Start Of Enzyme Replacement Therapy Research Articles

#1575 Cardio-renal syndrome in patients with Fabry disease on enzyme replacement therapy

Abstract Background and Aims Fabry disease (FD) is a rare X-linked lysosomal storage disorder in which mutations of the GLA gene cause a decreased or absent activity of the alpha-galactosidase A (α-Gal A) and intracellular accumulation of globotriaosylceramide and other sphingolipids [1]. FD causes a variety of symptoms, including heart and kidneys damage - cardiorenal syndrome (CRS) type 5. In patients with FD, CRS is known to increase the risk of cardiovascular events and death [2]. The aim of our study was to assess renal function and outcomes in patients with FD and CRS receiving enzyme replacement therapy (ERT). Method We performed a retrospective analysis of the medical records of 10 patients (pts) from 7 unrelated families with established diagnosis of FD and cardiac and renal involvement. Pts #1 and #3 are siblings, pt # 10 is their mother; pt #9 is mother of pt #8 (Table 1). The diagnosis was confirmed by DNA diagnostics in all plus levels of α-Gal A enzymatic activity, globotriaosylsphingosine concentrations in some patients. All the patients underwent ERT. Seven out of 10 patients received blockers of the renin-angiotensin-aldosterone system, 3 - did not receive due to contraindications. Results All 10 patients, including 3 women, had left ventricular hypertrophy - left ventricular wall thickness (LVWT) ≥ 1.2 cm. (Table 1). Average LVWT was 1.850 ± 0.097 cm. Two patients had atrial fibrillation. None of the patients had proteinuria 1 g/24 h or higher. In all еGFR was below 60 ml/min/1,73 m2: 4 patients had CKD-G3a, 4 – G3b, 1 – G4 and 1 – G5. Average еGFR was 41,111 ± 8.069 ml/min/1,73 m2 excluding hemodialysis (HD) patient. There were 4 unfavorable outcomes in our group: death occurred in 3 patients from cardiac pathology (congestive heart failure), one patient reached CKD-G5 at 25 years of age and started HD treatment. Patient on HD, brother of deceased pt #1, began receiving ERT after the start of renal replacement therapy. The death of pt #1, who had a very high Lyso-Gb3 level - 118.36 ng/ml (normal 0.05-3.0 ng/ml), appears to be related to the late diagnosis and delayed start of ERT. Conclusion Patients with FD and CRS are likely to have a high risk of cardiovascular complications, loss of kidney function and death, especially with a late start of enzyme replacement and cardio-renoprotective therapy. Early diagnosis of FD and timely initiation of treatment are important in preventing the serious complications and death.

Extensive mongoloid spots in mucopolysaccharidosis Type I Hurler syndrome

Lysosomal storage diseases are inherited metabolic disorders that are caused by enzyme deficiencies within the lysosomes. The most common lysosomal storage disorder associated with Mongolian spots (MSs) is GM1 gangliosidosis Type-1. We are reporting a case of Hurler disease with extensive MS. A 9-month-old girl, born to a consanguineously married couple, presented with a developmental delay with uneventful birth history. The presence of multiple mongoloid spots over the lumbosacral region and lateral abdominal wall was noticed since birth. Examination showed coarse facies with a depressed nasal bridge and a low-set ear. Multiple mongoloid macules were noted in the lumbosacral region. Serum enzyme assay level had decreased activity of alpha-L-iduronidase (IDUA). Exome sequencing revealed a homozygous mutation in exon 8 of the IDUA gene. Extensive MS can be seen in mucopolysaccharidosis (MPS) Type 1 in addition to commonly described GM1 gangliosidosis. The early diagnosis helps to start enzyme replacement therapy in MPS Type I, compared to currently no specific treatment available for GM1 gangliosidosis.

Impact of kidney biopsy on deciding when to initiate enzyme replacement therapy in children with Fabry disease

BackgroundRecommendations on when to start enzyme replacement therapy (ERT) in children with Fabry disease (FD) differ between guidelines. In this study, kidney biopsies of a cohort of 14 untreated children and one treated child were analyzed for their morphologic changes to determine whether early initiation of ERT is indicated.MethodsAll pediatric FD patients (< 18 years old) diagnosed between 2003 and 2021 in our department who received a kidney biopsy were enrolled. Clinical symptoms; laboratory parameters regarding kidney function, such as eGFR, plasma urea, protein-creatinine, and albumin/creatinine ratio; and 14 kidney biopsies prior to ERT and one under treatment were retrospectively analyzed.ResultsA total of 14 patients were enrolled, including 9 male and 5 female children, aged 3–18 years (median age 11). Seven of the enrolled children were 10 years old or younger. Histological analysis of kidney biopsy samples revealed severe vacuolization and accumulation of inclusions in podocytes and renal tubules. The majority of cases had no FD-specific clinical or laboratory features independent of age, gender, or genotype. The youngest FD patient presenting with isolated abnormal kidney biopsy was 3 years old.ConclusionsWe demonstrate that histological lesions, typical for FD, can be observed in kidney biopsies at a very young age in patients without classical clinical symptoms or laboratory abnormalities. Thus, we recommend kidney biopsies as a possible tool for early diagnosis of renal involvement in FD. As a consequence of these early biopsy findings without a clinical correlate, an early initiation of ERT should be considered.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

P353 A CASE OF FABRY DISEASE WITH ISOLATED CARDIAC INVOLVEMENT

Abstract A 64–year–old patient,hypertensive,ex–smoker,no family history of CAD or MCI,with electrocardiographic abnormalities during checkups for sports activity at age 40,came to our observation for reported brief episodes of heart palpitation.On ecg sinus rhythm,PR 200 msec,elevated QRS voltages,negative T waves from V3–V6 and infero–laterally,isolated BEV. Echocardiogram showed asymmetric left ventricular hypertrophy with involvement of septum and mid–apical segments,absence of obstruction,grade II diastolic dysfunction,enlarged left atrium,ectasia of aortic bulb,ascending aorta and arch with mild valvular insufficiency. Cardiac MRI showed asymmetric hypertrophy with prevalent involvement of the SIV and apex,normal systolic function.Right ventricle within limits.LAM elongated,biatrial dilatation.Areas of enhancement with intramural extension to the inferior SIV and extensive subendocardial area to the infero–lateral wall,picture suggestive of Fabry disease. Holter ecg was performed:RS at mean fc 61 bpm,numerous isolated BEVs and pairs,1 run of TVNS of 11 beats,for which dual–chamber ICD implantation was performed in primary prevention.Genetic examination showed absence of alpha galactosidase enzyme activity and mutation in exon 5 of GLA gene(p.N215S). The patient had no other systemic symptoms typical of Fabry‘s disease such as CRI,acroparesthesias,angiokeratomas,cornea verticillata,gastrointestinal disturbances nor central neurological involvement.In addition,he was starting enzyme replacement therapy with alpha galactosidase on a home regimen.Hypertrophic cardiomyopathy is a frequent finding in clinical practice.In MF, the age of cardiac involvement is usually later than in other forms of cardiomyopathy. Cardiac MRI is the most appropriate technique to place a correct differential diagnosis;numerous studies have demonstrated preferential localization of areas of "delayed enhancement" at the infero–lateral and posterolateral basal wall,present even in the absence of frank ventricular hypertrophy. Systemic involvement, may help in the differential diagnosis because of the presence of characteristic symptoms.In the reported clinical case,however,the diagnosis is even more insidious since in late forms or cardiac variants of MF,as with the p.N215S gene variant,cardiomyopathy may be the only significant clinical manifestation.

Association between changes in pulmonary function and in patient reported outcomes during enzyme therapy of adult patients with late-onset Pompe disease".

Pompe disease is a rare, progressive, metabolic myopathy. Reduced pulmonary function is one of the main problems seen in adult patients with late-onset Pompe disease (LOPD). We aimed to explore the association between changes over time in pulmonary function and in patient-reported outcome measures (PROMs), in these patients treated with enzyme replacement therapy (ERT). This is a post-hoc analysis of two cohort studies. Pulmonary function was assessed as Forced Vital Capacity in the upright position (FVCup ). As PROMs, we assessed the physical component summary score (PCS) of the Medical Outcome Study 36-item Short-Form Health Survey (SF-36) and daily life activities (Rasch-Built Pompe-Specific Activity [R-PACT] scale). We fitted Bayesian multivariate mixed-effects models. In the models of PROMs, we assumed a linear association with FVCup , and adjusted for time (non-linear), sex, and age and disease duration at the start of ERT. One hundred and one patients were eligible for analysis. PCS and R-PAct were positively associated with FVCup , while their relation with time was non-linear (initial increase then decrease). A 1%-point increase in FVCup is expected to increase PCS by 0.14 points (95% Credible Interval: [0.09;0.19]) and R-PACT by 0.41 points [0.33;0.49] at the same time point. In the first year of ERT, we expect a change of PCS and R-PAct scores by +0.42 and + 0.80 points, and in the 5th year of +0.16 and + 0.45, respectively. We conclude that the physical domain of quality of life and daily life activities improve when FVCup increases during ERT.

Effects of enzyme replacement therapy on cardiac function in classic infantile Pompe disease

ObjectivePatients with classic infantile Pompe disease are born with a hypertrophic cardiomyopathy, which resolves after treatment with Enzyme replacement therapy (ERT). We aimed to assess potential deterioration of cardiac function over time using myocardial deformation analysis. MethodsTwenty-seven patients treated with ERT were included. Cardiac function was assessed at regular time intervals (before and after start with ERT) using conventional echocardiography and myocardial deformation analysis. Separate linear mixed effect models were used to asses temporal changes within the first year and the long-term follow-up period. Echocardiograms of 103 healthy children served as controls. ResultsA total of 192 echocardiograms were analyzed. Median follow-up was 9.9 years (IQR: 7.5–16.3). Mean LVMI before start of ERT was increased 292.3 g/m2 (95% CI: 202.8–381.8, mean Z-score + 7.6) and normalized after 1 year of ERT 87.3 g/m2 (CI: 67.5–107.1, mean Z-score + 0.8, p < 0.001). Mean shortening fraction was within normal limits before start of ERT, up to 22 years of follow-up. Cardiac function measured by RV/LV longitudinal, and circumferential strain was diminished before start of ERT, but normalized (<−16%) within 1 year after start of ERT, and all remained within normal limits during follow-up. Only LV circumferential strain gradually worsened in Pompe patients (+0.24%/year) during follow-up compared to controls. LV longitudinal strain was diminished in Pompe patients, but did not change significantly over time compared to controls. ConclusionCardiac function, measured using myocardial deformation analysis, normalizes after start of ERT, and seems to remain stable over a median follow-up period of 9.9 years.

1029 FABRY DISEASE: A RARE CAUSE TO REMEMBER WHEN FACING ACUTE KIDNEY INJURY IN YOUNG

Abstract Introduction Anderson-Fabry disease (FD) is a rare X-linked hereditary disease caused by mutations in the alpha-galactosidase A (GLA) gene, a lysosomal hydrolase that catabolizes lipids. GLA deficency leads to a progressive accumulation of undegraded glycosphingolipids, mainly Globotriaosylceramide (GB3), within lysosomes of cells (epithelial and endothelial cells, neurons, cardiomyocytes and renal cells), leading to cellular dysfunction. The incidence of FD is 1:117.000 but in patients with end stage renal disease (ESRD), incidence is higher, ranging from 0.04% up to 1.16% in male dialysis patients. Classical form of the disease shows renal, cardiac and cerebrovascular involvements usually. Cardiac involvement includes hypertrophic cardiomyopathy, arrhythmias such as complete heart block, valve dysfunction and myocardial infarction. Renal manifestations include proteinuria, progressive loss of renal function with chronic kidney disease (CKD) that leads to ESRD. The diagnosis of FD can be very difficult and often is delayed due to subtle clinical manifestations, but an early diagnosis is crucial to start enzyme replacement therapy (ERT), based on recombinant human GLA, as soon as possible. Clinical Case we describe the case of a 36-years-old male admitted to the Emergency Room of our hospital due to asthenia, nausea, dysphagia, anuria and loss of weight. At physical examination, apical systolic murmur and a bilateral ankle edema. Blood pressure was 195/100 mmHg, heart rate 125 beats per minute, peripheral oxygen saturation 100%. Blood test showed Hemoglobin 8 g/dL, Blood Urea 422 mg/dL, Creatinine 20 mg/dL, Na+ 135 mEq/L, K+ 4 mEq/L, Phosphorus 9 mg/dL. Arterial blood gas analysis showed metabolic and lactic acidosis. The diagnosis of acute kidney injury (AKI) was made, and a dialytic treatment was scheduled. During dialytic session, the patient had a syncope. EKG showed a complete left bundle branch block (LBBB) with advanced atrio-ventricular block (2:1, complete). An echocardiogram highlighted a severe myocardial hypertrophy (septal wall 25 mm) involving also the right ventricle with “ground glass” aspect of the posterolateral, posterior and inferior septum, with minimal pericardial effusion. Heart MRI scan confirmed LV myocardial hypertrophy with circumferential aspect (interventricular septum 26.6 mm), mild decrease in left ventricular ejection fraction (47%) and myocardial hypointensity area in the FSE sequences. Renal ultrasound showed bilateral cortical hyperecogenity, small cortico-medullary border, initial reduction of kidney volume and diffuse perirenal edema. In consideration of the high probability of a storage disease, we performed genetic testing for FD and Gaucher disease, peri-umbilical fat biopsy for Amyloid Disease and a renal biopsy. The genetic test resulted positive for typical mutation of FD and renal biopsy documented ESRD secondary to glycosphingolipid storage disease ceramid type from FD. Conclusion Differential diagnosis of AKI in a young male should include FD, as suggested by the clinical case reported, and nephrologist should screen young patients for α-GLA enzyme deficiency (diagnostic for FD) possibly coupled with renal biopsy in uncertain cases.

Evaluating brain white matter hyperintensity, IQ scores, and plasma neurofilament light chain concentration in early-treated patients with infantile-onset Pompe disease

The study aimed to describe central nervous system (CNS) progression in patients with infantile-onset Pompe disease (IOPD) and explore the potential clinical impact and predictors. Patients with IOPD treated with enzyme replacement therapy were longitudinally followed with brain magnetic resonance imaging (MRI) and evaluation for IQ scores from 2004 to 2021. Investigation of CNS involvement focused on white matter (WM) abnormalities and was quantified using a scoring system for metachromatic leukodystrophy. MRI scores were correlated with plasma neurofilament light chain (NfL) concentration and IQ scores. A total of 19 patients who started enzyme replacement therapy at a mean age of 26 days were analyzed; the median age at last examination was 12.1 (range= 1.7-19) years. MRI abnormalities were found in all patients, from supratentorial central WM to U-fibers, then to infratentorial WM, and eventually to gray matter. MRI scores progressed (n= 16) at variable rates (range= 0.8-2.7/y) and were positively correlated with age (n= 16) and negatively correlated with IQ scores (n= 8). Plasma NfL concentration was positively correlated with MRI scores (r2= 0.8569; P < .001; n= 13). Our results suggest that the progression of CNS involvement in IOPD may be associated with neuroaxonal injury and decreased IQ scores. NfL could serve as a biomarker for CNS involvement in IOPD.

Lysosomal glycogen accumulation in Pompe disease results in disturbed cytoplasmic glycogen metabolism.

Pompe disease is an inherited metabolic myopathy caused by deficiency of acid alpha-glucosidase (GAA), resulting in lysosomal glycogen accumulation. Residual GAA enzyme activity affects disease onset and severity, although other factors, including dysregulation of cytoplasmic glycogen metabolism, are suspected to modulate the disease course. In this study, performed in mice and patient biopsies, we found elevated protein levels of enzymes involved in glucose uptake and cytoplasmic glycogen synthesis in skeletal muscle from mice with Pompe disease, including glycogenin (GYG1), glycogen synthase (GYS1), glucose transporter 4 (GLUT4), glycogen branching enzyme 1 (GBE1), and UDP-glucose pyrophosphorylase (UGP2). Expression levels were elevated before the loss of muscle mass and function. For first time, quantitative mass spectrometry in skeletal muscle biopsies from five adult patients with Pompe disease showed increased expression of GBE1 protein relative to healthy controls at the group level. Paired analysis of individual patients who responded well to treatment with enzyme replacement therapy (ERT) showed reduction of GYS1, GYG1, and GBE1 in all patients after start of ERT compared tobaseline. These results indicate that metabolic changes precede muscle wasting in Pompe disease, and imply a positive feedforward loop in Pompe disease, in which lysosomal glycogen accumulation promotes cytoplasmic glycogen synthesis and glucose uptake, resulting in aggravation of the disease phenotype.

Early enzyme replacement therapy prevents dental and craniofacial abnormalities in a mouse model of mucopolysaccharidosis type VI.

Mucopolysaccharidosis VI (MPS VI) is a hereditary lysosomal storage disease caused by the absence of the enzyme arylsulfatase B (ARSB). Craniofacial defects are common in MPS VI patients and manifest as abnormalities of the facial bones, teeth, and temporomandibular joints. Although enzyme replacement therapy (ERT) is the treatment of choice for MPS VI, the effects on the craniofacial and dental structures are still poorly understood. In this study, we used an Arsb-deficient mouse model (Arsb m/m ) that mimics MPS VI to investigate the effects of ERT on dental and craniofacial structures and compared these results with clinical and radiological observations from three MPS VI patients. Using micro-computed tomography, we found that the craniofacial phenotype of the Arsb m/m mice was characterized by bone exostoses at the insertion points of the masseter muscles and an overall increased volume of the jaw bone. An early start of ERT (at 4 weeks of age for 20 weeks) resulted in a moderate improvement of these jaw anomalies, while a late start of ERT (at 12 weeks of age for 12 weeks) showed no effect on the craniofacial skeleton. While teeth typically developed in Arsb m/m mice, we observed a pronounced loss of tooth-bearing alveolar bone. This alveolar bone loss, which has not been described before in MPS VI, was also observed in one of the MPS VI patients. Interestingly, only an early start of ERT led to a complete normalization of the alveolar bone in Arsb m/m mice. The temporomandibular joints in Arsb m/m mice were deformed and had a porous articular surface. Histological analysis revealed a loss of physiological cartilage layering, which was also reflected in an altered proteoglycan content in the cartilage of Arsb m/m mice. These abnormalities could only be partially corrected by an early start of ERT. In conclusion, our results show that an early start of ERT in Arsb m/m mice achieves the best therapeutic effects for tooth, bone, and temporomandibular joint development. As the MPS VI mouse model in this study resembles the clinical findings in MPS VI patients, our results suggest enzyme replacement therapy should be started as early as possible.

Efficacy of Intravenous Elosulfase Alfa for Mucopolysaccharidosis Type IVA: A Systematic Review and Meta-Analysis.

Mucopolysaccharidosis type IVA (MPS IVA or Morquio A), a lysosomal storage disease with an autosomal recessive inherited pattern, is induced by GALNS gene mutations causing deficiency in N-acetylgalactosamine-6-sulfatase activity (GALNS; EC 3.1.6.4). Currently, intravenous (IV) enzyme replacement therapy (ERT) with elosulfase alfa is employed for treating MPS IVA patients. A systematic literature review was conducted to evaluate the efficacy and safety of IV elosulfase alfa for MPS IVA by searching the National Center for Biotechnology Information, U.S. National Library of Medicine National Institutes of Health (PubMed), Excerpta Medica dataBASE, and Cochrane Library databases, limited to clinical trials. Four cohort studies and two randomized controlled trials, with a total of 550 participants (327 on ERT treatment versus 223 on placebo treatment), satisfied the inclusion criteria. Pooled analysis of proportions and confidence intervals were also utilized to systematically review clinical cohort studies and trials. Per the pooled proportions analysis, the difference in means of urinary keratan sulfate (uKS), 6-min walk test, 3-min stair climb test, self-care MPS-Health Assessment Questionnaire, caregiver assistance and mobility, forced vital capacity, the first second of forced expiration, and maximal voluntary ventilation between the ERT and placebo treatment groups were −0.260, −0.102, −0.182, −0.360, −0.408, −0.587, −0.293, −0.311, and −0.213, respectively. Based on the currently available data, our meta-analysis showed that there is uKS, physical performance, quality of life, and respiratory function improvements with ERT in MPS IVA patients. It is optimal to start ERT after diagnosis.

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

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

A Multi-Centre Prospective Study of the Efficacy and Safety of Alglucosidase Alfa in Chinese Patients With Infantile-Onset Pompe Disease.

Background: A high prevalence of infantile-onset Pompe disease (IOPD) in the Chinese population has been noted, but there are currently no reported clinical trials of enzyme replacement therapy (ERT) for IOPD in this population. The purpose of this study was to evaluate the efficacy and safety of alglucosidase alfa in Chinese patients with IOPD. Materials and Methods: A multicentre, single-arm, prospective, open-label clinical trial was performed at 4 sites in China. Eligible Chinese subjects with IOPD received an infusion of alglucosidase alfa at a dose of 20 mg/kg every 2 weeks for up to 52 weeks. The primary endpoints of clinical efficacy were the survival rate and changes in the left ventricular mass index (LVMI). The safety assessment was based on the incidence of adverse events (AEs). Results: A total of 10 eligible subjects were enrolled in the study. The mean age at the start of ERT was 5.36 ± 1.56 months. Nine subjects had survived after 52 weeks of treatment. One subject discontinued the study and died after mechanical ventilation was withdrawn. The intent-to-treat analysis demonstrated that the survival rate was 90.0% (95% confidence interval: 55.5–99.7%). The mean LVMI at week 52 was 70.59 ± 39.93 g/m2 compared to that of 298.02 ± 178.43 g/m2 at baseline, with a difference of -227.60 ± 155.99 g/m2. All subjects had left ventricular mass (LVM) Z scores >10 at baseline, and eight subjects (80%) achieved Z scores <5 at week 52. No treatment-related AEs were observed, and no AEs led to the discontinuation of treatment. Conclusions: This clinical trial is the first study of ERT for IOPD in China, indicating that alglucosidase alfa has favourable efficacy and safety for the treatment of Chinese patients with IOPD (ClinicalTrials.gov number, NCT03687333).

Antibodies against recombinant human alpha-glucosidase do not seem to affect clinical outcome in childhood onset Pompe disease

BackgroundEnzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA, alglucosidase alfa) has improved survival, motor outcomes, daily life activity and quality of life in Pompe patients. However, ERT in Pompe disease often induces formation of antibodies, which may reduce the efficacy of treatment and can lead to adverse events. In this study antibody formation and their effect on clinical outcome in patients with childhood onset Pompe disease treated with enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA) are analyzed.MethodsEnzyme-linked immunosorbent assay (ELISA) was used to determine anti-rhGAA antibody titers at predefined time points. The effect of antibodies on rhGAA activity (neutralizing effects) was measured in vitro. Clinical effects were evaluated by assessing muscle strength (MRC score) and function (QMFT-score), pulmonary function and infusion associated reactions (IARs).ResultsTwenty-two patients were included (age at start ERT 1.1–16.4 years, median treatment duration 12.4 years). Peak antibody titers were low (< 1:1250) in 9%, intermediate (1:1250–1:31,250) in 68% and high (≥ 1:31250) in 23% of patients; three patients (14%) had more than one titer of ≥ 1:31,250. Four patients (18%) experienced IARs; two patients from the high titer group had 86% of all IARs. Inhibition of intracellular GAA activity (58%) in vitro was found in one sample. The clinical course did not appear to be influenced by antibody titers.ConclusionsNinety-one percent of childhood onset Pompe patients developed anti-rhGAA antibodies (above background level), a minority of whom had high antibody titers at repeated time points, which do not seem to interfere with clinical outcome. High antibody titers may be associated with the occurrence of IARs. Although the majority of patients does not develop high titers; antibody titers should be determined in case of clinical deterioration.

Early start of enzyme replacement therapy in pediatric male patients with classical Fabry disease is associated with attenuated disease progression.

Enzyme replacement therapy (ERT) slows disease progression of Fabry disease (FD), especially when initiated before the onset of irreversible organ damage. However, with the clinically asymptomatic progression of renal, cardiac and cerebral disease manifestations spanning decades, optimal timing of ERT initiation remains unclear. In this cross-sectional retrospective study, seven male FD patients with a classical disease phenotype (cFD) who started treatment with agalsidase-beta in childhood were evaluated after 10years of treatment (median age at evaluation 24years, range 14-26). Cardiac imaging (echocardiography and MRI), electrophysiological and biochemical data of these patients were compared to those of untreated male cFD patients (n=23, median age 22years, range 13-27). Albuminuria was less common and less severe in treated patients (albumin to creatinine ratio, ACR 0-8.8mg/mmol, median 0.4) compared to untreated patients (ACR 0-248mg/mmol, median 3.7, p=0.02). The treated group had a lower left ventricular mass, measured using echocardiography (median 80g/m2 versus 94g/m2, p=0.02) and MRI (median 53g/m2 versus 68g/m2, p=0.02). Myocardial fibrosis was absent in all included patients. eGFR was normal in all treated patients whereas 7/23 (30%) of untreated patients had abnormal eGFR. Cerebral manifestations did not differ. Start of treatment with ERT before age 16, in male cFD patients is associated with reduced occurrence of renal and cardiac manifestations of FD, as assessed by intermediate endpoints. Confirmation that this approach delays or even prevents renal failure and cardiac events requires another decade of follow-up.

Evaluation of the long-term treatment effects of intravenous idursulfase in patients with mucopolysaccharidosis II (MPS II) using statistical modeling: data from the Hunter Outcome Survey (HOS)

BackgroundMucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, life-limiting lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase can stabilize or improve many somatic manifestations, but there remains a need for further analysis of long-term treatment outcomes. Using data from patients with MPS II enrolled in the Hunter Outcome Survey (HOS), mixed modeling was performed to evaluate and predict the effects of IV idursulfase treatment on selected clinical parameters for up to 8 years following treatment start. The modeling population comprised male patients followed prospectively in HOS who had received IV idursulfase for at least 5 years and who had data available for two or more time points (at least one post-ERT). Age at ERT start and time since ERT start were included as covariates.ResultsIn total, 481 patients were eligible for inclusion in at least one model. At 8 years post-ERT start, improvement from baseline was predicted for each age group (< 18 months, 18 months to < 5 years and ≥ 5 years at treatment start) in the following parameters: mean urinary glycosaminoglycan levels (percentage changes of > –75% in each group), mean left ventricular mass index (decreases of ~ 1 g/m2) and mean palpable liver size (decreases of > 2 cm). Improvements in mean 6-min walk test distance (increase of > 50 m) and stabilization in percent predicted forced vital capacity and forced expiratory volume in 1 s (decreases of ~ 4 and ~ 9 percentage points, respectively) at 8 years post-ERT start were predicted for patients aged ≥ 5 years at ERT start (these assessments are unsuitable for patients aged < 5 years). Predicted changes over time were similar across the three age groups; however, overall outcomes were most favorable in children aged < 18 months at ERT start.ConclusionsThese findings suggest that the previously reported positive effects of IV idursulfase on the somatic manifestations of MPS II are predicted to be maintained for at least 8 years following ERT initiation and highlight the value of statistical modeling to predict long-term treatment outcomes in patients with rare diseases.

A review of the clinical outcomes in idursulfase-treated and untreated Filipino patients with mucopolysaccharidosis type II: data from the local lysosomal storage disease registry

BackgroundMucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycan (GAG) accumulation, caused by a deficiency of iduronate-2-sulfatase (I2S). Enzyme replacement therapy (ERT) with recombinant idursulfase (IDS), the standard of care, was started in the Philippines in 2017. This study reviewed the clinical outcomes in idursulfase-treated and untreated Filipino MPS II patients who were included in the local Lysosomal Storage Disease (LSD) registry of the Institute of Human Genetics-National Institutes of Health (IHG-NIH) from January 1999 to December 2019.MethodsA retrospective audit of records of MPS II patients listed in the registry was done. Qualified patients were divided into two cohorts: idursulfase-treated group (patients on enzyme replacement therapy, ERT, for ≥ 6 months) and untreated group. Baseline characteristics, including demographic data, biochemical results, neurocognitive classification, respiratory involvement, mortality, and adverse events, were recorded. Height, weight, cardiac pathology, liver and spleen sizes, six-minute walking test (6MWT), joint mobility, were determined at baseline and at year 1 and 2 of follow up.ResultsForty male patients were included in this review, with only 8 receiving ERT since 2017. The mean age at diagnosis was 6.99 years (SD 4.15; 0.75–20) and mean age at start of ERT was 14.03 years (SD 7.1; 4–21.5), more delayed than previous reports. Eighty percent have early progressive phenotype which was higher than reported average. The early growth pattern differed in our Filipino cohort, but was followed by the expected slowed growth in later years. Improvements in the following endpoints were observed in the treated cohort: height and weight, cardiac disease, liver and spleen sizes, and joint mobility. There were also positive effects on respiratory involvement and mortality rate. Adverse events were consistent with previous reports.ConclusionsERT is generally well tolerated and effective in reducing GAG storage and improving clinical endpoints among our Filipino MPS II patients. In untreated patients, typical disease progression was observed.

MO127CLEARED PODOCYTES AND NORMAL KIDNEY FUNCTION IN CLASSICAL FABRY MALES 15 YEARS AFTER START OF ENZYME REPLACEMENT THERAPY AT YOUNG AGE*

Abstract Background and Aims Fabry nephropathy may progress to kidney failure despite enzyme replacement therapy (ERT) when the treatment is initiated at a relatively late stage of the disease. This study evaluates long term effects of agalsidase in serial kidney biopsies and functional measurements in men with classical Fabry disease that commenced ERT at a young age. Method Six male Fabry patients with a median age of 20 years (range 7-30 years) at start of ERT were monitored over a median time of 15 years (range 14.5-17.0 years). The patients were treated with an agalsidase dose of 1.0 mg/kg/every other weak (eow) for 8.3 years (range 5-12 years) and with an agalsidase dose of 0.2-0.5 mg/kg/eow for 7.6 years (range 3-10 years). Kidney biopsies were evaluated with the scoring system of the International Study Group of Fabry Nephropathy (ISGFN) using both plastic embedded and paraffin embedded tissue with scoring of podocyte globotriaocylceramide (Gb3) in semithin toluidine blue sections (maximum score 4.0) and scoring of vacuolization in PAS-sections (maximum score 3.0). ISGFN composite score consists of both tissue scores giving a maximum score of 7.0. Renal function was evaluated with measurement of glomerular filtration rate (GFR) with iohexol clearance (mGFR) and urinary albumin creatinine ratio (uACR). Values are given in median (range). Results Kidney biopsies at baseline contained 24 (13-42) evaluable glomeruli and had an ISGFN composite score of 7.0 (6.9-7.0). After 15 years the ISGFN composite score had decreased to 0.56 (0-4.29), scored in 24 (9-52) evaluable glomeruli. At baseline mGFR was 106 (86-113) ml/min/1.73 m2 and after 15 years mGFR decreased to 97 (73-134) ml/min/1.73 m2. uACR was 5.6 (0.1-13.6) mg/mmol at baseline and had after 15 years increased to 10.0 (1.0-107) mg/mmol. The youngest patient had significant proteinuria with uACR 107 mg/mmol due to a chronic C3-glomerulonephritis superimposed on Fabry disease. Median uACR without this patient was at 15 years 5.8 (1.0-17.7) mg/mmol. The two youngest patients had no Gb3 visible (ISGFN composite score of 0) in their last biopsy and mGFR was normal in both. In all patients the reduction of podocyte-Gb3 was higher on an agalsidase dose of 1 mg/kg/eow; change composite score -4.66 (-7.9 to -1.8), compared to on an agalsidase dose of 0.2-0.5 mg/kg/eow; change composite score -0.15 (-5.1 to + 1.0). Conclusion Initiation of ERT at a relatively young age may clear the long living kidney cells of Gb3 and protect the kidneys from significant functional loss over a very long time period. The reduction of Gb3 in podocytes is higher on high dose compared to low dose of agalsidase.

Fabry disease and kidney involvement: starting from childhood to understand the future.

The accumulation of globotriaosylceramide (Gb-3) in multiple organs, such as the heart, kidney, and nervous system, due tomutations in the galactosidase alpha (GLA) gene, represents the key point of Fabry disease (FD). The common symptoms appear in childhood or adolescence, including neuropathic pain, angiokeratoma, acroparesthesia, and corneal opacities. A multi-organ involvement induces a significant deterioration in the quality of life with high mortality in adulthood. The accumulation of Gb-3 involves all types of kidney cells beginning at fetal development, many years before clinical manifestations. A decline in the glomerular filtration rate is rare in children, but it can occur during adolescence. Pediatric patients rarely undergo kidney biopsy that could assess the efficacy of enzyme replacement therapy (ERT) behind its diagnostic role. To date, diagnosis is achieved by detecting reduced α-Gal-A activity in leukocytes and plasma, allowing for the early start of ERT. This review focuses on pediatric kidney involvement in FD, analyzing in depth its diagnostic processes and treatment options.

Changes in Left Ventricle Mechanics in Patients with Anderson - Fabry Disease under Enzyme Replacement Therapy

Background: Sixty percent of patients with Fabry disease (FD) have cardiovascular involvement at the time of diagnosis. Among patients with heart failure of all causes, about 50% show normal or preserved left ventricular systolic function. We reported the evolution and echocardiographic findings of five patients with Fabry disease before undergoing enzyme replacement therapy and after 48 months of follow-up. Method: Systolic and diastolic functions were assessed in 5 patients with FD using transthoracic echocar- diography. They were matched with echocardiography performed between 36 to 48 months after treatment was started. Results: At initial evaluation, heart failure symptoms were positive in 3 patients. No history of fainting or cardiac arrhythmia was found on the initial approach. The mean LVEF before ERT was 57.25 ± 3.3. After 48 months of follow-up we observed a significant change increased on the LVEF to 68.7 ± 4.2 (p=0.04). All patients had increased interventricular septum thickness (IVT). The mean relative parietal thickness decreased from 0.63 to 0.59, after 48 months. Patients with mutation c.971T>A were more likely to increase the RPT. If the patient was free of dialysis the RWT tends to decrease. Diastolic function assessment revealed significantly higher E velocities, E wave increase from 73.6 to 81 m sec (p=0.04). But E/A ratio did not change after 48 months of ERT (1 vs. 1.1, p=NS). Two patients had diastolic dysfunction before ERT. After 2 years, four patients have diastolic dysfunction grade II. Before starting enzyme replacement therapy, all strain measures were abnormal. However, it was observed that their measurements did not worsen after ERT was started. The left ventricular twist was assessed, finding a decrease in it with a mean pre-ERT of 10o ± 4 vs. 13.7o ± 2.5 at 48 months (normal value 20 ± 7.3°), this was not significant. Conclusion: After 2 years of follow-up, we found an improvement in LVEF, a decrease in the ventricular septum. We found no progression in diastolic dysfunction. Even though enzyme replacement therapy in Fabry has proven efficacy, there are very few evaluation and monitoring tools to assess its effects at the cardio- vascular level. Systolic function is affected only in the late stages of the disease, although the diastolic function is affected earlier, it does not vary greatly over time once ERT has started. We found that conventional parameters, ven- tricular mass and septum diameter are useful as a baseline evaluation.