Enzyme replacement therapy in mucopolysaccharidosis type I

Mucopolysaccharidosis (MPS) type I is a lysosomal storage disorder caused by deficiency of the enzyme α- l -iduronidase (IDUA), which presents with a wide spectrum of phenotypes. Recently, enzyme replacement therapy (ERT) became available for patients with MPS I and has been demonstrated to be safe and effective in patients with the milder Hurler–Scheie and Scheie phenotypes. Treatment for 26 weeks with recombinant human IDUA (laronidase) has been shown to significantly increase the percentage of predicted normal forced vital capacity and the distance walked in the 6-minute walk test. There was also a clear reduction in the volume of the liver and the levels of urinary glycosaminoglycan excretion. The drug was generally well tolerated. There were no drug-related severe adverse events, and although the majority of patients developed IgG antibodies, these declined by the end of the study.
Conclusion: ERT seems to be a very promising new therapeutic regimen for patients with MPS I, especially for those with the less severe variants. However, as laronidase does not cross the blood–brain barrier it will probably not influence the central nervous manifestations in the most severely affected patients with the Hurler phenotype, although it may improve general lung and heart function, making bone marrow transplantation easier to tolerate.     

Diagnosis and treatment trends in mucopolysaccharidosis I: findings from the MPS I Registry

Our objective was to assess how the diagnosis and treatment of mucopolysaccharidosis I (MPS I) have changed over time. We used data from 891 patients in the MPS I Registry, an international observational database, to analyze ages at symptom onset, diagnosis, treatment initiation, and treatment allocation (hematopoietic stem cell transplantation, enzyme replacement therapy with laronidase, both, or neither) over time for all disease phenotypes (Hurler, Hurler-Scheie, and Scheie syndromes). The interval between diagnosis and treatment has become shorter since laronidase became available in 2003 (gap during 2006-2009: Hurler--0.2 year, Hurler-Scheie--0.5 year, Scheie--1.4 years). However, the age at diagnosis has not decreased for any MPS I phenotype over time, and the interval between symptom onset and treatment initiation remains substantial for both Hurler-Scheie and Scheie patients (gap during 2006-2009, 2.42 and 6.71 years, respectively). Among transplanted patients, an increasing proportion received hematopoietic stem cells from cord blood (34 out of 64 patients by 2009) and was also treated with laronidase (42 out of 45 patients by 2009). CONCLUSIONS: Despite the availability of laronidase since 2003, the diagnosis of MPS I is still substantially delayed for patients with Hurler-Scheie and Scheie phenotypes, which can lead to a sub-optimal treatment outcome. Increased awareness of MPS I signs and symptoms by primary care providers and pediatric subspecialists is crucial to initiate early treatment and to improve the quality of life of MPS I patients.     

Hurler syndrome. Early diagnosis and successful enzyme replacement therapy: a new therapeutic approach. Case report]

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder due to alpha-L-iduronidase deficiency. Its severe prognosis has been significantly improved by enzyme replacement therapy using recombinant human alpha-L-iduronidase (laronidase). We report the case of a boy who was diagnosed at 19 months of age with Hurler's disease, the most severe form of MPS I, and received thereafter a treatment by laronidase, resulting in clinical and biological improvement. The aim of this case report is to draw physicians' attention on the presenting signs of Hurler's disease, in order to enable an earlier diagnosis, increasing the treatment's benefits.     

Enzyme replacement therapy: efficacy and limitations

Enzyme replacement therapy (ERT) is available for mucopolysaccharidosis (MPS) I, MPS II, MPS VI, and MPS IVA. The efficacy of ERT has been evaluated in clinical trials and in many post-marketing studies with a long-term follow-up for MPS I, MPS II, and MPS VI. While ERT is effective in reducing urinary glycosaminoglycans (GAGs) and liver and spleen volume, cartilaginous organs such as the trachea and bronchi, bones and eyes are poorly impacted by ERT probably due to limited penetration in the specific tissue. ERT in the present formulations also does not cross the blood–brain barrier, with the consequence that the central nervous system is not cured by ERT. This is particularly important for severe forms of MPS I and MPS II characterized by cognitive decline. For severe MPS I patients (Hurler), early haematopoietic stem cell transplantation is the gold standard, while still controversial is the role of stem cell transplantation in MPS II. The use of ERT in patients with severe cognitive decline is the subject of debate; the current position of the scientific community is that ERT must be started in all patients who do not have a more effective treatment. Neonatal screening is widely suggested for treatable MPS, and many pilot studies are ongoing. The rationale is that early, possibly pre-symptomatic treatment can improve prognosis. All patients develop anti-ERT antibodies but only a few have drug-related adverse reactions. It has not yet been definitely clarified if high-titre antibodies may, at least in some cases, reduce the efficacy of ERT.     

Mucopolysaccharidosis type I: identification of alpha-L-iduronidase mutations in Tunisian families]

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease due to mutations in the gene encoding alpha-l-iduronidase (IDUA) leading to variable clinical phenotypes with progressive severe organomegaly, bone and neurological involvement in the most severe forms. The aim of our study was to propose in Tunisia a strategy of molecular and prenatal diagnosis of the MPS I. POPULATION AND METHODS: Our study was carried out on 8 MPS I patients recruited from different Tunisian regions and issued from 5 unrelated families. All the patients were offspring of consanguineous marriages. RESULTS: The clinical and biological study led to diagnose 5 Hurler patients and 3 Hurler-Scheie patients. Three IDUA mutations were identified by molecular analysis within 6 different families: a novel mutation p.F602X and 2 already described mutations p.P533R and p.R628X. DISCUSSION: MPS I is a heterogeneous disease characterized by variability of the phenotypes. The missense mutation p.P533R associated with the intermediate phenotype was the most frequent in the Tunisian but also in the Moroccan population. In Tunisia, the incidence of p.P533R mutation seems to be associated with the high frequency of consanguineous marriages. CONCLUSION: The identification of known MPS I mutations (p.P533R and p.R628X) and of the novel mutation p.F602X permits reliable genetic counselling of at-risk relatives and molecular prenatal diagnosis.     

Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues and organs. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy and, in most patients, neurological decline. Death usually occurs in the second decade of life, although some patients with less severe disease have survived into their fifth or sixth decade. Until recently, there has been no effective therapy for MPS II, and care has been palliative. Enzyme replacement therapy (ERT) with recombinant human iduronate-2-sulphatase (idursulfase), however, has now been introduced. Weekly intravenous infusions of idursulfase have been shown to improve many of the signs and symptoms and overall wellbeing in patients with MPS II. This paper provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS II and provides recommendations for the use of ERT. The issue of treating very young patients and those with CNS involvement is also discussed. ERT with idursulfase has the potential to benefit many patients with MPS II, especially if started early in the course of the disease.     

Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase)

OBJECTIVE: To confirm the efficacy and safety of recombinant human alpha-L-iduronidase (laronidase) in patients with mucopolysaccharidosis I (MPS I). STUDY DESIGN: This was a randomized, double-blinded, multinational study of 45 patients with MPS I administered 100 U/kg (0.58 mg/kg) laronidase, or placebo intravenously weekly for 26 weeks. The coprimary efficacy end points compared the median change from baseline to week 26 between groups in percentage of predicted normal forced vital capacity (FVC) and in 6-minute walk test (6MWT) distance through the use of the Wilcoxon rank sum test. RESULTS: The laronidase (n=22) and placebo (n=23) groups had similar baseline characteristics. After 26 weeks, patients receiving laronidase compared with placebo showed mean improvements of 5.6 percentage points in percent of predicted normal FVC (median, 3.0; P=.009) and 38.1 meters in 6MWT distance (median, 38.5; P=.066; P=.039, analysis of covariance). Laronidase also significantly reduced hepatomegaly and urinary glycosaminoglycans, and, in more severely affected patients, improved sleep apnea/hypopnea and shoulder flexion. Laronidase was well-tolerated. Nearly all patients receiving enzyme had development of IgG antibodies, without apparent clinical effects. CONCLUSIONS: In patients with MPS I, laronidase significantly improves respiratory function and physical capacity, reduces glycosaminoglycan storage, and has a favorable safety profile.     

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. CONCLUSION: 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.     

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.
Conclusion : 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.     

Early diagnosis and management of cardiac manifestations in mucopolysaccharidoses: a practical guide for paediatric and adult cardiologists

Mucopolysaccharidoses (MPS) are a group of hereditary disorders caused by lysosomal storage of glycosaminoglycans (GAGs) and characterized by a wide variability of phenotypes from severe fetal-neonatal forms to attenuated diseases diagnosed in adult individuals. The clinical picture generally worsens with age due to progressive storage involving mucosal tissue, upper airways and lungs, bones and joints, central and peripheral nervous system, heart, liver, eye, and ear. Cardiac storage of GAGs involves valves, heart muscle, and vessels (particularly the coronary arteries), and can be specific in relation to different MPS types and enzyme defects. MPS I, II, and VI are those with the most severe cardiac involvement. The cardiologist is a key figure in MPS, and their role is expanding from cardiac-specific management to early diagnosis when the mild disease phenotypes have not yet been recognized by other specialists. Familial and personal history, electrocardiography, imaging, and laboratory findings represent important steps in the clinical investigation of these patients. New treatments have led to an increased need for cardiologists to be on the lookout for MPS patients since they can significantly improve the lives of people with MPS if they suspect the diagnosis and refer them for enzyme replacement therapy or bone marrow transplantation.     

黏多糖贮积症Ⅰ型二例基因突变检测及产前诊断

目的 对黏多糖贮积症Ⅰ型病例进行基因检测,对再孕母亲进行产前诊断.方法 用酶学检测方法 确诊2例黏多糖贮积症Ⅰ型先证者;采用PCR扩增技术结合序列分析的方法,检测2例先证者血液及其再孕母亲羊水细胞中IDUA基因外显子及其两侧内含子.结果 在2例经酶学检测确诊的先证者中共检测出4种基因突变:p.L238R、c.883InsC、c.531InsT、p.L346R,2种为插入突变,2种为错义突变.在先证者1母亲羊水细胞IDUA基因中未发现致病基因突变,羊水细胞中IDUA酶活性为9.0 nmol/(h·mg蛋白);在先证者2母亲羊水细胞IDUA基因中检测到与先证者相同的两个致病突变,羊水细胞中IDUA酶活性为0.5 mol/(h·mg蛋白).结论 从黏多糖贮积症Ⅰ型先证者发现的4种突变中,p.L346R为已知突变,p.L238R,c.883InsC,c.531InsT为首次发现的新突变.胎儿1未获得与先证者相同致病基因,为正常胎儿.胎儿2获得与先证者相同致病基因,为受累胎儿.产前基因诊断结果 与酶学产前诊断结果 相符合.

Abstract：

Objectiye Mucopolysaccharidosis type Ⅰ(MPS Ⅰ; MIM# 252800)is an autosomal recessive disease that results from the deficiency in the lysosomal enzyme α-L-iduronidase(IDUA).IDUA is one of the enzymes involved in degradation of glycosaminoglycans heparan sulphate and dermatan sulphate.The deficiency of IDUA leads to widespread accumulation of partially degraded mucopolysaccharides inside lysosomes,resulting in progressive cellular and multiorgan dysfunction. Up to now there is no definitely effective treatment for this disorder,therefore it is important to provide an accurate genetic diagnosis and prenatal diagnosis for the MPS Ⅰ families.This study was conducted to detect IDUA gene mutation in patients with MPS Ⅰ and make a definite diagnosis of homozygote or heterozygote and make first trimester prenatal diagnosis.Method The 2 male probands included in this study were diagnosed as MPS Ⅰ patients in Peking Union Medical College Hospital,case 1 was 2 years old and case 2 was 5 years old.Genomic DNA was extracted from leucocytes in the 2 patients and 2 mothers' cultured amniocytes.IDUA gene DNA sequence was amplified by polymerase chain reaction(PCR)and the PCR products were sequenced directly.Novel mutations were analyzed in 100 normal chromosomes.Result The genotype of case 1 was p.L238R/c.883InsC,while of case 2 was c.531InsT/p.L346R.The fetal case 1 did not inherit the same pathogenic inherited the same pathogenic mutations with the proband,the genotype of fetal 2 was c.531InsT/p.L346R,in 2 MPS Ⅰ patients,p.L238R,c.883InsC,c.531InsT were novel.The fetal case 1 was diagnosed as normal fetus while the fetus 2 was diagnosed as affected.The results of the two kinds of prenatal diagnostic methods were correspondent with each other.     

Cardiac functional and histopathologic findings in humans and mice with mucopolysaccharidosis type I: implications for assessment of therapeutic interventions in hurler syndrome

Hurler syndrome (mucopolysaccharidosis type I [MPS I]) is a uniformly lethal autosomal recessive storage disease caused by absence of the enzyme alpha-l-iduronidase (IDUA), which is involved in lysosomal degradation of sulfated glycosaminoglycans (GAGs). Cardiomyopathy and valvar insufficiency occur as GAGs accumulate in the myocardium, spongiosa of cardiac valves, and myointima of coronary arteries. Here we report the functional, biochemical, and morphologic cardiac findings in the MPS I mouse. We compare the cardiac functional and histopathological findings in the mouse to human MPS I. In MPS I mice, we have noted aortic insufficiency, increased left ventricular size, and decreased ventricular function. Aortic and mitral valves are thickened and the aortic root is dilated. However, murine MPS I is not identical to human MPS I. Myointimal proliferation of epicardial coronary arteries is unique to human MPS I, whereas dilation of aortic root appears unique to murine MPS I. Despite the differences between murine and human MPS I, the murine model provides reliable in vivo outcome parameters, such as thickened and insufficient aortic valves and depressed cardiac function that can be followed to assess the impact of therapeutic interventions in preclinical studies in Hurler syndrome.     

Hematopoietic stem cell transplantation effects on spinal cord compression in Hurler

Hurler syndrome type 1 (MPS‐1) is an autosomal recessive lysosomal disorder due to the deficiency of the enzyme alpha‐L‐iduronidase which is necessary for the degradation of dermatan and heparan sulfate. It is characterized by deposit of glycosaminoglycans in tissues, progressive multisystem dysfunction, and early death. HSCT for children with MPS‐I is effective, resulting in increased life expectancy and improvement of clinical parameters. The spinal MRI performed on a female 10 yr old undergoing HSCT at the age of 18 months and receiving ERT revealed a considerable decrease in soft tissue around the tip of odontoid causing a significant reduction in spinal cord compression. In light of this result, we suppose that combined ERT and HSCT are successful in Hurler I disease.     

Neurobehavioral phenotypes of neuronopathic mucopolysaccharidoses

Mucopolysaccharidoses (MPS) are a group of lysosomal multisystemic, chronic, and progressive diseases characterized by the storage of glycosaminoglycans (GAGs) that may affect the central nervous system. Neuronopathic MPS such as MPS IH, MPS II, MPS IIIA–D, and MPS VII are characterized by neurocognitive regression. In severe MPS I (MPS IH, or Hurler syndrome) initial developmental trajectory is usually unremarkable but cognitive development shows a plateau by 2 to 4 years of age and then progressively regresses with aging. Patients with neuronopathic MPS II have a plateau of cognitive and adaptive development on average by 4 to 4.5 years of age, although there is significant variability, followed by progressive neurocognitive decline. In patients with classic MPS III, developmental trajectory reaches a plateau around 3 years of age, followed by regression. Sleep disturbances and behavioral problems occur early in MPS II and III with features of externalizing disorders. Acquired autism-like behavior is often observed in children with MPS III after 4–6 years of age. Impaired social and communication abilities do occur, but MPS III children do not have restricted and repetitive interests such as in autism spectrum disorder. MPS type VII is an ultra-rare neuronopathic MPS with a wide clinical spectrum from very severe with early mortality to milder phenotypes with longer survival into adolescence and adulthood. Most patients with MPS VII have intellectual disability and severely delayed speech development, usually associated with hearing impairment. Cognitive regression in neuronopathic MPS runs parallel to a significant decrease in brain tissue volume. Assessment of the developmental profile is challenging because of low cognitive abilities, physical impairment, and behavioral disturbances. Early diagnosis is crucial as different promising treatment approaches have been extensively studied in animal MPS models and are currently being applied in clinical trials.     

Enzyme replacement therapy in a feline model of MPS VI: modification of enzyme structure and dose frequency

Enzyme replacement therapy (ERT) in the MPS VI cat is effective at reducing or eliminating pathology in most connective tissues. One exception is that cartilage and chondrocytes remained distended with extensive lysosomal vacuolation after long-term, high-dose ERT. In this study, we demonstrate that recombinant human N-acetylgalactosamine-4-sulphatase (4S) is taken up by chondrocytes via a mannose-6-phosphate-dependent mechanism and is effective at removing MPS storage. In vitro, the penetration of 4S into articular cartilage is low (partitioning coefficient = 0.06) and i.v. administered enzyme does not distribute significantly into articular cartilage in vivo. To alter the tissue distribution of 4S, the enzyme was coupled to ethylene diamine or poly-L-lysine, increasing its overall charge and diffusion into cartilage, and the dosing frequency of unmodified 4S was increased. Modification resulted in active 4S that maintained its ability to correct MPS storage and increased the partitioning coefficient of 4S into cartilage by 77% and 50% for ethylene diamine and poly-L-lysine, respectively. However, in vivo ERT studies demonstrated that response to therapy was not significantly improved by either the enzyme modifications or change to the dosing regimen, when compared with ERT with unmodified enzyme. Distribution experiments indicated the majority of enzyme is taken up by the liver irrespective of modification. To optimize therapy and improve the amount of enzyme reaching cartilage and other tissues demonstrating poor uptake, it may be necessary to bypass the liver or prolong plasma half-life so that proportionately more enzyme is delivered to other tissues.     

Mucopolysaccharidosis VI: the Italian experience

The current paper describes the natural history and management of mucopolysaccharidosis VI (MPS VI) in all patients currently diagnosed with the disease in Italy. Nine patients (5.5–14.4 years) were included in the data review in March 2008. Gestational and perinatal data were normal for all patients. Median age at diagnosis was 1.9 years. During the course of the disease, all patients developed coarsened facial features, short stature, heart valve disease, eye problems, musculoskeletal problems, hepatosplenomegaly and neurological abnormalities. All patients received rhASB enzyme replacement therapy (ERT) and showed improvement or stabilisation in clinical manifestations after onset of therapy. The most frequently reported improvements were increased joint mobility and reduced hepatosplenomegaly. No relevant safety issues of ERT were reported. In conclusion, patients in Italy with MPS VI are diagnosed early in life. All patients have access to ERT and appear to benefit from this therapy.     

Correlation between severity of mucopolysaccharidoses and combination of the residual enzyme activity and efficiency of glycosaminoglycan synthesis

Aim: To develop a method for prediction of severity and clinical course of mucopolysaccharidoses (MPS), a group of inherited metabolic diseases.
Methods: Various biochemical and clinical parameters (including estimation of the level of clinical severity, presence of specific mutations, residual enzyme activity, urinary glycosaminoglycan (GAG) excretion, storage of GAG in fibroblasts and efficiency of GAG synthesis) of patients suffering from MPS types II, IIIA and IIIB were determined. Correlations between genetic, biochemical and clinical parameters were tested.
Results: We found that efficiency of GAG synthesis may contribute to the level of severity of MPS. It appears that (i) combination of low or average efficiency of GAG synthesis and the presence of residual activity of the enzyme is responsible for an attenuated phenotype, (ii) a lack of detectable residual enzyme activity causes a severe phenotype, irrespective of the efficiency of GAG synthesis and (iii) high efficiency of GAG synthesis leads to a severe phenotype, even if residual enzyme activity is detected. This correlation was found to be valid in 15 out of 17 patients tested.
Conclusion: Analysis of efficiency of GAG synthesis and residual activity of the enzyme may be considered for prediction of severity of MPS patients' clinical phenotypes.     

Sonographic ocular findings in patients with mucopolysaccharidoses I,II and VI

Background Ophthalmological complications in patients with mucopolysaccharidosis (MPS) are clouding of the cornea, glaucoma, optic neuropathy, and degeneration of the retina. These changes may impair visual function to the point of total loss of vision. Objective To document the ophthalmological changes demonstrated by grey-scale US in patients with MPS. Materials and methods A total of 65 patients with MPS (18 type I, 12 type II, 35 type VI) including a subgroup of 30 undergoing enzyme replacement therapy (ERT) were studied by US of the globe and optic nerve. Results Average scleral thickness at the posterior pole of the globe measured 2.02–2.58 mm (normal range 1.4–1.7 mm), the average diameter of the optic nerve and its sheath measured 5.35–6.71 mm (normal <4.5 mm). All medians were statistically significantly different from those of healthy volunteers. Concomitantly there was hypermetropia of up to 7.5 dioptres. During a mean follow-up of 3.1 years there was no distinct progression in scleral or optic nerve complex thickness. Conclusion The optic nerve sheath and sclera were clearly thickened in comparison to normal values. Many morphological changes in the eye and optic nerve were already present at the time of the initial clinical diagnosis, and thus seem to develop very early in the course of the disease. ERT in our patients did not seem to alter the US characteristics of the globe or optic nerve.     

The role of enzyme replacement therapy in severe Hunter syndrome-an expert panel consensus

Intravenous enzyme replacement therapy (ERT) with idursulfase for Hunter syndrome has not been demonstrated to and is not predicted to cross the blood-brain barrier. Nearly all published experience with ERT with idursulfase has therefore been in patients without cognitive impairment (attenuated phenotype). Little formal guidance is available on the issues surrounding ERT in cognitively impaired patients with the severe phenotype. An expert panel was therefore convened to provide guidance on these issues. The clinical experience of the panel with 66 patients suggests that somatic improvements (e.g., reduction in liver volume, increased mobility, and reduction in frequency of respiratory infections) may occur in most severe patients. Cognitive benefits have not been seen. It was agreed that, in general, severe patients are candidates for at least a 6-12-month trial of ERT, excluding patients who are severely neurologically impaired, those in a vegetative state, or those who have a condition that may lead to near-term death. It is imperative that the treating physician discuss the goals of treatment, methods of assessment of response, and criteria for discontinuation of treatment with the family before ERT is initiated. CONCLUSION: The decision to initiate ERT in severe Hunter syndrome should be made by the physician and parents and must be based on realistic expectations of benefits and risks, with the understanding that ERT may be withdrawn in the absence of demonstrable benefits.