Effects Of Enzyme Replacement Therapy Research Articles

T.P.15: Enzymotherapy in late onset Pompe disease patients: a 4-year longitudinal study using quantitative MRI

Considering the clinical heterogeneity of patients with a late onset form of Pompe disease, we clearly need reliable quantitative surrogate markers allowing to accurately determine the effects of enzyme replacement therapy (ERT). In the present study, we investigated, using quantitative MRI and usual clinical tests, the effects ERT in three patients with a late onset form of the Pompe disease. Data were compared before and throughout a 4-year ERT period. MR images were processed using a robust automatic segmentation tool in order to quantify muscle, subcutaneous adipose tissue and intramuscular adipose tissue. Motor (6-min walking test (6MWT), manual motor testing, Motor Function Measure scale) and respiratory function (vital capacity, (FVC)) were investigated once a year. Clinical tests remained stable in patient 2 and worsened in patient 1. In patient 3, the 6MWT improved whereas the FVC remained stable. In two patients (patient 1 and 2), the rate of intramuscular infiltration was substantially slowed throughout the treatment period whereas it increased in patient 3 who required nocturnal ventilation. We demonstrated a variable effect of the ERT while clinical and MRI results were not directly related. The quantitative MRI kinetic index we selected might be of interest for further investigations in a larger group which are warranted in order to clearly delineate the effects of ERT in adult patients with Pompe disease.

T.P.20: Effect of enzyme replacement therapy in late onset Pompe disease: Open pilot study of 60 weeks follow up

Late-onset Pompe disease (LOPD) is an autosomal recessive disorder caused by deficiency of the enzyme acid glucosidase alfa (GAA), Recently, enzyme replacement therapy (ERT) using recombinant human GAA (rhGAA) became clinically available, and is expected to modify clinical course of LOPD. In this study, we have evaluated the efficacy and adverse events of ERT for 60weeks in Korean LOPD patients. Five Korean LOPD patients were included in the study. At baseline, clinical and laboratory features including motor and pulmonary function was assessed, and rhGAA was infused every two weeks. Then, patients were examined at every 12weeks interval to evaluate their changes in motor and pulmonary function for 48weeks along with adverse reactions of ERT. The motor and pulmonary function of the patients demonstrated mild improvement or stabilization after 60weeks of ERT. And none of them showed deterioration in their ambulatory or respiratory status. One of our patients developed a serious anaphylactic reaction which necessitated the cessation of further ERT. This is the first report of clinical study on the ERT of Korean LOPD patients. Our study showed ERT for 48weeks produced only mild improvement or stabilization of motor and pulmonary function in LOPD patients, suggesting that advanced pathological change is responsible for the limited efficacy of ERT.

Long term effects of enzyme replacement therapy in an Italian cohort of type 3 Gaucher patients

BackgroundThe chronic neuropathic form of Gaucher disease (GD3) is characterised by hepatosplenomegaly, anaemia, thrombocytopenia, bone alterations and central neurological involvement. Enzyme replacement therapy (ERT) has been demonstrated to be effective in non neuropathic Gaucher disease, but long term results in patients with GD3 are still limited and contrasting. A possible role of genotype in determining the response to ERT has been hypothesised. Patients and methodsAll patients affected by GD3, treated with ERT, and followed-up in 4 different Italian centres (Udine, Catanzaro, Sassari and Florence) were included. Data on clinical conditions, laboratory values, neurological and neuropsychological examinations, radiological and electrophysiological features were collected retrospectively from clinical records. ResultsTen patients (6 females, 4 males) with four different genotypes (L444P/L444P, L444P/F231I, P159T/unknown, C.115+1G>A/N188S) were identified. They received ERT infusions from 3 to 21years. Haematological parameters and organomegaly improved/normalised in all patients. Three patients showed severe progressive skeletal deformities. 6/10 patients were neurologically asymptomatic when they started ERT for systemic symptoms. During the follow-up, 2/6 developed an important central nervous system disease; 2/6 developed mild central symptoms; and 2/6 did not show any neurological symptom after 5, and 20years of treatment respectively, despite the presence of epileptiform abnormalities at the electroencephalogram. Overall, neurological involvement worsened over time in 6/10 patients, 3 of whom developed progressive myoclonic encephalopathy and died. ConclusionsERT improved the systemic manifestations in patients with GD3, but was not able to counteract the progression of neurological symptoms in the long term.

Effectiveness of enzyme replacement therapy in adults with late-onset Pompe disease: results from the NCS-LSD cohort study.

To determine the effectiveness of enzyme replacement therapy (ERT) for adults with late-onset Pompe disease. A longitudinal cohort study including prospective and retrospective clinical outcome data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. Consenting adults (N = 62) with a diagnosis of late-onset Pompe disease who attended a specialist treatment centre in England. This cohort represented 83% of all patients in the UK with a confirmed diagnosis of this rare condition. At study entry, all but three patients were receiving ERT (range of treatment duration, 0 to 3.1years). Percent predicted forced vital capacity (%FVC); ventilation dependency; mobility; 6min walk test (6MWT); muscle strength and body mass index (BMI). An association was found between time on ERT and significant increases in the distance walked in the 6MWT (p < 0.001) and muscle strength scores (p < 0.001). Improvements in both these measures were seen over the first 2years of treatment with ERT. No statistically significant relationship was found between time on ERT and respiratory function or in BMI. These data provide some further evidence of the effectiveness of ERT in adults with late-onset Pompe disease. The results of this longitudinal cohort study of 62 adults with late-onset Pompe disease, provide further evidence on the effectiveness of ERT in this rare condition.

THU0361 Bone and Joint Disease in Mucopolysaccharidosis Involves Tlr4-Related Inflammation and Improves upon Treatment with Pentosan Polysulphate

BackgroundThe mucopolysaccharidoses (MPS) comprise a group of lysosomal storage disorders (LSDs) resulting from inherited deficiencies of 11 specific glycosaminoglycan (GAG) degrading enzymes. In certain types of MPS (those without significant...

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 effectiveness of enzyme replacement therapy in children with Gaucher disease: results from the NCS‐LSD cohort study

To determine the effectiveness of enzyme replacement therapies (ERT) for children with Gaucher disease (GD). A longitudinal cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Children on treatment contributed data before and during treatment. Children not on treatment contributed natural history data. Consenting children (N = 25, aged 1.1 to 15.6years) with a diagnosis of GD (14 with GD1 and 11 with GD3) who attended a specialist treatment centre in England. At recruitment, 24 patients were receiving ERT (mean treatment duration, 5.57years; range 0-13.7years). Clinical outcomes chosen to reflect disease progression, included platelet count; haemoglobin and absence/presence of bone pain. Duration of ERT was associated with statistically significant improvements in platelet count (p < 0.001), haemoglobin (p < 0.001), and reported bone pain (p = 0.02). The magnitude of effect on haematological parameters was greater in children with GD3 than in those with GD1. These data provide further evidence of the long-term effectiveness of ERT in children with GD.

Effect of enzyme replacement therapy on isokinetic strength for all major muscle groups in four patients with Pompe disease—a long-term follow-up

Pompe disease is a rare, inherited metabolic myopathy characterized by progressive weakness of the proximal limb and respiratory muscles. We report the findings from four patients with late-onset Pompe disease treated with α-glucosidase (Myozyme) for 2 (n=2) and 6 (n=2) years, and monitored with isokinetic dynamometry, 6-minute walking test (6MWT), and vital capacity. Patients were evaluated after 6, 12, 24, 36, 48, 60, and 72months. In two patients, muscle size estimated by MRI and DXA scanning was also performed prior to and following 6months of treatment. After 2years of α-glucosidase treatment, maximal isokinetic muscle strength increased by 11% (0%–50%) [median (range)] and 6MWT improved by 18% (2%–40%). In the two patients treated for 6years, the increase in muscle strength stabilized at 40% and 6MWT stabilized at 32%. The improvements primarily occurred during the first 6months of treatment. Interestingly, the weakest muscle groups seemed to benefit more than those less affected, and greater improvements occurred for flexor muscles compared to extensor muscles. Vital capacity did not improve on treatment.

The NCS‐LSD cohort study: a description of the methods and analyses used to assess the long‐term effectiveness of enzyme replacement therapy and substrate reduction therapy in patients with lysosomal storage disorders

Lysosomal storage disorders (LSDs) comprise more than 50 extremely rare, inherited metabolic diseases resulting from a deficiency of specific lysosomal enzymes required for normal macromolecular metabolism. The National Collaborative Study for Lysosomal Storage Disorders (NCS-LSD), was a longitudinal cohort study which collected prospective and retrospective clinical data, and patient-reported data from adults and children with a confirmed diagnosis of Gaucher disease, Fabry disease, mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), Pompe disease and Niemann Pick disease type C (NPC) in the UK. The study aimed to determine the natural history of these conditions and estimate the effectiveness and cost of therapies. Clinical outcomes were chosen to reflect disease progression. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment while untreated patients contributed natural history data. A total of 711 adults and children were recruited to this study from the seven LSD treatment centres in England. Data was collected from 2008 to 2011. This paper describes the methods used to collect and analyse clinical data for this study. The clinical findings are reported separately in a series of condition-specific articles in this issue.

Long‐term effectiveness of enzyme replacement therapy in adults with Gaucher disease: results from the NCS‐LSD cohort study

To determine the effectiveness of enzyme replacement therapies (ERT) for adults with Gaucher disease (GD). A longitudinal, multi-centre 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. Untreated patients contributed natural history data. Consenting adults (N = 150, aged 16 to 83years) with a diagnosis of GD who attended a specialist treatment centre in England. At recruitment, 131 patients were receiving ERT (mean treatment duration, 10.8years; range 0-18years). Clinical outcomes chosen to reflect disease progression, included platelet count; haemoglobin; absence/presence of bone pain; spleen and liver volumes and AST levels. One hundred and fifty adults were recruited. Duration of ERT was associated with statistically significant improvements in platelet count (p < 0.001), haemoglobin (p < 0.001), liver and spleen volumes (p < 0.001) and AST levels (p = 0.02). These data provide further evidence of the long-term effectiveness of ERT in adults with GD.

Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta‐analysis

Current available evidence on long-term effectiveness of enzyme replacement therapy (ERT) for Fabry disease is limited. More insight is needed whether ERT effectiveness differs in patients with and without baseline end-organ damage. Through a systematic review, untreated and ERT treated males and females with Fabry disease were compared for main clinical outcomes: renal function, left ventricular mass (LVmass), cerebral white matter lesions (WMLs) and end-organ complications. Through a meta-analysis ERT effectiveness was estimated in different disease stages. Two reviewers assessed quality of the included studies according to guidelines for prognosis research. Data were synthesized using a random effects meta-analysis. Thirty-one studies were systematically reviewed while six studies were included in the meta-analysis. In patients with a GFR > 60ml/min/1.73m(2), decline of renal function was similar for treated and untreated patients. Only ERT treated males with a GFR < 60ml/min/1.73m(2) had a slower rate of decline in renal function, possibly attributable to anti-proteinuric therapy. Regardless of left ventricular hypertrophy (LVH) at baseline, LVmass remained stable or increased in males despite ERT, however at a slower rate compared to untreated male patients. In ERT treated females with LVH LVmass decreased, and remained stable in females without LVH. WMLs can not be prevented by ERT. Stroke, cardiac and end-stage renal complications develop, though the incidence of new complications seems to be reduced during ERT. ERT is effective in reducing LVH, but has a limited effect on renal function. Improved treatment options are needed for Fabry disease.

The Effect of Recombinant Human Iduronate-2-Sulfatase (Idursulfase) on Growth in Young Patients with Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase. Early bone involvement leads to decreased growth velocity and short stature in nearly all patients. Our analysis aimed to investigate the effects of enzyme replacement therapy (ERT) with idursulfase (Elaprase) on growth in young patients with mucopolysaccharidosis type II. Analysis of longitudinal anthropometric data of MPS II patients (group 1, n = 13) who started ERT before 6 years of age (range from 3 months to 6 years, mean 3.6 years, median 4 years) was performed and then compared with retrospective analysis of data for MPS II patients naïve to ERT (group 2, n = 50). Patients in group 1 received intravenous idursulfase at a standard dose of 0.58 mg/kg weekly for 52–288 weeks. The course of average growth curve for group 1 was very similar to growth pattern in group 2. The average value of body height in subsequent years in group 1 was a little greater than in group 2, however, the difference was not statistically significant. In studied patients with MPS II, idursulfase did not appear to alter the growth patterns.

Enzyme replacement therapy in juvenile glycogenosis type II: a longitudinal study

Glycogenosis type II, a genetic muscle-wasting disorder, results in a spectrum of clinical phenotypes. Enzyme replacement therapy is effective in the infantile form of the disease, while little is known about its effectiveness in late-onset disease, especially in juvenile patients. The purpose of this retrospective cohort study was to assess the long-term effects of enzyme replacement therapy (ERT) in juvenile glycogenosis type II (GSDII). Eight Italian juvenile GSDII patients, receiving biweekly infusions of 20 mg/kg recombinant human α-glucosidase for at least 72 months, were enrolled (median age at therapy start was 11.8 years). Six-minute walk test (6MWT) and forced vital capacity (FVC), measured in upright position, were chosen as the principal outcome measures. Global motor disability (modified Walton scale (WS)), muscle enzymes levels [creatine phosphokinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), alanine transaminase (ALT)] and body mass index (BMI) were also analysed both at baseline (therapy start) and annually afterwards. At baseline, most patients (six out of eight) did not show muscle function impairment (WS ≤ 2). The performance at 6MWT showed a slight improvement during follow-up as well as FVC. Muscle enzymes levels showed a clear decrease after the 1st year of treatment while remained stable afterwards. An overall decrease in BMI was also observed during follow-up, although at the individual level, trends were variable. ERT is effective in stabilising both motor and lung functions in juvenile patients with GSDII, possibly slowing down the rate of disease progression. Randomised controlled trials are needed to understand whether early treatment allows juvenile patients to reach adulthood with a more beneficial residual muscular function than untreated patients.

Fabry disease: experience of screening dialysis patients for Fabry disease

The prevalence rate for Fabry disease is conventionally considered to be 1 case in 40,000; however, due to increased screening accuracy, reports now suggest that prevalence is 1 case in 1,500 among male children, and it is likely that the clinical importance of the condition will increase in the future. In dialysis patients to date, prevalence rates are between 0.16 and 1.2 %. Globotriaosylsphingosine (Lyso-GL-3), which is a substrate of α-galactosidase A (α-Gal A), has surfaced as a new biomarker, and is also effective in the determination and monitoring of the effects of enzyme replacement therapy. In terms of genetic abnormalities, the E66Q mutation has recently become a topic of discussion, and although doubts have been expressed over whether or not it is the gene responsible for Fabry disease, there is still a strong possibility that it is a functional genetic polymorphism. At present, the standard treatment for Fabry disease is enzyme replacement therapy, and in order to overcome the problems involved with this, a method of producing recombinant human α-Gal A using methanol-assimilating yeast, and chemical or medicinal chaperone treatment are of current interest. Migalastat hydrochloride is known as a pharmacological chaperone, but is currently in Phase III global clinical trials. Adding saposin B to modified α-N-acetyl galactosaminidase is also under consideration as a treatment method.

New insights in the field of muscle glycogenoses

This review highlights recent contributions regarding clinical heterogeneity, pathogenic mechanisms, therapeutic trials, and animal models of the muscle glycogenoses. Most recent publications have dealt with the clinical effects of enzyme replacement therapy (ERT) in glycogenosis type II (Pompe disease), including the cognitive development of children with the infantile form who have reached school age. Standardized exercise testing has shown the similarity between McArdle disease and one of the most recently described muscle glycogenoses, phosphoglucomutase deficiency. Cycle ergometry in patients with glycogenosis type III (debrancher deficiency) without overt weakness has documented exercise intolerance relieved by glucose infusion, consistent with the glycogenolytic block. A mouse model of McArdle disease faithfully recapitulates most features of the human disease and will prove valuable for a better understanding of pathogenesis and therapeutic modalities. Polyglucosan body myopathy with cardiomyopathy has been associated with mutations in RBCK1, a ubiquitin ligase, which have also been reported in children with early-onset immune disorder. The role of polyglucosan storage in muscle and in both central and peripheral nervous systems has been confirmed in the infantile and late-onset forms of glycogenosis type IV (brancher enzyme deficiency). Additional novel findings include the involvement of the heart in one patient with phosphofructokinase (PFK) deficiency and the presence of tubular aggregates in a manifesting heterozygote with phosphoglycerate mutase deficiency. Important recent developments in the field of muscle glycogenoses include a new disease entity, a new animal model of McArdle disease, and better knowledge of the pathogenesis in some glycogenoses and of the long-term effects of enzyme replacement therapy in Pompe disease.

Fabry Disease: A Rare Cause of Neuropathic Pain

Fabry disease is characterized by burning or shooting pains in hands and feet, which have a severe impact on the quality of life of patients. It is therefore of importance that Fabry patients receive adequate diagnosis, counseling, treatment and follow up. This review describes neuropathic pain in classical Fabry disease with the aim to help clinicians to recognize Fabry patients among patients presenting with chronic extremity pain. The diagnostic dilemmas in patients with neuropathic pain and a non-classical disease course are discussed, together with the available diagnostic modalities, pain medication options and the effect of enzyme replacement therapy on small fiber neuropathy.

P.17.4 Magnetic Resonance Imaging (MRI) to evaluate the effect of enzyme replacement therapy in Late Onset Pompe Disease (LOPD)

Pompe disease is a rare, progressive and often fatal neuromuscular disorder resulting from mutations in the gene for acid alpha-glucosidase (GAA), an enzyme necessary to degrade glycogen. The deficiency or dysfunction of the GAA enzyme leads to lysosomal glycogen accumulation in multiple tissues and results in cardiac and skeletal muscle dysfunction. Glycogen content may vary between muscle groups and in regions of the same muscle. Most importantly, glycogen content may change during the course of the disease. Enzyme replacement therapy (ERT) is the only FDA approved treatment for Pompe disease. However, translation from preclinical to clinical studies is challenged by the lack of reliable, noninvasive outcome measures suitable for repeated evaluations. Effect of treatment is commonly measured by muscle glycogen clearance using biochemical assays, which rely on muscle biopsy. In this study, we used Magnetic Resonance Imaging (MRI) of the thigh and lower leg muscles to evaluate the effect of 12 and 24 weeks of ERT in individuals affected by Late Onset Pompe Disease (LOPD) (n = 4; age 35–50). Maximum cross-sectional area (CSAmax) – an index of muscle mass – increased in average by 1.16- and 1.09-fold at 12 weeks, and by 1.13- and 1.09-fold at 24 weeks in the lower and upper legs respectively. In addition, we studied the MR proton traverse relaxation time (T2) – an index of muscle damage and edema – by applying a mono exponential decay equation to four echo times (TE). At 24 weeks, T2 values reduced by 1.20- and 1.10-fold in the lower and upper legs, respectively. These data demonstrate an increase in CSAmax associated accompanied by a reduction of T2 value, which may suggest a reduction of glycogen accumulation and an increase of contractile myofibers. In support of this hypothesis, biochemical assay from muscle biopsy specimens showed a reduction of glycogen concentration by 2.21-fold at week 24 compare to baseline.

Effects of enzyme replacement therapy for cardiac-type Fabry patients with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A)

ObjectiveCurrent studies of newborn screening for Fabry disease in Taiwan have revealed a remarkably high prevalence of cardiac-type Fabry disease with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A).DesignRetrospective cohort study.SettingTertiary...

AB0137 Characterization of joint disease in mucopolysaccharidosis type I mice and the effects of enzyme replacement therapy

BackgroundMucopolysaccharidosis type I (MPS I) is a lysosomal disorder caused by deficiency of alpha-L-iduronidase, which leads to storage of the glycosaminoglycans heparan sulphate and dermatan sulphate. Patients with MPS I...

Evoked potentails and neurocognitive functions in pediatric Egyptian Gaucher patients on enzyme replacement therapy: a single center experience

Effectiveness of enzyme replacement therapy (ERT) in reverting hematologic, skeletal, and visceral symptoms in Gaucher disease (GD) has been demonstrated, although, its efficacy in neurologic involvement is still debated. We evaluated the extent of neuro-cognitive dysfunction using brain stem evoked potential in GD3 patients, age-matched controls, and GD1 patients without neurological manifestations served as disease control group. Study included 56 GD (36 had type 1, 20 had type 3) under ERT. Investigations included complete blood count, beta glucosidase assay in peripheral leucocytes, plasma chitotriosidase and bone marrow examination, electroencephalography, brain stem auditory (AEP), somatosensory (SSEP) and visual evoked potentials (VEP) as well as IQ testing. Both types of GD showed significantly higher mean latency at 75 on left eye, lower PP amplitude ratio, higher latency at 75, 100, 145, lower amplitude, and higher Lat Diff LT-RT ms and Lt-Rt % compared to controls (p < 0.05) with no difference between both groups in other values of VEP. Both groups showed significantly prolonged latency of N 13-19 compared to controls (p < 0.05) with positive correlation between age and duration of therapy with parameters of SSEP (p < 0.01). Both groups of GD had significantly prolonged latency of the mean waves of AEP compared to controls (p < 0.05) with no significant difference between both groups. There was a negative correlation between age and waves II, III, I-III, I-V and threshold values of AEP. IQ level was positively correlated with AEP values. Severity scoring tool was positively correlated with AEP and SSEP values. Electrophysiological abnormalities were present in both types of GD and have been correlated to cognitive function and disease characteristics.