Long-term Effects Of Enzyme Replacement Therapy Research Articles

Cardiac involvement in MPS patients: incidence and response to therapy in an Italian multicentre study

BackgroundMucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders caused by the deficit of lysosomal hydrolases involved in the degradation of glycosaminoglycans (GAGs). The course is chronic and progressive, with multisystemic involvement that often leads to cardiovascular disease. We describe the overall incidence and type of cardiac damage in a cohort of Italian MPS patients, and their progression over time, also with reference to treatment efficacy in patients under Enzyme Replacement Therapy (ERT). Moreover, we report a possible association between genetic variants and cardiac phenotype in homozygous and hemizygous patients to understand whether a more aggressive clinical phenotype would predict a greater cardiac damage.ResultsOur findings confirm that cardiac involvement is very common, already at diagnosis, in MPS VI (85.7% of our cohort), and in MPS II (68% of our cohort) followed by MPS I subjects (55% of our cohort). The most frequent heart defect observed in each MPS and at any time-point of evaluation was mitral insufficiency; 37% of our patients had mitral insufficiency already at diagnosis, and 60% at post-ERT follow-up. After at least six years of treatment, we observed in some cases (including 6 MPS II, 2 MPS IV and 2 MPS VI) a total regression or improvement of some signs of the cardiac pathology, including some valve defects, though excluding aortic insufficiency, the only valvulopathy for which no regression was found despite ERT. The general clinical phenotype proved not to be strictly correlated with the cardiac one, in fact in some cases patients with an attenuated phenotype developed more severe heart damage than patients with severe phenotype.ConclusionsIn conclusion, our analysis confirms the wide presence of cardiopathies, at different extent, in the MPS population. Since cardiac pathology is the main cause of death in many MPS subtypes, it is necessary to raise awareness among cardiologists about early cardiac morpho-structural abnormalities. The encouraging data regarding the long-term effects of ERT, also on heart damage, underlines the importance of an early diagnosis and timely start of ERT.

Individualized Assessment of Exercise Capacity in Response to Acute and Long-Term Enzyme Replacement Therapy in Pediatric Pompe Disease.

Background: Enzyme replacement therapy (ERT) with alglucosidase alfa improves the prospect of patients with infantile-onset Pompe disease (IOPD). However, a progressive decline has been reported. Objective quantification of the response to ERT when assessing newer strategies is warranted. Methods: This combined retrospective-prospective study assessed the acute and long-term effects of ERT on exercise in IOPD patients. Evaluation included cardiopulmonary exercise testing (CPET), 6-min walking test (6MWT), spirometry, motor function test (GMFM-88) and enzyme blood levels. Results: Thirty-four CPETs (17 pre- and 17 two days-post ERT) over variable follow-up periods were performed in four patients. Two days following ERT, blood enzyme levels increased (median, 1.22 and 10.15 μmol/L/h (p = 0.003)). However, FEV1, FVC and GMFM-88, the median 6MWD and the peak VO2 were unchanged. Long-term evaluations showed stabilization in young patients but progressive deterioration in adolescents. Clinical deterioration was associated with more pronounced deterioration in peak VO2 followed in the decreasing order by 6MWD, FVC and GMFM-88. Conclusions: The peak VO2 and 6MWD might serve as more sensitive markers to assess clinical deterioration. More studies are needed to clarify the sensitivity of the peak VO2 and 6MWT for quantification of individualized response. This may be important when assessing newer strategies and formulations in IOPD.

Angiokeratomas and treatment with enzyme replacement therapy in a patient with Fabry disease

Angiokeratomas are the cutaneous hallmark of Fabry disease. Although it is well established that enzyme replacement therapy (ERT) prevents or slows the progression of disease on target organs in the majority of patients, the long-term effect of ERT on angiokeratomas remains unknown. We present a patient diagnosed with Fabry disease at age 11, with rapid progression of new angiokeratomas in typical regions before beginning treatment with ERT. To date, our patient has been treated with ERT for 10 years. During the treatment period, new angiokeratomas have not arisen nor have existing ones enlarged during puberty, adolescence, and early adulthood. Furthermore, partial regression of the angiokeratomas has occurred in association with regression of left ventricular hypertrophy and anhidrosis. Overall, this case suggests that long-term ERT could stop the progression of angiokeratomas and induce their partial regression but does not produce complete resolution. Importantly, regression of angiokeratomas might be a marker of systemic target-organ efficacy of ERT.

An online survey of burden of illness in families with mucopolysaccharidosis type II children in the United States

Mucopolysaccharidosis type II (MPS II or Hunter's syndrome) is a rare X-linked recessive genetic disease caused by lack of the enzyme iduronate sulfatase, which leads to an accumulation of glycosaminoglycans (GAGs) throughout the body. As an X-linked disorder, MPS II occurs almost exclusively in males, although rarely females have been diagnosed. The disease has both severe and attenuated presentations, but there is a wide spectrum of clinical severity [1]. Severity of disease is usually based on the presence or absence of progressive neurological involvement and behavioral problems [[2], [3], [4]]. In severe MPS II children, coarse facial features, short stature, skeletal deformities, joint stiffness, cardiopulmonary disfunction, and neurocognitive deficits are typical. Disease onset occurs between two and four years of age, with somatic signs such as chronic ear infections, facial dysmorphism, enlarged tongue and tonsils, enlarged liver/spleen, and joint stiffness [2,[5], [6], [7]]. Cognitive development and adaptive ability begin to decline around 4 years of age, accompanied by severe speech and language delay [5,8]. Hearing loss begins around the age of 2 years, which affects speech and language development [2,9]. In addition, abnormal behavior such as hyperactivity, frustration, and impulsivity starts around 4 years of age [2,8]. Current treatment for MPS II in the United States (US) consists of enzyme replacement therapy (ERT), idursulfase, given intravenously (IV) usually on a weekly basis. The results of a phase II/III placebo-controlled clinical study of ERT with idursulfase demonstrated that weekly infusions produced significant improvements based on the six-minute walk test and pulmonary function as measured by the percentage of predicted forced vital capacity (FVC) [10]. However, these trials enrolled children with higher functioning who were likely not neuronopathic. Therefore, while ERT was shown to improve endurance and pulmonary function in these trials, the long-term effect of ERT on neurocognitive function specifically in neuronopathic children is not known, especially since IV ERT does not cross the blood-brain barrier. As severe MPS II is a chronic and debilitating condition, families with MPS II children experience significant economic, social, and humanistic burdens. Healthcare utilization, educational needs for the child, and caregiver burden in the US have not been well documented in the literature. A few non-US studies have assessed the burden of a variety of MPS types in terms of healthcare use, cost of care, caregiver time, and impact on work and family life. In France, a study assessed healthcare utilization in 51 MPS type II patients, primarily (69.2%) those with severe subtype [11]. Among respondents, 51% of the patients had been admitted to the hospital in the last 12 months for reasons associated with their disease, with a mean length of stay of 10.4 days (range 1–120 days), and 25.5% had been to the emergency room a mean number of 2 times, primarily for respiratory symptoms. In a 12-month period, 49% had seen an ear, nose and throat specialist, 30% had seen an orthopedic surgeon, and 29% had seen an ophthalmologist at least once. Eighty-four percent had seen a physical therapist (for an average of 7.4 times/year) and 40% had seen a speech therapist (for an average of 5.3 times/year). More than two-thirds (72.5%) reported they used social services assistance for help with home care aides and financial assistance. A study conducted by Pentek et al. in seven European countries assessed disease burden in 120 patients (74 children and 46 adults) and 66 caregivers among the MPS community, across many disease types, as part of a project referred to as BURQOL-RD (www.burqol-rd.org) [12]. Most caregivers (65 of 66) responding to the survey were the parent of the patient. These caregivers reported spending similar amounts of time per week caring for adult patients with MPS as the time reported caring for children with MPS (52 vs 51 h respectively), indicating that challenges to perform activities of daily living likely continue throughout life. The purpose of this study was to gather, via an online survey, real-world data from families in the US caring for sons with severe MPS II to quantify children's healthcare resource use, to describe educational needs, and to assess parents' work productivity and caregiving time.

Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates

Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human α-Gal A in wild-type (WT) mice, α-Gal A-deficient mice, and WT non-human primates (NHPs). The pharmacokinetics and distribution of h-α-Gal A mRNA encoded protein in WT mice demonstrated prolonged half-lives of α-Gal A in tissues and plasma. Single intravenous administration of h-α-Gal A mRNA to Gla-deficient mice showed dose-dependent protein activity and substrate reduction. Moreover, long duration (up to 6weeks) of substrate reductions in tissues and plasma were observed after a single injection. Furthermore, repeat i.v. administration of h-α-Gal A mRNA showed a sustained pharmacodynamic response and efficacy in Fabry mice model. Lastly, multiple administrations to non-human primates confirmed safety and translatability. Taken together, these studies across species demonstrate preclinical proof-of-concept of systemic mRNA therapy for the treatment of Fabry disease and this approach may be useful for other lysosomal storage disorders.

The beneficial effects of long-term enzyme replacement therapy on cardiac involvement in Japanese Fabry patients

Fabry disease is a hereditary disorder that occurs due to the reduction or absence of alpha-galactosidase A activity, which leads to cardiac involvement including left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) provides better patient outcomes by preventing serious complications. However, there have been very few studies on the long-term effects of ERT on the cardiac manifestations in Japanese Fabry patients. We retrospectively analyzed the data from the medical records of 42 Fabry patients (male, n = 17; female, n = 25) who were followed at Jikei University Hospital, and in whom the long-term effects of ERT could be evaluated (median follow-up period: male, 11 years; female, 8 years). The slope of the left ventricular mass (LVM) increase was 3.02 ± 3.41 g/m2/year in males and 1.69 ± 2.73 g/m2/year in females. In a subgroup analysis, the slopes of males with and without LVH did not differ to a statistically significant extent; however, the slope in female patients without LVH was significantly smaller than that of female patients with LVH. We then compared our data to the natural historical data that have previously been reported. In comparison to the previously reported data, we found a significant reduction in the LVM changes (g/height2.7/year) of patients who received long-term ERT (male, 4.07 ± 1.03 to 1.25 ± 1.39; female, 2.31 ± 0.81 to 0.78 ± 1.23). Long-term ERT effectively prevents LVH in Fabry patients. This effect was also observed in the patients with LVH prior to the initiation of ERT.

Abstract WP388: Basilar Artery Diameter is Associated With Cerebral Small Vessel Disease and the Duration of Enzyme-replacement Therapy in Fabry Disease

Introduction: Fabry disease (FD), an X-linked lysosomal storage disorder, causes intracellular accumulation of glycosphingolipids leading to progressive renal, cardiac, and cerebrovascular disease. Enzyme replacement therapy (ERT) is effective in reducing cardiac hypertrophy but has a limited effect on renal function, whereas there is still no clear evidence of the benefit of ERT for incident stroke. An enlarged basilar artery (BA) diameter has been of particular interest as an early and potential risk factor for stroke. However, the long-term effect of ERT for BA diameter in patients with FD are unknown. Hypothesis: We hypothesized that effect of ERT exerts a certain influence on for BA diameter in patients with FD. The aim of our study was to investigate the clinical characteristics of BA diameter in patients with FD. Methods: We retrospectively enrolled consecutive patients with FD who were treated ERT and underwent brain MRI. The short axis of BA diameter was measured at the midpons level on the axial T2-weighted image. Baseline MRI was used to determine cerebral small vessel disease (SVD); lacuna, white matter hyperintensities [WMH] and atrophy. Linear regression analyses were performed to evaluate the variables associated with BA diameter. Results: We enrolled 30 patients (mean age; 41.3 ± 15.1 years, male; 14). The baseline BA diameter was 3.16 ± 0.51 mm. Hypertension, cardiomegaly, chronic kidney disease, previous stroke, lacuna, and WMH were associated with initial BA diameter. Follow-up MRI was performed in 18 patients (male; 10) after a mean interval of 5.2 ± 3.7 years. Annual change in BA diameter was 0.06 ± 0.12 mm. Enlargement of BA diameter was positively correlated with baseline lacuna and severity of WMH. Furthermore, the duration of therapy between baseline ERT and follow-up MRI was inversely correlated with annual change of BA diameter (β= -0.518, P= 0.033). Given the stratification of the patient groups for gender, only male patients are observed for the significant correlation (β=-0.706, P= 0.022). Conclusion: In FD patients, enlarged BA diameter was associated with SVD. Furthermore, ERT might modify the natural course of BA diameter, especially for male patients.

RUSSIAN PEDIATRIC EXPERIENCE ON ASSESSING THE EFFECTIVENESS OF IMIGLUCERASE FOR LONG-TERM ENZYME REPLACEMENT THERAPY OF GAUCHER DISEASE TYPE 1 IN CHILDREN

Background: Today the gold standard for the treatment of Gaucher’s disease (GD) is an enzyme replacement therapy (ERT) which allows to stop the main clinical manifestations of the disease and to improve the quality of life in patients. In Russian pediatric practice, there are no publications which assess the effects of long-term ERT in children with GD type 1.Aim: To evaluate the effectiveness of imiglucerase for the treatment of Gaucher’s disease of type 1 in child population of the Russian Federation.Materials and methods: An evaluation of the effectiveness of enzyme replacement therapy was carried out by analyzing the monitoring data of 60 patients who were entered in the Russian pediatric registry of Gaucher disease at the National Scientific and Practical Center for Children’s Health for the period 2013−2016. Patients received continuous infusions of imiglucerase at a dose of 30−60 U/kg/2 weeks. Among of 60 children with Gaucher’s disease type 1, in 35 (group I) were recorded the dynamics of clinical and laboratory-instrumental indices during three years of therapy and in 25 (group II) ― an assessment of changes in quality of life parameters according to the PedsQL questionnaire within one year of treatment.Results: In group I, statistically significant changes for all key parameters (p0.001) were detected: median hemoglobin level and platelet count increased from 106 to 128 g/l and from 85 to 165×109/l, respectively; median chitotriosidase level decreased from 8303 to 1680 nmol/h/mL; median linear size of length and width of the spleen decreased by 54.5% and 40.0%, respectively, and the right lobe of the liver by 15%; parameters of physical development (height and weight) improved and median bone mineral density Z-score for the lumbar spine increased from -1.3 to -0.3. In group II: basing on the answers of children and parents, a statistically significant improvement (p0,05) of physical, emotional, and social functioning and the total score of quality of life was observed in 17 children aged 5−18 years; according to the parents’ answers, the increase of physical functioning was detected in 8 children aged 2−4 years.Conclusions: The timely appointment of ERT with imiglucerase in adequate dose and the regular infusion regime allows achievement of the key points of the treatment within 3 years and significant improvement of the quality of life parameters in children with GD type 1 in a year.

Effectiveness of enzyme replacement therapy in Fabry disease: Long term experience in Argentina

Evidence regarding long term effectiveness of enzyme replacement therapy (ERT) in Fabry disease (FD) is needed. The aim of this study was to analyze in a cohort of FD patients in Argentina, the long term effectiveness of ERT on renal, cardiac and cerebrovascular parameters. MethodsPatients with genetically proven FD were included from GADYTEF (Argentinean group for the treatment of FD) between 2001 and 2014. Renal, cardiac, and cerebral outcomes were prospectively studied in patients treated with ERT. Additionally, the occurrence of major cardiac complications, stroke, end-stage renal disease and death was analyzed during follow up. ResultsDuring the follow-up 8 major complications occurred in 5 patients (n=2 deaths, n=4 cases of end stage renal disease and n=1 atrial fibrillation), 4 of them males and only 1 female who suffered an atrial fibrillation. Sudden death or stroke did not occur. Four (40%) of 10 males with baseline left ventricular hypertrophy (LVH) reduced left ventricular mass index (LVMI) from 163.1±64.7 to 123.4±49.8g/m2, 2 stabilized LVMI and 4 increased LVMI from157.9±32.3 to 261.6±48.6g/m2. Estimated glomerular filtration was stable in 30 patients (17 males and 13 females). ConclusionsWe observed a few major complications during the follow up. Future studies are necessary to show the effectiveness of ERT in affected patients.

Long-term exposure to Myozyme results in a decrease of anti-drug antibodies in late-onset Pompe disease patients.

Immunogenicity of recombinant human acid-alpha glucosidase (rhGAA) in enzyme replacement therapy (ERT) is a safety and efficacy concern in the management of late-onset Pompe disease (LOPD). However, long-term effects of ERT on humoral and cellular responses to rhGAA are still poorly understood. To better understand the impact of immunogenicity of rhGAA on the efficacy of ERT, clinical data and blood samples from LOPD patients undergoing ERT for >4 years (n = 28) or untreated (n = 10) were collected and analyzed. In treated LOPD patients, anti-rhGAA antibodies peaked within the first 1000 days of ERT, while long-term exposure to rhGAA resulted in clearance of antibodies with residual production of non-neutralizing IgG. Analysis of T cell responses to rhGAA showed detectable T cell reactivity only after in vitro restimulation. Upregulation of several cytokines and chemokines was detectable in both treated and untreated LOPD subjects, while IL2 secretion was detectable only in subjects who received ERT. These results indicate that long-term ERT in LOPD patients results in a decrease in antibody titers and residual production of non-inhibitory IgGs. Immune responses to GAA following long-term ERT do not seem to affect efficacy of ERT and are consistent with an immunomodulatory effect possibly mediated by regulatory T cells.

Long-term effectiveness of enzyme replacement therapy in Fabry disease: results from the NCS-LSD cohort study.

To determine the effectiveness of enzyme replacement therapy (ERT) for adults and children with Fabry disease. Cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment and untreated patients contributed natural history data. Consenting adults (N = 289) and children (N = 22) with a confirmed diagnosis of Fabry disease attending a specialist Lysosomal Storage Disorder treatment centre in England. At recruitment 211 adults and seven children were on ERT (range of treatment duration, 0 to 9.7 and 0 to 4.2years respectively). Clinical outcomes chosen to reflect disease progression included left ventricular mass index (LVMI); proteinuria; estimated glomerular filtration rate (eGFR); pain; hearing and transient ischaemic attacks (TIA)/stroke. We found evidence of a statistically significant association between time on ERT and a small linear decrease in LVMI (p = 0.01); a reduction in the risk of proteinuria after adjusting for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (p < 0.001) and a small increase in eGFR in men and women without pre-treatment proteinuria (p = 0.01 and p < 0.001 respectively). The same analyses in children provided no statistically significant results. No associations between time on ERT and pain, risk of needing a hearing aid, or risk of stroke or TIAs, were found. These data provide some further evidence on the long-term effectiveness of ERT in adults with Fabry disease, but evidence of effectiveness could not be demonstrated in children.

Long‐term outcome of enzyme‐replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications

ObjectiveThe long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease.MethodsA total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain.ResultsDuring a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min−1 per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry.ConclusionDespite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.

The right ventricle in Fabry disease: natural history and impact of enzyme replacement therapy

BackgroundStorage of globotriaosylceramides is present in the left and right ventricles of patients with Fabry disease. Improvement of left ventricular morphology and function during enzyme replacement therapy (ERT) has previously...

Use of cardiac magnetic resonance imaging to evaluate cardiac structure, function and fibrosis in children with infantile Pompe disease on enzyme replacement therapy

Background Pompe disease (acid α-glucosidase deficiency) is one of several lysosomal storage diseases amenable to treatment with enzyme replacement therapy (ERT). While echocardiography (echo) has been the standard method to evaluate the cardiac response to ERT, cardiac magnetic resonance imaging (CMR) has the advantage of a better tissue definition and characterization of myocardial fibrosis. However, CMR for Pompe disease is not frequently performed due to a high risk of sedation. We report the first use of CMR in a feasible protocol to quantify left ventricular (LV) mass, function, and the presence of myocardial fibrosis in the Pompe population. Methods Children with Pompe disease on ERT were assessed with transthoracic echo and CMR over a 3 year period at a single institution. Echocardiography was performed using standard techniques without sedation. CMR was performed using retrospectively gated and real-time imaging, with and without sedation. LV mass indexed to body surface area (LVMI) and ejection fraction (EF) were measured by both echo and CMR, and evaluated for change over time. Myocardial fibrosis was assessed by CMR with delayed enhancement imaging 5–10 min after gadolinium contrast using single shot inversion recovery sequences with inversion time set to null the signal from normal myocardium. Results Seventeen CMR scans were successfully performed in 10 subjects with Pompe disease (median age at first CMR is 9 months, range 1–38 months, 80% male), with sedation only performed in 4 studies. There was a median interval of 5 months (range 0–34 months) from the start of ERT to first CMR (baseline). At baseline, the median indexed LVMI by CMR (140.0 g/m 2, range 43.8–334.0) tended to be lower than that assessed by echo (median 204.0 g/m 2, range 52.0–385.0), but did not reach statistical significance. At baseline, CMR EF was similar to that assessed by echo (55% vs. 55%). Overall, there was no significant decrease in CMR measured LVMI over time (CMR median LVMI at baseline 94 g/m 2 (range 43.8–334) vs. CMR median at most recent study 44.5 g/m 2 (range 34–303), p = 0.44). In 5 patients with serial CMR scans over time, LVMI decreased in 2, was similar in 2, and increased in 1 patient with high sustained antibodies to exogenous enzyme. Delayed enhancement was noted in only l separate patient who also had high sustained antibodies to exogenous enzyme. Conclusion CMR is an imaging tool that is feasible to use to serially follow LVMI and EF in children with Pompe disease on ERT. Real-time imaging is adequate for quantification purposes in these patients and minimizes the need for sedation. Quantitative CMR LVMI is generally lower than echo derived LVMI. Delayed enhancement appears to be a rare finding by CMR in Pompe disease. A further follow-up is necessary to better understand the long term effects of ERT in infantile Pompe survivors, especially those with high sustained antibody titers or advanced cardiac disease at treatment outset.

Wirkung der Enzymersatztherapie (ERT) auf die Nierenfunktion von Patienten mit Morbus Fabry

Fabry's disease is an inherited lysosomal storage disorder characterized by the lack of enzyme alpha-galactosidase A (alpha-Gal A) which degrades globotriaosylceramides (Gb3) into products with lower molecular weight. The accumulation of Gb3 in different cell types is responsible for the variety of clinical manifestations. The renal function, estimated via proteinuria, hematuria and reduction of glomerular filtration rate (GRF), is heavily affected. Currently, substitution of alpha-Gal A remains the only therapeutic option for patients with Fabry's disease. Two products are approved for the treatment of Fabry's disease: agalsidase alfa and agalsidase beta. Both of these enzymes have shown a stabilization of renal function in various studies when evaluated by the creatinine clearance, estimated GFR, and serum creatinine. The pro gnosis has proven to be significantly better in cases of mild or moderate renal insufficiency from the baseline. For this reason, an early substitution of the lacking enzyme is necessary. Furthermore, enzyme replacement therapy (ERT) has proven efficient in reducing the amount of intracellular Gb3 and Gb3 in urine. Without treatment, an eGFR reduction of approximately 12 ml/min/year has been reported. After diverse studies of ERT, no significant correlation between enzyme substitution and improvement of patients' proteinuria could be shown. Furthermore, renoprotective drugs have not been consistently applied so far in the ERT trials. In any case, further studies to evaluate the long-term effect of ERT on the morbidity and mortality of patients with Fabry's disease are necessary.

Enzyme-replacement therapy from birth delays the development of behavior and learning problems in mucopolysaccharidosis type IIIA mice.

Mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome) is a lysosomal storage disorder characterized by severe CNS degeneration, resulting in behavioral abnormalities and loss of learned abilities. Early treatment is vital to prevent long-term clinical pathology in lysosomal storage disorders. We have used naturally occurring MPS IIIA mice to assess the effects of long-term enzyme-replacement therapy initiated either at birth or at 6 wk of age. MPS IIIA and normal control mice received weekly i.v. injections of 1 mg/kg recombinant human sulfamidase until 20 wk of age. Sulfamidase is able to enter the brain until the blood-brain barrier completely closes at 10-14 d of age. MPS IIIA mice that were treated from birth demonstrated normal weight, behavioral characteristics, and ability to learn. MPS IIIA mice that were treated from birth performed significantly better in the Morris water maze than MPS IIIA mice that were treated from 6 wk of age or left untreated. A reduction in storage vacuoles in cells of the CNS in MPS IIIA mice that were treated from birth is consistent with the improvements observed. These data suggest that enzyme that enters the brain in the first few weeks of life, before the blood-brain barrier matures, is able to delay the development of behavior and learning difficulties in MPS IIIA mice.