Duration Of Enzyme Replacement Therapy Research Articles

Is time growth? The impact of early initiation and duration of enzyme replacement therapy on growth in Hurler syndrome

Is time growth? The impact of early initiation and duration of enzyme replacement therapy on growth in Hurler syndrome

Effects of enzyme replacement therapy on bone density in late onset Pompe disease

Pompe disease is an autosomal recessive disorder caused by a deficiency of α-glucosidase, resulting in the accumulation of glycogen in smooth, cardiac, and skeletal muscles, leading to skeletal muscle dysfunction, proximal muscle weakness, and early respiratory insufficiency. Although many patients exhibit decreased bone mineral density (BMD) and increased fractures, there is currently no official protocol for surveillance and management of osteoporosis and osteopenia in late onset Pompe disease (LOPD). Enzyme replacement therapy (ERT) has therapeutic effects on muscle function; however, very few studies report on the effect of ERT on bone mineralization in LOPD patients. Our study included 15 Pompe patients from 25 to 76 years of age on ERT for variable durations. Progressive impact of ERT on BMD of the hips and spine, and the frequency of osteopenia or osteoporosis was studied using DEXA scanning, and correlations were made with age of initiation of ERT, duration of ERT and six-minute walk test. We found a significant positive correlation between the age of ERT initiation and age of the subject, with increases in the Z-scores for the femur and lumbar region. Females had a significantly higher risk for developing osteoporosis compared to males. These results highlight the significance of ERT on reducing progression of osteoporosis in LOPD patients.

A survey on the patient journey in Fabry disease in Japan

BackgroundFabry disease (FD) is a rare X-linked lysosomal storage disease caused by a deficiency in α-galactosidase that is frequently diagnosed late after disease onset. While previous studies have focused on the multisystem manifestations that can lead to delayed or incorrect diagnosis and management, none have investigated the entire patient journey, and few have examined the patient's disease experience. ObjectiveTo investigate the path to diagnosis from disease onset, and the impact of the disease on daily life, among individuals with FD in Japan. MethodsA nationwide survey of patients with FD receiving enzyme replacement therapy (ERT) was conducted between March 27 and June 11, 2018. Participants were recruited via patient support groups or physicians. Respondents completed a questionnaire eliciting information on sociodemographic status, self-perceived health status, initial and current clinical manifestations, the process of diagnosis, and impact on their life. Responses were analyzed descriptively. ResultsData from 40 respondents were analyzed (17 males and 23 females; 77.5% aged ≥30 years). Mean ERT duration was 7.7 years. Mean time from disease onset to diagnosis was 18.7 years (16.7 years [males] vs 20.3 years [females]). The final diagnosis was made most commonly by pediatricians (38%). Forty percent of respondents felt relieved and 30% felt anxious when diagnosed, and when initiating ERT, 48% felt more positive about their daily life. Nevertheless, 85% reported that treatment affected their lives/work, and most (73%) experienced difficulties in their relationships with others. ConclusionEfforts are needed to achieve early diagnosis of patients with FD in Japan, to improve clinician awareness, and improve the psychosocial issues associated with FD.

Long-term effects of enzyme replacement therapy in an elderly cohort of late-onset Pompe disease

Enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) in late-onset Pompe disease (LOPD) shows beneficial effects in the first years often followed by a decline. We aimed to examine long-term ERT effects in an elderly LOPD cohort. Patients with age at diagnosis/start of ERT >50 years and ERT duration > seven years were included. Outcome parameters were MRC sum-score, 6 Minute Walk Test 6MWT, Quick Motor Function Test QMFT, forced vital capacity FVC sitting/supine, CK levels and rhGAA IgG antibody titers. We retrospectively analysed six patients with a median age at diagnosis/start of ERT of 63 years (range 52–69), and a median ERT duration of eight years (range 7–12). 6MWT improved in 4/6, and 2/6 each showed an improvement or stabilization in muscle strength and FVC supine. In contrast, FVC showed a decline in all patients in a sitting position, and QMFT worsened in 5/6. CK levels decreased in all patients. Antibody titers were not associated with treatment effects. Highest titers were present in best responders who were female, still ambulatory and without ventilatory support at follow-up. ERT effects were very heterogeneous and showed best results in 6MWT, followed by muscle strength in manual testing and FVC supine.

Fabry nephropathy before and after enzyme replacement therapy: important role of renal biopsy in patients with Fabry disease.

BackgroundIn Fabry disease, the presence of globotriaosylceramide (GL3) deposits in various kidney cells leads to progressive renal dysfunction. However, kidney biopsy studies in patients with Fabry disease are limited. In the present study, the pathologic findings of patients with Fabry nephropathy receiving enzyme replacement therapy (ERT) and untreated patients without albuminuria were investigated.MethodsThe present study included 15 patients with Fabry disease who underwent renal biopsy while receiving ERT (group 1: n = 9, age 19–58 years, two males and seven females) or before ERT initiation (group 2: n = 6, age 11–66 years, one male and five females). All patients in group 2 were normoalbuminuric.ResultsGroup 1 showed improved clinical symptoms, such as acroparesthesia. The ERT duration was 1.2 to 8 years and seven of the nine patients showed GL3 deposits in various kidney cells and segmental foot process effacement (FPE) of podocytes. GL3 deposits and FPE were not observed in the two remaining patients in group 1. Group 2 showed segmental FPE and podocyte GL3 deposits. Most patients in group 2 also showed GL3 deposits in the mesangium, endothelium, or tubular epithelium.ConclusionThe study results showed that segmental FPE and GL3 deposits can persist in Fabry nephropathy despite ERT. In addition, segmental FPE and GL3 deposits were observed in various kidney cells in normoalbuminuric patients with Fabry disease. These findings indicated that kidney biopsies at baseline and follow-up evaluation of Fabry nephropathy are essential for timely ERT initiation and ERT response assessment.

Reduction in Intravenous Infusion Duration of Enzyme Replacement Therapy to Ten Minutes with Velaglucerase Alfa in Adult Patients with Type 1 Gaucher Disease

Safe and effective intravenous enzyme replacement therapy (ERT) has been available for more than 25 years for patients with Gaucher disease (GD). The safety of the several ERTs for GD has also afforded the possibility of home infusions. Yet, ERT is usually a life-long commitment to infusions and many patients find the every-other-week (EOW) hourly infusions onerous. Previous experience with rapid intravenous infusion of biological materials, in particular monoclonal antibodies, have defined a variable potential for reactions, ranging from mild local irritations at the access site to life-threatening hypersensitivities and anaphylactoid reactions as well as various inflammatory and immunological responses. Particularly in the home environment, these reactions could conceivably occur too quickly for an effective response by a medical team. Thus, we designed a “change in practice” study to assess the safety and efficacy of rapid infusions in adult with type I GD who had already been treated for at least 3 months with velaglucerase alfa. The switch from infusion time of 60 minutes to 10 minutes was done using a step-wise reduction.Methods: Fifteen patients, (8 female), mean age 32 (range 22-44) years, genotype N370S homozygous (n=7) or heterozygous, stable on treatment for a mean of 9.6 (range: 2.5-17) years at doses of treated at 15-60 units/kg body weight/infusion were recruited. Study was started with three months at the standard infusion time of 60 minutes EOW in the home setting. Next was a rate change with one infusion at 30 minutes, one infusion at 20 minutes, and then four infusions over 10 minutes, all in the hospital clinic setting. The final stage was infusions over 10 minutes at home with every three months study evaluations in the clinic. Safety was determined by adverse events (AEs) during or directly after infusions as monitored by an experienced nurse. Efficacy parameters included hemoglobin concentration and platelet counts, spleen and liver volume estimation by ultrasound, the biomarker LysoGb1 (Centogene, Rostock Germany ) and anti-velaglucerase alfa antibodies formation. Seven visual analogue scales were used to assess disease related impact including [1] dependence on others; [2] fatigue; [3] bone pain; [4] depression ; [5] satisfaction with treatment; [6] family impact [7] pessimistic/optimistic view of the future. Local investigational review board approval was granted for the study and all participating patients provided written informed consent before commencing study procedures.Results: Patients were followed for a mean±SD of 60±19 weeks on this study. No serious AEs associated with the 10 minute infusions, in the clinic or at home, were reported. The only mild AE was a single patient who experienced discomfort (feeling cold) in the infused arm during two 10 minute infusions. All patients maintained stability in the key disease features including the hematological parameters and organ volumes. Mean (range) LysoGb1 levels at baseline and last evaluation were 80.8 (11.5-246) ng/mL and 84 (13.8-200) ng/mL, respectively. A single patient showed increased values of LysoGb1, yet her platelet counts were unaffected. On week 36 evaluation - no patient developed antibodies. Twelve patients completed the disease impact questionnaire; mean responses to the specific questions and mean score, ranging from 5.3-9.4 at baseline and 7.6-9.7 on 10 minute infusion, were not altered over the study period. Pharmacokinetics studies are pending.Discussion: With this study protocol, we established that step-wise shortening of infusion duration, from one hour to 10 minutes in three stages and as home infusions, did not compromise the safety or efficacy of treatment in adult patients with type 1 GD receiving velaglucerase alfa EOW at dosages ranging from 15-60 units/kg body weight. Rapid administration of velaglucerase alfa was generally well tolerated and disease-specific parameters were maintained over the course of the study. Willingness of patients to continue with 10 minute infusion confirms the importance of convenience, specifically decreased infusion duration, to patients for whom ERT infusions are currently envisioned to be a life-long commitment. Moreover, this approach may also have wider implications for healthcare providers and payers because of the possibility of reducing the costs engendered by prolonged intravenous administrations and the reliance on a hospital setting. DisclosuresZimran:Shire: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding. Elstein:Shire: Consultancy. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding.

Urinary mulberry bodies as a potential biomarker for early diagnosis and efficacy assessment of enzyme replacement therapy in Fabry nephropathy.

The inability of enzyme replacement therapy (ERT) to prevent progression of Fabry nephropathy (FN) in the presence of >1 g/day proteinuria underscores the necessity of identifying effective biomarkers for early diagnosis of FN preceding proteinuria. Here we attempted to identify biomarkers for early detection of FN. Fifty-one Fabry disease (FD) patients were enrolled. Urinary mulberry bodies (uMBs) were immunostained for globotriaosylceramide (Gb3) and renal cell markers to determine their origin. The association between semiquantitative uMB excretion and the histological severity of podocyte vacuolation was investigated in seven patients using the vacuolated podocyte:glomerular average area ratio. The association between the semiquantitative estimate of uMB excretion and duration of ERT was analyzed. A longitudinal study was conducted to assess the effect of ERT on uMB excretion. Thirty-two patients (63%) had uMBs, while only 31% showed proteinuria. The uMBs were positive for Gb3, lysosomal-associated membrane protein 1 and podocalyxin, suggesting they were derived from lysosomes with Gb3 accumulation in podocytes. We observed more severe podocyte vacuolation with increased uMB excretion (P = 0.03 for trend); however, the same was not observed with increased proteinuria. The percentage of patients with substantial uMB excretion increased with shorter ERT duration (P = 0.018). Eighteen-month-long ERT reduced uMB excretion (P = 0.03) without affecting proteinuria. uMB excretion, implying ongoing podocyte injury, preceded proteinuria in most patients. Semiquantitative uMB estimates can serve as novel biomarkers for early FN diagnosis and for monitoring the efficacy of FD-specific therapies.

Liver steatosis is highly prevalent and is associated with metabolic risk factors and liver fibrosis in adult patients with type 1 Gaucher disease.

Gaucher disease (GD) is associated with peculiar metabolic abnormalities (ie hypermetabolic state, peripheral insulin resistance, dyslipidaemia), partially reverted by enzyme replacement therapy (ERT) at the expense of weight gain. Such metabolic alterations together with an unhealthy lifestyle acquired by an ageing GD population may favour the development of liver steatosis. We aimed at evaluating the prevalence of significant liver steatosis and at identifying the factors associated with liver steatosis in a cohort of patients with type 1 GD. Twenty adult type 1 GD patients from an Italian academic referral centre were prospectively submitted to vibration-controlled transient elastography (Fibroscan®) with controlled attenuation parameter (CAP); significant steatosis was defined as CAP values ≥250dB/min. Median CAP values were 234 [165-358] dB/min and 8 patients (40%) had significant steatosis. Significant steatosis was associated with indices of adiposity (weight, BMI and waist circumference), high blood pressure, insulin resistance and metabolic syndrome. GD-related variables and dose and duration of ERT were not associated with significant steatosis. In the subgroup of 16 patients on stable ERT for at least 24months, CAP resulted significantly and positively associated with liver stiffness (rho 0.559, P=.024). Significant steatosis is highly prevalent in adult type 1 GD patients and is strongly associated with a worse metabolic profile, featuring metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD may determine liver fibrosis progression in GD patients on stable ERT and may be a risk factor for long-term liver-related complications.

AUTOPHAGIC MYOPATHIES / MYOFIBRILLAR MYOPATHIES / DISTAL MYOPATHIES / POMPE DISEASE: P.06 Long-term effects of enzyme replacement therapy in an elderly cohort of late-onset Pompe disease patients

First longitudinal studies showed that enzyme replacement therapy (ERT) effects in late-onset Pompe disease (LOPD) seem to peak at 2-3 y often followed by a secondary decline. We aimed to examine long-term ERT effects in an elderly cohort of LOPD. Main inclusion criteria were age at diagnosis and onset of ERT > 50 y and ERT duration > 7 y. Outcome parameters included MRC sum-score (% of max.), 6-minute walk test 6MWT (% predicted), Quick Motor Function Test QMFT (% of max.), forced vital capacity FVC sitting and supine (% predicted), CK levels, and IgG antibody titers against alglucidase alfa. Six patients (3 f/3 m) qualified for the study, all were ambulatory at time of diagnosis. The median age at onset was 49 y (range 40-64), age at diagnosis and start of ERT 63 y (52-69), and age at last outcome 72.5 y (59-80). The median ERT duration was 8 y (7-12). Two patients became wheelchair-dependent. Two females were still able to walk unassisted and did not need noninvasive ventilation at the end of follow-up. There was no association between clinical outcome and genetic data, skeletal muscle histology, residual enzyme activity, and antibody titers. Peak antibody titers ranged from 0 to high with highest titers in best responders. Patients with lower ERT dosages had higher antibody titers. At least 50% of patients initially benefited from ERT. All patients showed a decline in FVC sitting during long-term follow-up, whereas 33% had a stabilization or improvement of FVC supine. 33% showed a stabilization or improvement of muscle strength. In contrast, QMFT deteriorated in 83% over time. However, 6MWT improved in 67% during a median ERT period of 8 y. CK levels continuously decreased in all patients. Best long-term results were seen in 6MWT, FVC supine and MRC sum-scores. Better ERT effects on FVC supine vs. sitting might hint to a preferential long-term effect on diaphragm muscles. In conclusion, ERT effects were heterogeneous but in general beneficial in elderly LOPD patients.

Analysis of Renal and Cardiac Outcomes in Male Participants in the Fabry Outcome Survey Starting Agalsidase Alfa Enzyme Replacement Therapy Before and After 18 Years of Age.

PurposeTo determine the impact of initiating enzyme replacement therapy (ERT) with agalsidase alfa early in the course of Fabry disease, we evaluated renal and cardiac outcomes for ≤10 years after ERT initiation in males from the Fabry Outcome Survey (FOS).Patients and MethodsMale patients from FOS were stratified into three cohorts by age at ERT initiation: ≤18 years (cohort 1), >18 and ≤30 years (cohort 2), and >30 years (cohort 3). Analysis included age at symptom onset, diagnosis, and ERT initiation; ERT duration; FOS-Mainz Severity Score Index (FOS-MSSI); estimated glomerular filtration rate (eGFR); proteinuria level; and left ventricular mass indexed to height (LVMI). Mixed-effect models estimated renal and cardiac outcomes during follow-up between and within cohorts.FindingsThe analysis included 560 male patients: 151 (27.0%) in cohort 1, 155 (27.7%) in cohort 2, and 254 (45.4%) in cohort 3. Mean±SD duration of ERT for cohorts 1, 2, and 3 was 6.3±4.3, 8.6±4.9, and 7.9±4.9 years, respectively. Mean±SD baseline FOS-MSSI scores increased with age from 9.8±7.2 in cohort 1 to 24.7±11.4 in cohort 3. Cohort 3 showed the lowest baseline mean±SD value for eGFR (87.1±29.0 mL/min/1.73m2) and highest baseline mean±SD values for proteinuria (801.9±952.6 mg/day) and LVMI (56.7±16.0 g/m2.7) among the three cohorts. Evaluation of mean annual rates of change in eGFR, proteinuria, and LVMI revealed no significant differences in any parameter for cohort 1. For cohort 2, proteinuria and LVMI remained stable, whereas eGFR significantly deteriorated annually (–1.12 mL/min/1.73m2; P<0.001). Cohort 3 demonstrated significant annual deteriorations in eGFR (–2.60 mL/min/1.73m2; P<0.001), proteinuria (+34.10 mg/day; P<0.001), and LVMI (+0.59 g/m2.7; P=0.001).ImplicationsRenal and/or cardiac disease progression appears attenuated in patients starting ERT in childhood or early adulthood versus patients starting ERT in later adulthood. These findings support early ERT initiation in Fabry disease. ClinicalTrials.gov identifier: NCT03289065.

Gaucher disease status and treatment assessment: pilot study using magnetic resonance spectroscopy bone marrow fat fractions in pediatric patients

ObjectiveTo assess magnetic resonance spectroscopy (MRS) bone marrow fat fractions' ability to discern between untreated Gaucher disease patients and healthy controls based on assessment of bone marrow infiltration and evaluate response to enzyme replacement therapy (ERT) on serial imaging. MethodsThis retrospective case-controlled study compared conventional MRI and bone marrow MRS findings in six pediatric and young adult Gaucher disease patients with age- and sex-matched controls, examining femoral neck and lumbar spine bone marrow fat fractions and bone marrow burden (BMB) scores. Separate analysis of six patients with serial imaging on ERT was performed with analysis of fat fractions, BMB scores, organ volumes, and serum chitotriosidase. ResultsUntreated patients had significantly lower femoral and lumbar spine fat fractions than controls (0.32 versus 0.67, p = 0.041 and 0.17 versus 0.34, p = 0.041, respectively). Total BMB scores were significantly higher in patients (8.0 versus 3.5, p = 0.015). In patients on ERT with average follow-up of 3.5 years, femoral neck fat fraction was the sole significant predictor of treatment duration (R square: 0.804, p < 0.001) when adjusted for age. Femoral neck fat fraction also correlated with lumbar spine fat fraction, liver volume and chitotriosidase (p < 0.05). MRS test-retest reliability was excellent (Pearson correlations: 0.96, 0.99; p-values <0.001). BMB inter-rater reliability was good overall with an intra-class correlation coefficient of 0.79 for total score, although lumbar spine score reliability was poor at 0.45. ConclusionMRS-derived bone marrow fat fractions appear capable of detecting Gaucher disease severity and monitoring treatment-related changes as a predictor of ERT duration in pediatric and young adult patients.

Bone Marrow Involvement in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long Term Enzyme Replacement Therapy (median 18 years)

Bone complications are the most dramatic and life-impairing outcomes of type 1 Gaucher disease (GD1), a common lysosomal storage disorder. Bone marrow infiltration by Gaucher cells substantially decreases the bone marrow fat fraction (FF), and the extent of this reduction correlates with the overall severity of skeletal manifestations in this disorder. Previous studies have demonstrated that the degree of infiltration can best be estimated by magnetic imaging resonance (MRI)-based quantitative chemical shift imaging (QCSI) and that the fat fraction (FF) score so derived can predict the risk of clinically important bone events. The aim of this study was to evaluate bone marrow involvement in GD1 patients who had received enzyme replacement therapy (ERT) for at least 5 years. Methods: Patients from SZMC Gaucher unit, ≥ 18 years, who were treated with ERT for ≥ 5 years, with a stable dose in the previous 6 months, were recruited. Patients taking another experimental drug, with past exposure to taliglucerase-alfa, presence of any medical, emotional, behavioral or psychological condition were excluded. Energy x-ray absorptiometry (DEXA) was performed at SZMC and the QSCI was performed at the Academic Medical Center in Amsterdam, Netherlands as previously described [Mass et al, Am J Radiol 2002:179:961-965]. A QCSI score of &lt;0.30 was indicative of bone at risk. This investigator initiated clinical trial was approved IRB at SZMC and AMC and sponsored by Pfizer. Study number registration- MOH-2017-04-000351. Results: Thirty patients (13 females) at a median (range) age of 46 (19-71) years consented to participate in this study and to perform the QCSI test. GBA mutations of study patients included N370S homozygote (n=12), N370S compound heterozygote (n=17), and T431 homozygote (n=1). The median (range) duration of ERT was 18 (5-26) years. Thirteen patients were receiving imiglucerase as the primary ERT [median (range) duration, 19 (9-26) years], five patients were receiving velaglucerase alfa [median (range) duration, 11 ( 5-12) years], and 12 patients converted from imiglucerase to velaglucerase alfa [median (range) duration, 7 (6-10) years]. The majority of patients received low-dose regimen, i.e. 15 Units/kg/2 weeks (Table 1). The median (range) T score for lumbar spine from DEXA scans, available for 26 of 30 patients, was −1.3 (−2.8-0.0). The median (range) QCSI score was 0.42 (0.24-0.66). Seven patients, 23% (95% confidence interval 10%-42%), had abnormal QCSI FF scores (&lt;0.30). Abnormal QSCI score was more common in female compared to male (Table 1) (p=0.025). Only one of these was menopausal. No differences were found in age, gender, genotype, history of splenectomy, duration and type of ERT and GD-related parameters between those with QSCI score of bone at risk to those with normal score (Table 1). In summary, these findings demonstrate that, despite prolonged treatment with imiglucerase and/or velalgucerase alfa, 23% of patients still had QCSI scores indicative of an inadequate response in bones. Nevertheless, most patients with prolonged low-dose ERT maintain a normal QCSI, indicative of a positive bone status. The higher prevalence of women in the cohort with low FF is not related to menopausal phase and remains unexplained. As no other patient-related nor GD-related parameter predicted abnormal bone marrow infiltration, a more widely available, quantitative measure of bone marrow infiltration is required for the assessment of response in bones to ERT for patients with GD1. The second phase of this study will evaluate the impact of a switch to a third ERT in those patients from this study with QCSI scores of &lt;0.30. These patients will be offered treatment with taliglucerase alfa at equivalent doses and subsequent reassessment of any impact on clinical symptoms and QCSI scores evaluated. Disclosures Revel-Vilk: Takeda: Honoraria, Other: Travel, Research Funding; Prevail therapeutics: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding. Szer:Alexion: Honoraria, Other: Travel, Research Funding; Amgen: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Prevail Therapeutics: Honoraria, Other: Travel, Research Funding. Zimran:Centogene: Other: research grant; Shire: Consultancy, Honoraria, Research Funding; TAKEDA: Honoraria; Pfize: Honoraria, Research Funding; Bio-events: Honoraria; Targeted Cell Therapies: Consultancy; Prevail Therapeutics: Consultancy.

PRO4 IMPACT OF ENZYME REPLACEMENT THERAPY ON THE RISK OF DEVELOPING GAUCHER DISEASE-RELATED COMPLICATIONS

Enzyme replacement therapy (ERT) prevents or delays the onset of clinical manifestations of type 1 Gaucher disease (GD). This study assessed the impact of ERT initiation timing on the risk of developing new GD-related complications. Patients with GD and ≥1 ERT prescription, with available data for ≥3 years prior and ≥1 year after ERT initiation were selected from the Maccabi Healthcare Services database, an Israeli health insurer. Two longitudinal models were constructed to evaluate the association between ERT use and the risk of new GD-related complications, adjusting for patient age and number of prior complications as time-varying covariates. Model 1 evaluated ERT duration and Model 2 evaluated current use of ERT. Using the model results, the risk of a new complication and the cumulative number of complications were simulated over time for patients initiating ERT at 10, 20, and 40 years of age. 64 patients (40.6% male) met inclusion criteria and were included in the analysis. Mean (range) age at diagnosis was 27.4 (0.1–85.7) years, and age at ERT initiation was 32.3 (2.0–86.7) years. Patients experienced an average of 2 GD-related complications prior to ERT initiation versus 0.25 in the 5 years following ERT initiation. The most common complications were thrombocytopenia, splenomegaly, and anemia. A significantly decreased risk of developing a new complication was associated with both longer duration of ERT (odds ratio [OR]: 0.75, 95% confidence interval [CI]: 0.63–0.90) and current use of ERT (OR: 0.37, 95% CI: 0.21–0.67). After 4 years of treatment, patients who initiated ERT at an earlier age had a 12–33% lower risk of developing a new complication and an 8–19% reduction in the total number of cumulative complications. Earlier treatment with ERT was associated with a decreased risk of developing a new GD-related complication.

Hyperimmunoglobulinemia and IgG Subclass Abnormalities in Children With Gaucher Disease.

Gaucher disease (GD) is the most common lysosomal storage disorder, the aim of the current study was to investigate hyperimmunoglobulinemia and abnormalities of serum immunoglobulin G (IgG) subclasses in children with GD and the relation of those findings to the GD phenotype and genotype, duration of enzyme replacement therapy (ERT), and infection frequency. The study included 20 Egyptian children with GD receiving ERT and 20 age-matched and sex-matched healthy children as controls. Serum Ig and serum IgG subclass levels were measured in the children with GD. Serum IgG subclass levels were measured in the control subjects. Hyperimmunoglobulinemia was present in 15 of the 20 (75%) children with GD. In addition, it is found significantly lower IgG2 levels and significantly higher IgG3 levels in the GD group than in the control group (P<0.001 and <0.006, respectively). Patients with 12 infections per year had significantly higher IgG3 levels compared with patients with 6 infections per year (P=0.022). In conclusion, hyperimmunoglobulinemia and IgG subclass abnormalities occur in children with GD who are on ERT and may be related to recurrent infections.

White matter lesions in treated late onset Pompe disease are not different to matched controls

IntroductionGenetic deficiency of α-1,4-glucosidase leads to multi-systemic glycogen storage and causes muscular disorder known as classic infantile Pompe disease (CIOPD) and late onset Pompe disease (LOPD). Treatment with recombinant human alglucosidase alfa is available as enzyme replacement therapy (ERT). Recently progressive white matter lesions (WML) have been observed as a new phenotype in CIOPD patients on treatment with ERT. ObjectiveTo investigate the impact of disease and ERT for the development of WML in LOPD. MethodsWML were analysed in 19 treated LOPD patients and compared with findings of 38 matched controls. ResultsPatients median age was 54.4 years (range 19 to 82 years) with median disease duration of 7 years (range 2 to 40 years). Median ERT duration was 63 months (range 9 to 135 months).Grading of WML by Fazekas Score was not different in LOPD patients and controls: Mean of total Fazekas score in LOPD was 2.42 ± 2.40 and in controls 1.60 ± 2.64; p = 0.68. Also volume of WML was similar in patients and controls (mean 5.27 ml ± 5.88 and 7.89 ml ± 11.40 respectively, p = 0.35). Total Fazekas grade correlated directly with the age in LOPD patients (r = 0.60; p = 0.007) and in controls (r = 0.32; p = 0.04). There was a negative correlation of ERT duration and total Fazekas grade (r = −0.41; p = 0.04). ConclusionThe study suggests that WML in LOPD mainly result from concomitant cerebrovascular risk factors rather than from the Pompe disease itself.

Effect of Enzyme Replacement Therapy on Basilar Artery Diameter in Male Patients With Fabry Disease.

Background and Purpose- The effect of enzyme replacement therapy (ERT) on cerebrovascular complications remains largely unexplored. We aimed to investigate the relationship between basilar artery (BA) diameter and long-term ERT in patients with Fabry disease. Methods- We obtained baseline magnetic resonance imaging data from 30 patients (40.5±16.3 years, male: 14) in the single institution; among them, 21 patients prospectively had follow-up magnetic resonance imaging assessments. The short axis of BA diameter was measured at the midpons level on axial T2-weighted images. Brain magnetic resonance imaging measurements included markers of cerebral small vessel disease (lacunas, white matter hyperintensities, and cerebral microbleeds). We assessed variables associated with baseline BA diameter and annual BA diameter change using linear regression analyses. Results- Hypertension, left ventricular hypertrophy, estimated glomerular filtration rate, and white matter hyperintensities correlated with the initial BA diameter. After a mean interval of 7.2±4.6 years, the annual BA diameter change correlated positively with severe white matter hyperintensities and inversely with the duration of ERT (β=-0.48, P=0.033). After stratifying patients by sex, a significant correlation between the duration of ERT and BA diameter was found only in men (β=-0.72, P=0.019). Conclusions- Our results show a possible relationship between ERT and changes in BA diameter. Future studies to elucidate the clinical impact of BA changes as a potential surrogate marker are needed.

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.

Conjunctival lymphangiectasia associated with classic Fabry disease

BackgroundFabry disease (FD) is a treatable multisystem disease caused by a defect in the alpha-galactosidase gene. Ocular signs of FD, including corneal verticillata, are among the earliest diagnostic findings. Conjunctival...

Correlations between Endomyocardial Biopsies and Cardiac Manifestations in Taiwanese Patients with the Chinese Hotspot IVS4+919G>A Mutation: Data from the Fabry Outcome Survey.

We retrospectively evaluated correlations between cardiac manifestations and globotriaosylceramide (Gb3) accumulation in cardiomyocytes from Taiwanese patients with Fabry disease and the IVS4+919G>A (IVS4) mutation who underwent endomyocardial biopsy (Shire; Fabry Outcome Survey data; extracted January 2015). Of 24 males and six females (median age [Q1; Q3] at biopsy 60.4 [57.4; 64.1] and 61.3 [60.4; 65.1] years, respectively), 13 males (54.2%) and five females (83.3%) received agalsidase alfa enzyme replacement therapy (ERT) before biopsy. Median left ventricular mass indexed to height (LVMI) within ±6 months of biopsy was 65.3 (52.7; 93.1) in males and 53.2 (42.0; 55.0) g/m2.7 in females. A moderate, positive, statistically significant correlation was found between the percentage area Gb3 accumulation in cardiomyocytes and LVMI (Spearman’s ρ, 0.45; p = 0.014); a smaller, positive, non-statistically significant correlation was observed between cardiomyocyte diameter and LVMI (Spearman’s ρ 0.16, p = 0.394). Moderate, statistically significant, negative correlations were found between Gb3 accumulation and ERT duration (Spearman’s ρ, −0.49, p = 0.007) and between cardiomyocyte size and ERT duration (Spearman’s ρ, −0.37, p = 0.048). Longer ERT duration was associated with smaller amounts of Gb3 accumulation and smaller cardiomyocyte size. Further follow-up is recommended to confirm these trends in a larger sample size.

P.67 - Effect of enzyme replacement therapy with alglucosidase alfa (Myozyme®) in 12 patients with advanced late-onset Pompe disease

Glycogen storage disease type II (Pompe disease) is a lysosomal disorder caused by deficiency in acid α-glucosidase. Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (Myozyme®, Genzyme) is available since 2006. So far, treatment benefit in adults has been mostly evaluated in patients who maintained ability to walk, and without permanent ventilator assistance. The aim of this study is to evaluate ERT efficacy in twelve patients with advanced Pompe disease, identified from the French Pompe registry. Inclusion criteria were wheelchair dependency and ventilation support (>12 h/24) upon ERT initiation. Home mechanical ventilation hours, forced vital capacity (FVC), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), ability to walk a few steps and motor function measure (MFM) scale prior and after ERT were studied, where available. Age at ERT initiation ranged from 20 to 73 years (mean = 49.3) and disease duration from 13 to 40 years (mean = 23.9). Years on ventilation varied from 4 to 40 (mean = 15.4) and of wheelchair use from 1 to 20 (mean = 9). ERT duration ranged from 9 to 111 months (mean 54.4). During follow-up, one patient reduced his daily time of ventilatory support, 9 remained fully dependant (24 h/24) and two became fully dependant of assisted ventilation. Values of FVC, MIP and MEP did not change significantly. At ERT initiation, 3 patients could walk a few meters with aid. Two of them increased their walking distance, while a decrease was observed in the third one. There were no significant changes of MFM values between start of ERT and last follow-up. Moreover, 5 patients died, after a treatment period ranging from 9 to 64 months (mean = 33.4). In our series of 12 patients who started ERT in an advanced stage of Pompe disease, we observed a clinically meaningful improvement of respiratory or muscle functions in two patients. Five patients died and five remained wheelchair bound and fully dependant of ventilatory support.