 age-matched controls underwent the same MR study. Scans were focused on the femoral neck, and T1 relaxation times were measured by means of a mixed spin-echo inversion recovery sequence. The T1 relaxation times in Gaucher patients were significantly longer than normal (p < 0.05). After enzyme replacement therapy, T1 relaxation times gradually became closer to those of control subjects, and there was also a significant decrease (p < 0.01) with respect to values before therapy, probably due to an increase in the fat/water ratio. Evaluation of T1 relaxation time may supply a useful indication of Gaucher disease regression after enzyme replacement therapy particularly in those cases in which a normal skeletal appearance corresponds to prolonged T1 relaxation times.